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Why is the microbial ecosystem of the gut so susceptible to disruption by pathogens?

Why is the microbial ecosystem of the gut so susceptible to disruption by pathogens?


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From all accounts, it seems as if the Escherichia, Enterobacter, etc. that live and thrive in the human gut are pretty well entrenched. I know that these microbial populations are often analyzed as an ecosystem.

What surprises me is that it seems like minor food poisoning can throw the whole ecosystem off. I know superficially that Clostridium are contenders in the fight because they remain viable after traveling through the acid of the stomach, but why are these populations so sensitive to other invading bacteria?


There are two types of food poisoning:

Alimentary intoxication

This is the case when you consume food which is contaminated with some toxins, and those are responsible for development of the poisoning symptoms. The source organisms of these toxins might not be present anymore (killed by heating during cooking, for example). In this case there is no massive invasion of any foreign organisms into the gut.

Alimentary toxico-infection

This happens if you eat the food contaminated with microorganisms, and these start to massively proliferate in your alimentary system causing the symptoms of poisoning. The massive intake of the bacteria (even 2-3 spoons of contaminated food might contain millions of bacteria, like Staphilococcus in contaminated diary products). In this case the balance of gut microflora is dramatically changed due to introduction of a considerable amount of foreign microorganisms.

So, even the poisoning seems to be "minor" (e.g., its symptoms are not so dramatic), there could be different amounts of bacteria invading the guts.

The second important point here is the increased emptying of the gut due to diarrhea that leads to the washing out some of the "good" bacteria from the guts, especially in case of profuse diarrhea. The newly coming bacteria are not necessarily those that are present in normal microflora, and it takes days or even weeks until the microflora reaches homeostasis again.

One last point: even without poisoning, microflora varies, and the amount of different bacterial fractions can fluctuate over time. This is normal and depends upon your eating habits, your environment, immune status, and many other factors.


As requested, elaborating this into a full answer.

Three things to consider:

  1. "Alterations to gut microflora" need not only be the invasion of a different, aggressive species of bacteria. One of the most common, and most dramatic forms of alteration to our gut flora is something we do to ourselves: antibiotics. Most ecosystems, micro or macro, are pretty vulnerable to the equivalent of a sustained firebombing.
  2. Some of the "harmful bacteria" that benefit from a disruption of the gut microflora are constituent components of said flora. Clostridium difficile is part of the normal flora of many people - and acquired by many more transiently without incident - yet when the environment is sufficiently disrupted by antibiotics, peptic acid suppressors or some other factors, it proliferates and causes illness.
  3. While it may feel awful to you, many GI illnesses are really just a transient invasion before the body clears the infection, and are only marginally disruptive, or not disruptive at all. This can include the intake of toxins without the actual organism, or things like norovirus, which has a low enough infectious dose that even small amounts will make you ill.

Gut Microbiome

Gail A.M. Cresci PhD, RDN, CNSC , Kristin Izzo MS, RDN, CNSC , in Adult Short Bowel Syndrome , 2019

Introduction

The gut microbiome , as defined by molecular biologist Joshua Lederberg, is the totality of microorganisms, bacteria, viruses, protozoa, and fungi, and their collective genetic material present in the gastrointestinal tract (GIT). The gut microbiota is comprised of all the bacteria, commensal, and pathogenic, residing in the GIT. In the past decade the gut microbiota has been explored for potential gut microbe–host interactions including effects on metabolism, immune, and neuroendocrine responses. The gut microbiota plays an important role in nutrient and mineral absorption, synthesis of enzymes, vitamins and amino acids, and production of short-chain fatty acids (SCFAs). The fermentation byproducts acetate, propionate, and butyrate are important for gut health and provide energy for epithelial cells, enhance epithelial barrier integrity, and provide immunomodulation and protection against pathogens. Current investigations are exploring resident bacterial gene function and the potential corresponding role in human health and metabolism. Additionally, study of whether nonpathogenic bacterial strains can stimulate recovery of the immune responses to pathogenic causing diseases is ongoing ( Cresci and Bawden, 2015 ).

The human gut microbiota is divided into many groups called phyla. The gut microbiota is comprised primarily of four main phyla which include Firmicutes, Bacteriodetes, Actinobacteria, and Proteobacteria ( Belizario and Napolitano, 2015 ). While bacteria colonizes the human body, including oral cavity, placenta, vagina, skin, and GIT, the majority of bacteria reside within the GIT, with the majority of predominantly anaerobic bacteria housed in the colon ( Fig. 4.1 ). To gain perspective of the magnitude of bacterial presence and potential effects on the host, the human body expresses 20,000 eukaryotic genes while the gut microbiome expresses 3.3 million prokaryotic genes ( NIH, 2012 ).

Figure 4.1 . Gut microbiota predominance.

The development and alteration of the gut microbiome are affected by a variety of factors including birthing and infant feeding method, exposure to stress, environment, diet, medications, stage of lifecycle, and comorbid diseases ( Fig. 4.2 ). Dysbiosis is described as the alteration in microbial community that results in decreased diversity and numbers of commensal bacteria. Studies suggest relationships between gut dysbiosis and chronic health conditions such as inflammatory bowel disease, metabolic syndrome, cardiovascular disease, obesity, and cancer ( Carding et al., 2015 ).

Figure 4.2 . Factors known to impact the gut microbiome.


How Gut Microbiota Impacts HIV Disease

HIV is a disease of the gut, a concept that&rsquos easy to lose sight of with all the attention paid to sexual transmission and blood measurements of the virus and the CD4+ T cells it infects and kills. But the bottom line is that about two thirds of all T cells reside in the lymphoid tissue of the gut, where the virus spreads after exposure, even before it shows up in blood.

Blood, however, has been the focus of research and care because it is easy to sample and broadly represents what is going on throughout the entire body. The gut is a lot harder to access, which is why much of it remains a crudely delineated terrain that can only be examined with blunt and invasive tools. But a better understanding of the gut environment will be necessary to achieve the next level of advances in comprehending the disease and fashioning better interventions, researchers said last Wednesday at the annual Conference on Retroviruses and Opportunistic Infections in Boston. &ldquoWhy do we care about the microbiome?&rdquo asked Nichole Klatt, a University of Washington (U.W.) pathobiologist, whose lab focuses on mucosal immunology. Klatt, who organized and chaired the conference session, answered her own rhetorical question, summarizing that HIV infection decreases the number and diversity of beneficial bacteria and increases those that have negative effects on the gut. &ldquoThere are health consequences to dysbiosis,&rdquo she said.

One main area of investigation, dysbiosis, is a perturbation of the microbiome that allows organisms inside the gut to escape through the gut barrier wall into surrounding space and eventually enter the bloodstream. Dysbiosis is a general process where various forms of disruption involving different microbes, at locations along the roughly nine meters of the intestinal tract are likely to cause different medical problems.

Eight days after exposing monkeys to SIV, the simian equivalent of HIV, Adam Ericsen, an immunologist at the University of Wisconsin&ndashMadison saw &ldquoup to a 1,300-fold increase of bacteria circulating in the blood&rdquo of the animals. The temporal association&mdashthe number of bacteria increased in the blood before the SIV appeared in the blood&mdashled him to believe that the virus first attacks CD4+ T cells that help protect the gut wall from microbial translocation. But then, as the animal's immune system began to exercise some control over the virus and gut barrier function improved, the level of bacteria in the blood declined. He suggests that modulating this activity might reduce the initial burst of inflammation that fuels HIV infection and the establishment of viral set points and the seeding of reservoirs.

Meanwhile on the Pacific Coast, Jennifer Manuzak, a U.W. immunologist, administered a probiotic called VSL#3 to uninfected monkeys to modulate a more favorable microbial ecosystem in the gut and improve immune function. She found &ldquoan increase in IgA- [immunoglobulin-] producing B cells in both the colon and the lymph nodes&rdquo as well as an increase in T helper cells in the lymph nodes.*

These and other findings suggested that it is possible to enhance the immune response in the gut and could work as a way to increase immune responses to vaccination that typically are weaker in people infected with HIV, the elderly and other persons at risk. But Manuzak cautions against expecting commercially available probiotics to deliver the same results there is simply no data to support that belief.

Just how does HIV infection affect the human gut microbiome? The answer may depend on where you look. Jesus Luevano, a medical student at Harvard Medical School and a researcher the Ragon Institute examined bacterial communities from the gut of 145 people in Boston and 120 subjects in Uganda. He found very little difference between samples from the gut of HIV- positive and negative persons in Uganda, but a significant difference in Boston. Interestingly, the healthy HIV-negative Bostonians were the outliers, the guts of the other three groups was relatively similar that was particularly true of untreated persons on both continents. &ldquoHIV-uninfected patients had much greater richness in their samples as well as a unique population that was primarily composed of bacteria from the phylum Fermicutes,&rdquo Luevano says. Viral load and treatment also had effects on community composition, but the number of persons in each subgroup of the study was too small to say anything more.

Fecal microbial transplantation (FMT) has gained acceptance for treating Clostridium difficile infection, a life threatening and difficult to treat dysbiosis that often is caused by heavy use of antibiotics. The procedure, which has a 90 percent success rate, transplants the fecal microbial ecosystem from a healthy person into a sick one, often using a colonoscope for inserting the material, to restore a healthy equilibrium.

Ma Somsouk, gastroenterologist from the University of California, San Francisco, hoped that an FMT might restore balance to the gut of HIV patients experiencing dysbiosis and immune activation that can lead to things like cardiovascular disease. After trying it in six patients Somsouk found there was little benefit. Luckily, the subjects experienced the same few side effects as other patients who have tried FMT. The main problem appeared to have been minimal engraftment&mdashthe transplanted organisms did not thrive and supplant the bugs that were already present and causing dysbiosis. Somsouk, however, was not surprised. With C. difficile a combination of antibiotics and massive diarrhea wipes out most of the bacteria in the gut, so the transplanted organisms have little competition in colonizing the gut. Somsouk was transplanting his organisms into the microbial equivalent of Manhattan and most of them got lost in the crowd.

The next phase of the study will first &ldquocondition&rdquo patients with antibiotics to knock down the local population of bacteria, as has already taken place in trying unsuccessfully to treat C. difficile patients, Somsouk says. It is similar to how radiation and chemotherapy are used to &ldquocondition&rdquo patients for a bone marrow transplant, to improve engraftment of transplanted immune cells. Somsouk thought all along that conditioning probably would be necessary to improve the changes of engraftment but he wanted to first try the less invasive approach using no antibiotics. He hopes to begin that second study in 12 patients later this year.

*Editor's Note (3/17/16): This paragraph was edited after posting. The original incorrectly identified the probiotic, VSL#3, and the B cell, IgA.


Contents

In humans, the gut microbiota has the largest numbers of bacteria and the greatest number of species compared to other areas of the body. [5] In humans, the gut flora is established at one to two years after birth, by which time the intestinal epithelium and the intestinal mucosal barrier that it secretes have co-developed in a way that is tolerant to, and even supportive of, the gut flora and that also provides a barrier to pathogenic organisms. [6] [7]

The relationship between some gut flora and humans is not merely commensal (a non-harmful coexistence), but rather a mutualistic relationship. [4] : 700 Some human gut microorganisms benefit the host by fermenting dietary fiber into short-chain fatty acids (SCFAs), such as acetic acid and butyric acid, which are then absorbed by the host. [5] [8] Intestinal bacteria also play a role in synthesizing vitamin B and vitamin K as well as metabolizing bile acids, sterols, and xenobiotics. [4] [8] The systemic importance of the SCFAs and other compounds they produce are like hormones and the gut flora itself appears to function like an endocrine organ, [8] and dysregulation of the gut flora has been correlated with a host of inflammatory and autoimmune conditions. [5] [9]

The composition of human gut microbiota changes over time, when the diet changes, and as overall health changes. [5] [9] A systematic review from 2016 examined the preclinical and small human trials that have been conducted with certain commercially available strains of probiotic bacteria and identified those that had the most potential to be useful for certain central nervous system disorders. [10]

The microbial composition of the gut microbiota varies across the digestive tract. In the stomach and small intestine, relatively few species of bacteria are generally present. [11] [12] The colon, in contrast, contains the highest microbial density recorded in any habitat on Earth [13] with up to 10 12 cells per gram of intestinal content. [11] These bacteria represent between 300 and 1000 different species. [11] [12] However, 99% of the bacteria come from about 30 or 40 species. [14] As a consequence of their abundance in the intestine, bacteria also make up to 60% of the dry mass of feces. [15] Fungi, protists, archaea, and viruses are also present in the gut flora, but less is known about their activities. [16]

Over 99% of the bacteria in the gut are anaerobes, but in the cecum, aerobic bacteria reach high densities. [4] It is estimated that these gut flora have around a hundred times as many genes in total as there are in the human genome. [17]

Many species in the gut have not been studied outside of their hosts because most cannot be cultured. [12] [14] [18] While there are a small number of core species of microbes shared by most individuals, populations of microbes can vary widely among different individuals. [19] Within an individual, microbe populations stay fairly constant over time, even though some alterations may occur with changes in lifestyle, diet and age. [11] [20] The Human Microbiome Project has set out to better describe the microflora of the human gut and other body locations.

The four dominant bacterial phyla in the human gut are Firmicutes, Bacteroidetes, Actinobacteria, and Proteobacteria. [21] Most bacteria belong to the genera Bacteroides, Clostridium, Faecalibacterium, [11] [14] Eubacterium, Ruminococcus, Peptococcus, Peptostreptococcus, and Bifidobacterium. [11] [14] Other genera, such as Escherichia and Lactobacillus, are present to a lesser extent. [11] Species from the genus Bacteroides alone constitute about 30% of all bacteria in the gut, suggesting that this genus is especially important in the functioning of the host. [12]

Fungal genera that have been detected in the gut include Candida, Saccharomyces, Aspergillus, Penicillium, Rhodotorula, Trametes, Pleospora, Sclerotinia, Bullera, and Galactomyces, among others. [22] [23] Rhodotorula is most frequently found in individuals with inflammatory bowel disease while Candida is most frequently found in individuals with hepatitis B cirrhosis and chronic hepatitis B. [22]

Archaea constitute another large class of gut flora which are important in the metabolism of the bacterial products of fermentation.

Industralization is associated with changes in the microbiota and the reduction of diversity could drive certain species to extinction in 2018, researchers proposed a biobank repository of human microbiota. [24]

Enterotype Edit

An enterotype is a classification of living organisms based on its bacteriological ecosystem in the human gut microbiome not dictated by age, gender, body weight, or national divisions. [25] There are indications that long-term diet influences enterotype. [26] Three human enterotypes have been proposed, [25] [27] but their value has been questioned. [28]

Bacteriome Edit

Stomach Edit

Due to the high acidity of the stomach, most microorganisms cannot survive there. The main bacterial inhabitants of the stomach include: Streptococcus, Staphylococcus, Lactobacillus, Peptostreptococcus. [4] : 720 Helicobacter pylori is a gram-negative spiral bacterium that establishes on gastric mucosa causing chronic gastritis, and peptic ulcer disease, and is a carcinogen for gastric cancer. [4] : 904

Intestines Edit

Bacteria commonly found in the human colon [29]
Bacterium Incidence (%)
Bacteroides fragilis 100
Bacteroides melaninogenicus 100
Bacteroides oralis 100
Enterococcus faecalis 100
Escherichia coli 100
Enterobacter sp. 40–80
Klebsiella sp. 40–80
Bifidobacterium bifidum 30–70
Staphylococcus aureus 30–50
Lactobacillus 20–60
Clostridium perfringens 25–35
Proteus mirabilis 5–55
Clostridium tetani 1–35
Clostridium septicum 5–25
Pseudomonas aeruginosa 3–11
Salmonella enterica 3–7
Faecalibacterium prausnitzii ?common
Peptostreptococcus sp. ?common
Peptococcus sp. ?common

The small intestine contains a trace amount of microorganisms due to the proximity and influence of the stomach. Gram-positive cocci and rod-shaped bacteria are the predominant microorganisms found in the small intestine. [4] However, in the distal portion of the small intestine alkaline conditions support gram-negative bacteria of the Enterobacteriaceae. [4] The bacterial flora of the small intestine aid in a wide range of intestinal functions. The bacterial flora provide regulatory signals that enable the development and utility of the gut. Overgrowth of bacteria in the small intestine can lead to intestinal failure. [30] In addition the large intestine contains the largest bacterial ecosystem in the human body. [4] About 99% of the large intestine and feces flora are made up of obligate anaerobes such as Bacteroides and Bifidobacterium. [31] Factors that disrupt the microorganism population of the large intestine include antibiotics, stress, and parasites. [4]

Bacteria make up most of the flora in the colon [32] and 60% of the dry mass of feces. [11] This fact makes feces an ideal source of gut flora for any tests and experiments by extracting the nucleic acid from fecal specimens, and bacterial 16S rRNA gene sequences are generated with bacterial primers. This form of testing is also often preferable to more invasive techniques, such as biopsies.

Five phyla dominate the intestinal microbiota: bacteroidetes, firmicutes, actinobacteria, proteobacteria, and verrucomicrobia—with bacteroidetes and firmicutes constituting 90% of the composition. [33] Somewhere between 300 [11] and 1000 different species live in the gut, [12] with most estimates at about 500. [34] [35] However, it is probable that 99% of the bacteria come from about 30 or 40 species, with Faecalibacterium prausnitzii (phylum firmicutes) being the most common species in healthy adults. [14] [36]

Research suggests that the relationship between gut flora and humans is not merely commensal (a non-harmful coexistence), but rather is a mutualistic, symbiotic relationship. [12] Though people can survive with no gut flora, [34] the microorganisms perform a host of useful functions, such as fermenting unused energy substrates, training the immune system via end products of metabolism like propionate and acetate, preventing growth of harmful species, regulating the development of the gut, producing vitamins for the host (such as biotin and vitamin K), and producing hormones to direct the host to store fats. [4] Extensive modification and imbalances of the gut microbiota and its microbiome or gene collection are associated with obesity. [37] However, in certain conditions, some species are thought to be capable of causing disease by causing infection or increasing cancer risk for the host. [11] [32]

Mycobiome Edit

Fungi and protists also make up a part of the gut flora, but less is known about their activities. [38]

Virome Edit

Age Edit

It has been demonstrated that there are common patterns of microbiome composition evolution during life. [40] In general, the diversity of microbiota composition of fecal samples is significantly higher in adults than in children, although interpersonal differences are higher in children than in adults. [41] Much of the maturation of microbiota into an adult-like configuration happens during the three first years of life. [41]

As the microbiome composition changes, so does the composition of bacterial proteins produced in the gut. In adult microbiomes, a high prevalence of enzymes involved in fermentation, methanogenesis and the metabolism of arginine, glutamate, aspartate and lysine have been found. In contrast, in infant microbiomes the dominant enzymes are involved in cysteine metabolism and fermentation pathways. [41]

Diet Edit

Studies and statistical analyses have identified the different bacterial genera in gut microbiota and their associations with nutrient intake. Gut microflora is mainly composed of three enterotypes: Prevotella, Bacteroides, and Ruminococcus. There is an association between the concentration of each microbial community and diet. For example, Prevotella is related to carbohydrates and simple sugars, while Bacteroides is associated with proteins, amino acids, and saturated fats. Specialist microbes that break down mucin survive on their host's carbohydrate excretions. [42] One enterotype will dominate depending on the diet. Altering the diet will result in a corresponding change in the numbers of species. [26] A 2021 study suggests that childhood diet and exercise can substantially affect adult microbiome composition and diversity. Its authors show that in mice a diet high in fat and sugar still substantially affects the gut microbiome after what equates to six human years. [43] [44] [45]

Vegetarian and vegan diets Edit

While plant-based diets have some variation, vegetarian and vegan diets patterns are the most common. Vegetarian diets exclude meat products (which include fish) but still allow for eggs and dairy, while vegan diets exclude all forms of animal products. The diets of vegetarian and vegan individuals create a microbiome distinct from meat eaters, however there is not a significant distinction between the two. [46] [ unreliable medical source? ] In diets that are centered around meat and animal products, there are high abundances of Alistipes, Bilophila and Bacteroides which are all bile tolerant and may promote inflammation in the gut. In this type of diet, the group Firmicutes, which is associated with the metabolism of dietary plant polysaccharides, is found in low concentrations. [47] Conversely, diets rich in plant-based materials are associated with greater diversity in the gut microbiome overall, and have a greater abundance of Prevotella, responsible for the long-term processing of fibers, rather than the bile tolerant species. [48] [ unreliable medical source? ] Diet can be used to alter the composition of the gut microbiome in relatively short timescales. However, if wanting to change the microbiome to combat a disease or illness, long-term changes in diet have proven to be most successful. [47]

Geography Edit

Gut microbiome composition depends on the geographic origin of populations. Variations in a trade-off of Prevotella, the representation of the urease gene, and the representation of genes encoding glutamate synthase/degradation or other enzymes involved in amino acids degradation or vitamin biosynthesis show significant differences between populations from the US, Malawi or Amerindian origin. [41]

The US population has a high representation of enzymes encoding the degradation of glutamine and enzymes involved in vitamin and lipoic acid biosynthesis whereas Malawi and Amerindian populations have a high representation of enzymes encoding glutamate synthase and they also have an overrepresentation of α-amylase in their microbiomes. As the US population has a diet richer in fats than Amerindian or Malawian populations which have a corn-rich diet, the diet is probably the main determinant of the gut bacterial composition. [41]

Further studies have indicated a large difference in the composition of microbiota between European and rural African children. The fecal bacteria of children from Florence were compared to that of children from the small rural village of Boulpon in Burkina Faso. The diet of a typical child living in this village is largely lacking in fats and animal proteins and rich in polysaccharides and plant proteins. The fecal bacteria of European children were dominated by Firmicutes and showed a marked reduction in biodiversity, while the fecal bacteria of the Boulpon children was dominated by Bacteroidetes. The increased biodiversity and different composition of gut flora in African populations may aid in the digestion of normally indigestible plant polysaccharides and also may result in a reduced incidence of non-infectious colonic diseases. [49]

On a smaller scale, it has been shown that sharing numerous common environmental exposures in a family is a strong determinant of individual microbiome composition. This effect has no genetic influence and it is consistently observed in culturally different populations. [41]

Malnourishment Edit

Malnourished children have less mature and less diverse gut microbiota than healthy children, and changes in the microbiome associated with nutrient scarcity can in turn be a pathophysiological cause of malnutrition. [50] [51] Malnourished children also typically have more potentially pathogenic gut flora, and more yeast in their mouths and throats. [52] Altering diet may lead to changes in gut microbiota composition and diversity. [42]

Race and ethnicity Edit

Researchers with the American Gut Project and Human Microbiome Project found that twelve microbe families varied in abundance based on the race or ethnicity of the individual. The strength of these associations is limited by the small sample size: the American Gut Project collected data from 1,375 individuals, 90% of whom were white. [53] The Healthy Life in an Urban Setting (HELIUS) study in Amsterdam found that those of Dutch ancestry had the highest level of gut microbiota diversity, while those of South Asian and Surinamese descent had the lowest diversity. The study results suggested that individuals of the same race or ethnicity have more similar microbiomes than individuals of different racial backgrounds. [53]

Socioeconomic status Edit

As of 2020, at least two studies have demonstrated a link between an individual's socioeconomic status (SES) and their gut microbiota. A study in Chicago found that individuals in higher SES neighborhoods had greater microbiota diversity. People from higher SES neighborhoods also had more abundant Bacteroides bacteria. Similarly, a study of twins in the United Kingdom found that higher SES was also linked with a greater gut diversity. [53]

The establishment of a gut flora is crucial to the health of an adult, as well as the functioning of the gastrointestinal tract. [54] In humans, a gut flora similar to an adult's is formed within one to two years of birth as microbiota are acquired through parent-to-child transmission and transfer from food, water, and other environmental sources. [55] [6]

The traditional view of the gastrointestinal tract of a normal fetus is that it is sterile, although this view has been challenged in the past few years. [56] Multiple lines of evidence have begun to emerge that suggest there may be bacteria in the intrauterine environment. In humans, research has shown that microbial colonization may occur in the fetus [57] with one study showing Lactobacillus and Bifidobacterium species were present in placental biopsies. [58] Several rodent studies have demonstrated the presence of bacteria in the amniotic fluid and placenta, as well as in the meconium of babies born by sterile cesarean section. [59] [60] In another study, researchers administered a culture of bacteria orally to a pregnant dam, and detected the bacteria in the offspring, likely resulting from transmission between the digestive tract and amniotic fluid via the blood stream. [61] However, researchers caution that the source of these intrauterine bacteria, whether they are alive, and their role, is not yet understood. [62] [58]

During birth and rapidly thereafter, bacteria from the mother and the surrounding environment colonize the infant's gut. [6] The exact sources of bacteria is not fully understood, but may include the birth canal, other people (parents, siblings, hospital workers), breastmilk, food, and the general environment with which the infant interacts. [63] However, as of 2013, it remains unclear whether most colonizing arises from the mother or not. [6] Infants born by caesarean section may also be exposed to their mothers' microflora, but the initial exposure is most likely to be from the surrounding environment such as the air, other infants, and the nursing staff, which serve as vectors for transfer. [57] During the first year of life, the composition of the gut flora is generally simple and changes a great deal with time and is not the same across individuals. [6] The initial bacterial population are generally facultative anaerobic organisms investigators believe that these initial colonizers decrease the oxygen concentration in the gut, which in turn allows obligately anaerobic bacteria like Bacteroides, Actinobacteria, and Firmicutes to become established and thrive. [6] Breast-fed babies become dominated by bifidobacteria, possibly due to the contents of bifidobacterial growth factors in breast milk, and by the fact that breast milk carries prebiotic components, allowing for healthy bacterial growth. [58] [64] In contrast, the microbiota of formula-fed infants is more diverse, with high numbers of Enterobacteriaceae, enterococci, bifidobacteria, Bacteroides, and clostridia. [65]

Caesarean section, antibiotics, and formula feeding may alter the gut microbiome composition. [58] Children treated with antibiotics have less stable, and less diverse floral communities. [66] Caesarean sections have been shown to be disruptive to mother-offspring transmission of bacteria, which impacts the overall health of the offspring by raising risks of disease such as celiacs, asthma, and type 1 diabetes. [58] This further evidences the importance of a healthy gut microbiome. Various methods of microbiome restoration are being explored, typically involving exposing the infant to maternal vaginal contents, and oral probiotics. [58]

When the study of gut flora began in 1995, [67] it was thought to have three key roles: direct defense against pathogens, fortification of host defense by its role in developing and maintaining the intestinal epithelium and inducing antibody production there, and metabolizing otherwise indigestible compounds in food subsequent work discovered its role in training the developing immune system, and yet further work focused on its role in the gut-brain axis. [68]

Direct inhibition of pathogens Edit

The gut flora community plays a direct role in defending against pathogens by fully colonising the space, making use of all available nutrients, and by secreting compounds that kill or inhibit unwelcome organisms that would compete for nutrients with it, these compounds are known as cytokines. [69] Different strains of gut bacteria cause the production of different cytokines. Cytokines are chemical compounds produced by our immune system for initiating the inflammatory response against infections. Disruption of the gut flora allows competing organisms like Clostridium difficile to become established that otherwise are kept in abeyance. [69]

Development of enteric protection and immune system Edit

In humans, a gut flora similar to an adult's is formed within one to two years of birth. [6] As the gut flora gets established, the lining of the intestines – the intestinal epithelium and the intestinal mucosal barrier that it secretes – develop as well, in a way that is tolerant to, and even supportive of, commensalistic microorganisms to a certain extent and also provides a barrier to pathogenic ones. [6] Specifically, goblet cells that produce the mucosa proliferate, and the mucosa layer thickens, providing an outside mucosal layer in which "friendly" microorganisms can anchor and feed, and an inner layer that even these organisms cannot penetrate. [6] [7] Additionally, the development of gut-associated lymphoid tissue (GALT), which forms part of the intestinal epithelium and which detects and reacts to pathogens, appears and develops during the time that the gut flora develops and established. [6] The GALT that develops is tolerant to gut flora species, but not to other microorganisms. [6] GALT also normally becomes tolerant to food to which the infant is exposed, as well as digestive products of food, and gut flora's metabolites (molecules formed from metabolism) produced from food. [6]

The human immune system creates cytokines that can drive the immune system to produce inflammation in order to protect itself, and that can tamp down the immune response to maintain homeostasis and allow healing after insult or injury. [6] Different bacterial species that appear in gut flora have been shown to be able to drive the immune system to create cytokines selectively for example Bacteroides fragilis and some Clostridia species appear to drive an anti-inflammatory response, while some segmented filamentous bacteria drive the production of inflammatory cytokines. [6] [70] Gut flora can also regulate the production of antibodies by the immune system. [6] [71] One function of this regulation is to cause B cells to class switch to IgA. In most cases B cells need activation from T helper cells to induce class switching however, in another pathway, gut flora cause NF-kB signaling by intestinal epithelial cells which results in further signaling molecules being secreted. [72] These signaling molecules interact with B cells to induce class switching to IgA. [72] IgA is an important type of antibody that is used in mucosal environments like the gut. It has been shown that IgA can help diversify the gut community and helps in getting rid of bacteria that cause inflammatory responses. [73] Ultimately, IgA maintains a healthy environment between the host and gut bacteria. [73] These cytokines and antibodies can have effects outside the gut, in the lungs and other tissues. [6]

The immune system can also be altered due to the gut bacteria's ability to produce metabolites that can affect cells in the immune system. For example short-chain fatty acids (SCFA) can be produced by some gut bacteria through fermentation. [74] SCFAs stimulate a rapid increase in the production of innate immune cells like neutrophils, basophils and eosinophils. [74] These cells are part of the innate immune system that try to limit the spread of infection.

Metabolism Edit

Without gut flora, the human body would be unable to utilize some of the undigested carbohydrates it consumes, because some types of gut flora have enzymes that human cells lack for breaking down certain polysaccharides. [8] Rodents raised in a sterile environment and lacking in gut flora need to eat 30% more calories just to remain the same weight as their normal counterparts. [8] Carbohydrates that humans cannot digest without bacterial help include certain starches, fiber, oligosaccharides, and sugars that the body failed to digest and absorb like lactose in the case of lactose intolerance and sugar alcohols, mucus produced by the gut, and proteins. [5] [8]

Bacteria turn carbohydrates they ferment into short-chain fatty acids by a form of fermentation called saccharolytic fermentation. [35] Products include acetic acid, propionic acid and butyric acid. [14] [35] These materials can be used by host cells, providing a major source of energy and nutrients. [35] Gases (which are involved in signaling [79] and may cause flatulence) and organic acids, such as lactic acid, are also produced by fermentation. [14] Acetic acid is used by muscle, propionic acid facilitates liver production of ATP, and butyric acid provides energy to gut cells. [35]

Gut flora also synthesize vitamins like biotin and folate, and facilitate absorption of dietary minerals, including magnesium, calcium, and iron. [11] [20] Methanobrevibacter smithii is unique because it is not a species of bacteria, but rather a member of domain Archeae, and is the most abundant methane-producing archaeal species in the human gastrointestinal microbiota. [80]

Gut microbiota also serve as a source of Vitamins K and B12 that are not produced by the body or produced in little amount. [81] [82]

Pharmacomicrobiomics Edit

The human metagenome (i.e., the genetic composition of an individual and all microorganisms that reside on or within the individual's body) varies considerably between individuals. [83] [84] Since the total number of microbial and viral cells in the human body (over 100 trillion) greatly outnumbers Homo sapiens cells (tens of trillions), [note 1] [83] [85] there is considerable potential for interactions between drugs and an individual's microbiome, including: drugs altering the composition of the human microbiome, drug metabolism by microbial enzymes modifying the drug's pharmacokinetic profile, and microbial drug metabolism affecting a drug's clinical efficacy and toxicity profile. [83] [84] [86]

Apart from carbohydrates, gut microbiota can also metabolize other xenobiotics such as drugs, phytochemicals, and food toxicants. More than 30 drugs have been shown to be metabolized by gut microbiota. [87] The microbial metabolism of drugs can sometimes inactivate the drug. [88]

Gut-brain axis Edit

The gut-brain axis is the biochemical signaling that takes place between the gastrointestinal tract and the central nervous system. [68] That term has been expanded to include the role of the gut flora in the interplay the term "microbiome-gut-brain axis" is sometimes used to describe paradigms explicitly including the gut flora. [68] [89] [90] Broadly defined, the gut-brain axis includes the central nervous system, neuroendocrine and neuroimmune systems including the hypothalamic–pituitary–adrenal axis (HPA axis), sympathetic and parasympathetic arms of the autonomic nervous system including the enteric nervous system, the vagus nerve, and the gut microbiota. [68] [90]

A systematic review from 2016 examined the preclinical and small human trials that have been conducted with certain commercially available strains of probiotic bacteria and found that among those tested, Bifidobacterium and Lactobacillus genera (B. longum, B. breve, B. infantis, L. helveticus, L. rhamnosus, L. plantarum, and L. casei), had the most potential to be useful for certain central nervous system disorders. [10]

Effects of antibiotic use Edit

Altering the numbers of gut bacteria, for example by taking broad-spectrum antibiotics, may affect the host's health and ability to digest food. [91] Antibiotics can cause antibiotic-associated diarrhea by irritating the bowel directly, changing the levels of microbiota, or allowing pathogenic bacteria to grow. [14] Another harmful effect of antibiotics is the increase in numbers of antibiotic-resistant bacteria found after their use, which, when they invade the host, cause illnesses that are difficult to treat with antibiotics. [91]

Changing the numbers and species of gut microbiota can reduce the body's ability to ferment carbohydrates and metabolize bile acids and may cause diarrhea. Carbohydrates that are not broken down may absorb too much water and cause runny stools, or lack of SCFAs produced by gut microbiota could cause diarrhea. [14]

A reduction in levels of native bacterial species also disrupts their ability to inhibit the growth of harmful species such as C. difficile and Salmonella kedougou, and these species can get out of hand, though their overgrowth may be incidental and not be the true cause of diarrhea. [11] [14] [91] Emerging treatment protocols for C. difficile infections involve fecal microbiota transplantation of donor feces (see Fecal transplant). [92] Initial reports of treatment describe success rates of 90%, with few side effects. Efficacy is speculated to result from restoring bacterial balances of bacteroides and firmicutes classes of bacteria. [93]

The composition of the gut microbiome also changes in severe illnesses, due not only to antibiotic use but also to such factors as ischemia of the gut, failure to eat, and immune compromise. Negative effects from this have led to interest in selective digestive tract decontamination, a treatment to kill only pathogenic bacteria and allow the re-establishment of healthy ones. [94]

Antibiotics alter the population of the microbiota in the gastrointestinal tract, and this may change the intra-community metabolic interactions, modify caloric intake by using carbohydrates, and globally affects host metabolic, hormonal and immune homeostasis. [95]

There is reasonable evidence that taking probiotics containing Lactobacillus species may help prevent antibiotic-associated diarrhea and that taking probiotics with Saccharomyces (e.g., Saccharomyces boulardii ) may help to prevent Clostridium difficile infection following systemic antibiotic treatment. [96]

Pregnancy Edit

The gut microbiota of a woman changes as pregnancy advances, with the changes similar to those seen in metabolic syndromes such as diabetes. The change in gut microbiota causes no ill effects. The newborn's gut microbiota resemble the mother's first-trimester samples. The diversity of the microbiome decreases from the first to third trimester, as the numbers of certain species go up. [58] [97]

Probiotics, prebiotics, synbiotics, and pharmabiotics Edit

Probiotics are microorganisms that are believed to provide health benefits when consumed. [98] [99] With regard to gut microbiota, prebiotics are typically non-digestible, fiber compounds that pass undigested through the upper part of the gastrointestinal tract and stimulate the growth or activity of advantageous gut flora by acting as substrate for them. [35] [100]

Synbiotics refers to food ingredients or dietary supplements combining probiotics and prebiotics in a form of synergism. [101]

The term "pharmabiotics" is used in various ways, to mean: pharmaceutical formulations (standardized manufacturing that can obtain regulatory approval as a drug) of probiotics, prebiotics, or synbiotics [102] probiotics that have been genetically engineered or otherwise optimized for best performance (shelf life, survival in the digestive tract, etc.) [103] and the natural products of gut flora metabolism (vitamins, etc.). [104]

There is some evidence that treatment with some probiotic strains of bacteria may be effective in irritable bowel syndrome and chronic idiopathic constipation. Those organisms most likely to result in a decrease of symptoms have included:

  • Enterococcus faecium
  • Lactobacillus plantarum
  • Lactobacillus rhamnosus
  • Propionibacterium freudenreichii
  • Bifidobacterium breve
  • Lactobacillus reuteri
  • Lactobacillus salivarius
  • Bifidobacterium infantis
  • Streptococcus thermophilus[105][106][107]

Research Edit

Tests for whether non-antibiotic drugs may impact human gut-associated bacteria were performed by in vitro analysis on more than 1000 marketed drugs against 40 gut bacterial strains, demonstrating that 24% of the drugs inhibited the growth of at least one of the bacterial strains. [108]

Bacteria in the digestive tract can contribute to and be affected by disease in various ways. The presence or overabundance of some kinds of bacteria may contribute to inflammatory disorders such as inflammatory bowel disease. [11] Additionally, metabolites from certain members of the gut flora may influence host signalling pathways, contributing to disorders such as obesity and colon cancer. [11] Alternatively, in the event of a breakdown of the gut epithelium, the intrusion of gut flora components into other host compartments can lead to sepsis. [11]

Ulcers Edit

Helicobacter pylori infection can initiate formation of stomach ulcers when the bacteria penetrate the stomach epithelial lining, then causing an inflammatory phagocytotic response. [109] In turn, the inflammation damages parietal cells which release excessive hydrochloric acid into the stomach and produce less of the protective mucus. [110] Injury to the stomach lining, leading to ulcers, develops when gastric acid overwhelms the defensive properties of cells and inhibits endogenous prostaglandin synthesis, reduces mucus and bicarbonate secretion, reduces mucosal blood flow, and lowers resistance to injury. [110] Reduced protective properties of the stomach lining increase vulnerability to further injury and ulcer formation by stomach acid, pepsin, and bile salts. [109] [110]

Bowel perforation Edit

Normally-commensal bacteria can harm the host if they extrude from the intestinal tract. [6] [7] Translocation, which occurs when bacteria leave the gut through its mucosal lining, can occur in a number of different diseases. [7] If the gut is perforated, bacteria invade the interstitium, causing a potentially fatal infection. [4] : 715

Inflammatory bowel diseases Edit

The two main types of inflammatory bowel diseases, Crohn's disease and ulcerative colitis, are chronic inflammatory disorders of the gut the causes of these diseases are unknown and issues with the gut flora and its relationship with the host have been implicated in these conditions. [9] [111] [112] [113] Additionally, it appears that interactions of gut flora with the gut-brain axis have a role in IBD, with physiological stress mediated through the hypothalamic–pituitary–adrenal axis driving changes to intestinal epithelium and the gut flora in turn releasing factors and metabolites that trigger signaling in the enteric nervous system and the vagus nerve. [3]

The diversity of gut flora appears to be significantly diminished in people with inflammatory bowel diseases compared to healthy people additionally, in people with ulcerative colitis, Proteobacteria and Actinobacteria appear to dominate in people with Crohn's, Enterococcus faecium and several Proteobacteria appear to be over-represented. [3]

There is reasonable evidence that correcting gut flora imbalances by taking probiotics with Lactobacilli and Bifidobacteria can reduce visceral pain and gut inflammation in IBD. [96]

Irritable bowel syndrome Edit

Irritable bowel syndrome is a result of stress and chronic activation of the HPA axis its symptoms include abdominal pain, changes in bowel movements, and an increase in proinflammatory cytokines. Overall, studies have found that the luminal and mucosal microbiota are changed in irritable bowel syndrome individuals, and these changes can relate to the type of irritation such as diarrhea or constipation. Also, there is a decrease in the diversity of the microbiome with low levels of fecal Lactobacilli and Bifidobacteria, high levels of facultative anaerobic bacteria such as Escherichia coli, and increased ratios of Firmicutes: Bacteroidetes. [90]

Other inflammatory or autoimmune conditions Edit

Allergy, asthma, and diabetes mellitus are autoimmune and inflammatory disorders of unknown cause, but have been linked to imbalances in the gut flora and its relationship with the host. [9] As of 2016 it was not clear if changes to the gut flora cause these auto-immune and inflammatory disorders or are a product of or adaptation to them. [9] [114]

Asthma Edit

With asthma, two hypotheses have been posed to explain its rising prevalence in the developed world. The hygiene hypothesis posits that children in the developed world are not exposed to enough microbes and thus may contain lower prevalence of specific bacterial taxa that play protective roles. [115] The second hypothesis focuses on the Western pattern diet, which lacks whole grains and fiber and has an overabundance of simple sugars. [9] Both hypotheses converge on the role of short-chain fatty acids (SCFAs) in immunomodulation. These bacterial fermentation metabolites are involved in immune signalling that prevents the triggering of asthma and lower SCFA levels are associated with the disease. [115] [116] Lacking protective genera such as Lachnospira, Veillonella, Rothia and Faecalibacterium has been linked to reduced SCFA levels. [115] Further, SCFAs are the product of bacterial fermentation of fiber, which is low in the Western pattern diet. [9] [116] SCFAs offer a link between gut flora and immune disorders, and as of 2016, this was an active area of research. [9] Similar hypotheses have also been posited for the rise of food and other allergies. [117]

Diabetes mellitus type 1 Edit

The connection between the gut microbiota and diabetes mellitus type 1 has also been linked to SCFAs, such as butyrate and acetate. Diets yielding butyrate and acetate from bacterial fermentation show increased Treg expression. [118] Treg cells downregulate effector T cells, which in turn reduces the inflammatory response in the gut. [119] Butyrate is an energy source for colon cells. butyrate-yielding diets thus decrease gut permeability by providing sufficient energy for the formation of tight junctions. [120] Additionally, butyrate has also been shown to decrease insulin resistance, suggesting gut communities low in butyrate-producing microbes may increase chances of acquiring diabetes mellitus type 2. [121] Butyrate-yielding diets may also have potential colorectal cancer suppression effects. [120]

Obesity and metabolic syndrome Edit

The gut flora has also been implicated in obesity and metabolic syndrome due to the key role it plays in the digestive process the Western pattern diet appears to drive and maintain changes in the gut flora that in turn change how much energy is derived from food and how that energy is used. [113] [122] One aspect of a healthy diet that is often lacking in the Western-pattern diet is fiber and other complex carbohydrates that a healthy gut flora require flourishing changes to gut flora in response to a Western-pattern diet appear to increase the amount of energy generated by the gut flora which may contribute to obesity and metabolic syndrome. [96] There is also evidence that microbiota influence eating behaviours based on the preferences of the microbiota, which can lead to the host consuming more food eventually resulting in obesity. It has generally been observed that with higher gut microbiome diversity, the microbiota will spend energy and resources on competing with other microbiota and less on manipulating the host. The opposite is seen with lower gut microbiome diversity, and these microbiotas may work together to create host food cravings. [42]

Additionally, the liver plays a dominant role in blood glucose homeostasis by maintaining a balance between the uptake and storage of glucose through the metabolic pathways of glycogenesis and gluconeogenesis. Intestinal lipids regulate glucose homeostasis involving a gut-brain-liver axis. The direct administration of lipids into the upper intestine increases the long chain fatty acyl-coenzyme A (LCFA-CoA) levels in the upper intestines and suppresses glucose production even under subdiaphragmatic vagotomy or gut vagal deafferentation. This interrupts the neural connection between the brain and the gut and blocks the upper intestinal lipids' ability to inhibit glucose production. The gut-brain-liver axis and gut microbiota composition can regulate the glucose homeostasis in the liver and provide potential therapeutic methods to treat obesity and diabetes. [123]

Just as gut flora can function in a feedback loop that can drive the development of obesity, there is evidence that restricting intake of calories (i.e., dieting) can drive changes to the composition of the gut flora. [113]

Liver disease Edit

As the liver is fed directly by the portal vein, whatever crosses the intestinal epithelium and the intestinal mucosal barrier enters the liver, as do cytokines generated there. [124] Dysbiosis in the gut flora has been linked with the development of cirrhosis and non-alcoholic fatty liver disease. [124]

Cancer Edit

Some genera of bacteria, such as Bacteroides and Clostridium, have been associated with an increase in tumor growth rate, while other genera, such as Lactobacillus and Bifidobacteria, are known to prevent tumor formation. [11] As of December 2017 there was preliminary and indirect evidence that gut microbiota might mediate response to PD-1 inhibitors the mechanism was unknown. [125]

Neuropsychiatric Edit

Interest in the relationship between gut flora and neuropsychiatric issues was sparked by a 2014 study showing that germ-free mice showed an exaggerated HPA axis response to stress compared to non-GF laboratory mice. [68] As of January 2016, most of the work that has been done on the role of gut flora in the gut-brain axis had been conducted in animals, or characterizing the various neuroactive compounds that gut flora can produce, and studies with humans measuring differences between people with various psychiatric and neurological differences, or changes to gut flora in response to stress, or measuring effects of various probiotics (dubbed "psychobiotics in this context), had generally been small and could not be generalized whether changes to gut flora are a result of disease, a cause of disease, or both in any number of possible feedback loops in the gut-brain axis, remained unclear. [68] [96]

A systematic review from 2016 examined the preclinical and small human trials that have been conducted with certain commercially available strains of probiotic bacteria and found that among those tested, the genera Bifidobacterium and Lactobacillus (B. longum, B. breve, B. infantis, L. helveticus, L. rhamnosus, L. plantarum, and L. casei) had the most potential to be useful for certain central nervous system disorders. [10]

The composition of the human gut microbiome is similar to that of the other great apes. However, humans’ gut biota has decreased in diversity and changed in composition since our evolutionary split from Pan. [126] Humans display increases in Bacteroidetes, a bacterial phylum associated with diets high in animal protein and fat, and decreases in Methanobrevibacter and Fibrobacter, groups that ferment complex plant polysaccharides. [126] These changes are the result of the combined dietary, genetic, and cultural changes humans have undergone since evolutionary divergence from Pan.

In addition to humans and vertebrates, some insects also possess complex and diverse gut microbiota that play key nutritional roles. [127] Microbial communities associated with termites can constitute a majority of the weight of the individuals and perform important roles in the digestion of lignocellulose and nitrogen fixation. [128] These communities are host-specific, and closely related insect species share comparable similarities in gut microbiota composition. [129] [130] In cockroaches, gut microbiota have been shown to assemble in a deterministic fashion, irrespective of the inoculum [131] the reason for this host-specific assembly remains unclear. Bacterial communities associated with insects like termites and cockroaches are determined by a combination of forces, primarily diet, but there is some indication that host phylogeny may also be playing a role in the selection of lineages. [129] [130]

For more than 51 years it has been known that the administration of low doses of antibacterial agents promotes the growth of farm animals to increase weight gain. [95]

In a study carried out on mice the ratio of Firmicutes and Lachnospiraceae was significantly elevated in animals treated with subtherapeutic doses of different antibiotics. By analyzing the caloric content of faeces and the concentration of small chain fatty acids (SCFAs) in the GI tract, it was concluded that the changes in the composition of microbiota lead to an increased capacity to extract calories from otherwise indigestible constituents, and to an increased production of SCFAs. These findings provide evidence that antibiotics perturb not only the composition of the GI microbiome but also its metabolic capabilities, specifically with respect to SCFAs. [95]


Introduction

The gut microbiome is a complex ecosystem comprised of a diverse array of microbial organisms. The abundances of different species and strains can vary dramatically based on diet [1], host species [2], and the identities of other co-colonizing taxa [3]. These rapid shifts in community composition suggest that individual gut microbes may be adapted to specific environmental conditions, with strong selection pressures between competing species or strains. Yet, while these ecological responses have been extensively studied, much less is known about the evolutionary forces that operate within populations of gut bacteria, both within individual hosts and across the larger host-associated population. This makes it difficult to predict how rapidly strains of gut microbes will evolve new ecological preferences when faced with environmental challenges, such as drugs or diet, and how the genetic composition of the community will change as a result.

The answers to these questions depend on two different types of information. At a mechanistic level, one must understand the functional traits that are under selection in the gut and how they may be modified genetically. Recent work has started to address this question, leveraging techniques from comparative genomics [4–6], evolution in model organisms [7–9], and high-throughput genetic screens [10, 11]. Yet, in addition to the targets of selection, evolution also depends on population genetic processes that describe how mutations spread through a population of gut bacteria, both within individual hosts and across the larger population. These dynamical processes can strongly influence which mutations are likely to fix within a population, and the levels of genetic diversity that such populations can maintain. Understanding these processes is the goal of our present work.

Previous studies of pathogens [12], laboratory evolution experiments [13], and some environmental communities [14–17] have shown that microbial evolutionary dynamics are often dominated by rapid adaptation, with new variants accumulating within months or years [7, 14, 18–25]. However, it is not clear how this existing picture of microbial evolution extends to a more complex and established ecosystem like the healthy gut microbiome. On the one hand, hominid gut bacteria have had many generations to adapt to their host environment [26], and they may not be subjected to the same immune pressures as pathogens. The large number of potential competitors in the gut ecosystem may also provide fewer opportunities for a strain to adapt to new conditions before an existing strain expands to fill the niche [27, 28] or a new strain invades from outside the host. On the other hand, it is also possible that small-scale environmental fluctuations, either driven directly by the host or through interactions with other resident strains, might increase the opportunities for local adaptation [29]. If immigration is restricted, the large census population size of gut bacteria could allow residents to produce and fix adaptive variants rapidly before a new strain is able to invade. In this case, one could observe rapid adaptation on short timescales, which is eventually arrested on longer timescales as strains are exposed to the full range of host environments. Additional opportunities for adaptation can occur if the range of host environments also shifts over time (e.g., due to urbanization, antibiotic usage, etc.). Determining which of these scenarios apply to gut communities is critical for efforts to study and manipulate the microbiome.

While traditional amplicon sequencing provides limited resolution to detect within-species evolution [30], whole-genome shotgun metagenomic sequencing is starting to provide the raw polymorphism data necessary to address these questions [31]. In particular, several reference-based approaches have been developed to detect genetic variants within individual species in larger metagenomic samples [31–36]. While these approaches enable strain-level comparisons between samples, they have also documented substantial within-species variation in individual metagenomes [31, 35, 37]. This makes it difficult to assign an evolutionary interpretation to the genetic differences between samples, because they arise from unobserved mixtures of different bacterial lineages.

Several approaches have been developed to further resolve these mixed populations into individual haplotypes or "strains." These range from simple consensus approximations [35, 37, 38], to sophisticated clustering algorithms [39, 40] and the incorporation of physical linkage information [41]. However, while these methods are useful for tracking well-defined strains across samples, it is not known how their assumptions and failure modes might bias inferences of evolutionary dynamics, particularly among closely related strains. As a result, the evolutionary processes that operate within species of gut bacteria remain poorly characterized.

In this study, we take a different approach to the strain detection problem that is specifically designed for inferring evolutionary dynamics in a large panel of metagenomes. Building on earlier work by [4, 35], we show that many prevalent species have a subset of hosts for which a portion of the dominant lineage is much easier to identify. By focusing only on this subset of samples, we develop methods for resolving small differences between the dominant lineages with a high degree of confidence.

We use this approach to analyze a large panel of publicly available human stool samples [42–46], which allows us to quantify evolutionary dynamics within and across hosts in approximately 40 prevalent bacterial species. We find that the long-term evolutionary dynamics across hosts are broadly consistent with models of quasi-sexual evolution and purifying selection, with relatively weak geographic structure in many prevalent species. However, our quantitative approach also reveals interesting departures from standard population genetic models of these processes, suggesting that new models are required to fully understand the evolutionary dynamics that take place across the larger population.

We also use our approach to detect examples of within-host adaptation, in which nucleotide variants or gene gains or losses rapidly sweep to high frequency on 6-month timescales. We find evidence that some within-host sweeps may be seeded by recombination, in addition to de novo mutations, as might be expected for a complex ecosystem with frequent horizontal exchange. However, by analyzing differences between adult twins, we find that short-term evolution can eventually be overwhelmed by the invasion of distantly related strains on multi-decade timescales. This suggests that resident strains are rarely able to become so well adapted to a particular host that they prevent future replacements. Together, these results show that the gut microbiome is a promising system for studying the dynamics of microbial evolution in a complex community setting. The framework we introduce may also be useful for characterizing evolution of microbial communities in other environments.


So what is microbiota?

The gut microbiota definition refers to the microorganisms found in a specific environment by type. This includes bacteria, fungi, viruses, protozoa, and archaea, and the diversity of the microbiota will vary from person to person.

Different bacteria have specific names determined by a branch of science called taxonomy, where biology experts are tasked with allocating a name and a rank in the tree of life.

For example, the probiotic L. rhamnosus is actually a species of Lactobacillus, a genus that belongs to the Firmicutes phylum, which is a member of the Kingdom of Bacteria (as opposed to that of plants or animals).

Different bacteria live on different parts of the body, prefer different foods, and perform different functions. There is an oral microbiota of the mouth, a microbiota of the skin that has many subcategories (the armpits, nose, feet, etc.), and a gut microbiota - among many others of course.

☝️FACT☝️ Microbiota plural is often microbiota, but if referencing different types or a collection, the term microbiotas may be used.


Why is the microbial ecosystem of the gut so susceptible to disruption by pathogens? - Biology

It is becoming increasingly clear that our overall health and well-being is profoundly linked to the massive population of bacteria that reside in our gut.

The vital role of our microbiota for health
These microorganisms that colonise our bodies – and their genetic material, the ‘microbiome’ – are essential for life. They have coevolved with us and live in an innate relationship with us that’s vital to normal health. The biggest populations of microbes reside in our gut where they aid digestion, prevent infection by pathogens, produce certain vitamins and educate our immune system on what to fight. Although it’s well recognised that the gut microbiota contributes to normal immunity, scientists are still unravelling the ways in which this can go wrong and lead to disease. Autoimmune disease in particular – one of the fastest-growing causes of disability and death in the US – has been strongly connected to the health of the human microbiota.
A case of mistaken identity
Keeping the immune system in balance is no mean feat it must remain alert to spot and disarm foreign invaders but be smart enough to recognise the body’s own tissues and organs to spare them from attack. Autoimmunity can be thought of as a case of mistaken identity: the immune system reacts to its own tissues and cells as if they were pathogens. In healthy conditions, the gut microbiota does not provoke a pathologic immune response, even though our immune cells are constantly in contact with these microorganisms. In susceptible individuals, however, it is suspected that the microbiota may play a key role in kick-starting autoimmune disease. Exactly why and how this happens remains a mystery.
Changing this is Dr Martin Kriegel, Adjunct Assistant Professor of Immunobiology at Yale School of Medicine, who has devoted much of his career to understanding the influence of the microbiota on our immune system and autoimmune diseases. Research in the Kriegel lab aims to better understand the triggers and sustaining factors within the microbiota of autoimmune patients which are responsible for provoking the autoimmune process which leads to disease. The researchers are also interested in the influence of genetics and diet on gut microbial communities in autoimmunity, and the role of skin commensals in cutaneous lymphoma – a type of skin cancer for which there is currently no curative treatment. The overarching aim of this work is to develop novel and effective therapies for immune-related diseases.
Systemic lupus erythematosus: Lupus is a systemic autoimmune disorder that affects many organs as shown here. Clinical manifestations are due to the faulty immune system targeting these organs or tissues, which leads to inflammation and organ damage. Sick from your stomach
Excitingly, in a recent study Dr Kriegel and his research team showed that bacteria found in the small intestines of mice and humans can travel to other organs where they trigger an autoimmune response. Importantly, the team also found that this autoimmune reaction can be suppressed with antibiotic treatment or vaccines designed to target the bacteria. Recently published in the journal Science, these findings offer a new understanding of, and exciting promise for, the treatment of autoimmune conditions such as lupus and autoimmune liver disease.
To explore the link between gut microbial communities and autoimmune disease, the team looked carefully at an ordinarily harmless gut bacterium called Enterococcus gallinarum. In a series of elegant experiments using mice genetically prone to autoimmune conditions, the researchers discovered that the bacteria could spontaneously translocate they moved from the gut to the liver, spleen, and lymph nodes. Once in these tissues, the E. gallinarum bacteria then stimulated the production of auto-antibodies and caused inflammation – hallmarks of an autoimmune response. The team validated this mechanism of inflammation in experiments using liver cells of healthy individuals. They also showed that the E. gallinarum bacteria are present in the livers of patients with autoimmune liver disease and lupus but were not detected in livers from healthy controls.

Dr Kriegel’s ground-breaking research represents a novel paradigm for how autoimmunity can arise.

Alterations of the gut barrier by a gut bacterium: Highly magnified images of the gut lining with barrier molecules and gut wall structures stained with different colors. Shown are snapshots of the small intestine of animals colonised exclusively with the autoimmune-promoting bacterium E. gallinarum. Compared to germ-free animals without any bacteria, the pore-forming molecule Claudin-2 is upregulated (left image) and the barrier-tightening molecule Claudin-5 is downregulated (right image). Images taken from Manfredo Vieira et al., Science 2018. Notably, Kriegel’s group also demonstrated that they could suppress the autoimmune response in mice using either an oral antibiotic or a specific vaccine given in the muscle targeting E. gallinarum inside the body’s tissues. When the team administered other vaccines against different bacteria they found no change in death or autoimmunity of the immunised mice. Both the antibiotic and vaccine treatments suppressed the growth of the bacteria in the target organs and reduced the host’s autoimmune response, suggesting that they could reverse the effects of the bacteria on autoimmunity. This ground-breaking finding has exciting therapeutic implications, particularly for lupus and autoimmune liver disease, debilitating conditions for which there is currently no cure.
Molecular mimicry mediates autoimmunity
An ‘antigen’ is a substance which provokes an immune response and much of Kriegel’s research is directed towards exploring the vast pool of antigens presented by the microbiota. In particular, his lab at Yale has focused on the microbiota in the gut and other niches in the human body to test the concept of cross-reactivity in autoimmunity. If a microorganism within the benign gut microbiota possesses a structure that ‘mimics’ a host structure, then it is feasible that persistent exposure to this structure could lead to an immune response initially triggered by the bacteria, which over time may go on to cross-react with healthy tissue of a susceptible host, causing an autoimmune reaction.
Gut bacteria-immune cell interactions in autoimmunity: Many factors contribute to the development of autoimmune diseases. Shown are genetics, immune cells and the gut microbiome with arrows pointing towards autoimmune diseases although each factor can be influenced by the others. Such interactions are indicated by the bidirectional arrow between the microbiome and immune cells. Emerging research supports that the gut bacteria influence various immune cells in autoimmune diseases. The precise mechanisms of how and where they interact is not well understood but represents a major focus of the Kriegel laboratory. In a recently published study, the team, in collaboration with the lab of Sandra Wolin, provide compelling evidence that cross-reactivity indeed occurs in lupus – a chronic, debilitating multiorgan autoimmune disease which is poorly understood. Lupus patients have high levels of antibodies to a substance called Ro60. In other words, their immune cells recognise Ro60 as foreign and start to mount an immune response to it. These Ro60 antibodies are raised early on in their disease, even before the onset of symptoms. Focusing on Ro60, the research teams looked for the presence of Ro60-containing bacteria in various tissues of lupus patients, and identified them in the skin, mouth and the gut. They showed that blood taken from lupus patients (containing Ro60 antibodies) could bind strongly to the Ro60 from commensal microorganisms. However, blood from individuals with no Ro60 antibodies did not bind. The team also showed that immune cells from lupus patients could be activated by Ro60-containing bacteria residing in the skin or gut, functionally demonstrating that the immune cells could cross-react with host as well as bacterial Ro60. To validate their theory in vivo (in a living organism), the team used germ-free mice, that is, animals without any bacteria of their own, and colonised them with a human Ro60 gut bacterium obtained from a human commensal culture collection of the Goodman lab at the Yale Microbial Sciences Institute. The mice developed an autoimmune response to human Ro60, supporting the idea that these microorganisms drive autoimmunity. They were also able to visualise Ro60-containing skin bacteria deep within skin lesions of several lupus patients. These findings open the door to potential therapies that target specific bacteria within the skin or gut microbiota, rather than the immune system, which is the current mainstay of treatment.
Future direction: from bench to bedside
Current work in the Kriegel lab aims to further unravel the cross-reactivity theory in antiphospholipid syndrome (APS), a potentially deadly autoimmune clotting disorder often co-occurring with other rheumatic diseases such as lupus and scleroderma. The cause of APS is currently unknown. However, Kriegel and his team hypothesised that a certain bacterium in the gut may be responsible through cross-reactivity of both immune cells and antibodies with bacterial antigens from this bacterium. APS patients have high levels of antibodies to a substance called β2-glycoprotein I, and the researchers showed in work presented at last year’s American Association of Immunologists meeting that cross-reactivity of the gut bacterial antigens with the patient’s own β2-glycoprotein I may be the underlying cause. In this project the researchers have been using sophisticated techniques and molecular biology studies to formally show cross-reactivity between the bacterial protein in the gut and the abundant self-antigen β2-glycoprotein I that circulates in the blood. They have thus unravelled a potential persistent trigger of pathogenic autoantibody production in genetically prone APS patients.
It is becoming increasingly clear that our overall health and well-being is profoundly linked to the massive population of bacteria that reside in our gut. Dr Kriegel’s ground-breaking research represents a novel paradigm for how autoimmunity can arise and serves as a solid foundation for development of new and effective therapeutic approaches aimed at the gut and skin microbiota.

  • Manfredo Vieira S, Hiltensperger M, Kumar V, Zegarra-Ruiz D, Dehner C, Khan N, Costa FRC, Tiniakou E, Greiling T, Ruff W, Barbieri A, Kriegel C, Mehta SS, Knight JR, Jain D, Goodman AL, Kriegel MA: Translocation of a gut pathobiont drives autoimmunity in mice and humans. Science. 2018 Mar 9. PMID: 29590047
  • Greiling TM, Dehner C, Chen X, Hughes K, Iñiguez AJ, Boccitto M, Ruiz DZ, Renfroe SC, Vieira SM, Ruff WE, Sim S, Kriegel C, Glanternik J, Chen X, Girardi M, Degnan P, Costenbader KH, Goodman AL, Wolin SL, Kriegel MA: Commensal orthologs of the human autoantigen Ro60 as triggers of autoimmunity in lupus. Sci Transl Med. 2018 Mar 28. PMID: 29593104
  • Ruff WE, Kriegel MA: Autoimmune host-microbiota interactions at barrier sites and beyond. Trends Mol Med. 2015 Apr 2015 Mar 11. PMID: 25771098
  • Abstract of 2017 American Association of Immunologists meeting
  • NIH
  • Arthritis National Research Foundation
  • Lupus Research Institute
  • Arthritis Foundation
  • Women’s Health Research at Yale
  • O’Brien Center at Yale
  • Yale Rheumatic Diseases Research Core
  • Yale Liver Center
  • Yale Center for Clinical Investigation

Key lab members on work discussed here

  • Silvio Manfredo Vieira (gut commensal translocation)
  • Teri Greiling and Carina Dehner (Ro60 ortholog cross-reactivity)
  • William Ruff and Carina Dehner (commensal cross-reactivity in antiphospholipid syndrome)

Collaborators on work discussed here

  • Andrew Goodman , PhD, Associate Professor of Microbial Pathogenesis, HHMI Faculty Scholar, Yale Microbial Sciences Institute.
  • Sandra Wolin , MD PhD, Chief, RNA Biology Laboratory, Senior Investigator and Head of Section on Noncoding RNAs and RNPs, National Cancer Institute Professor Emeritus of Cell Biology at Yale.

Bio
Dr Kriegel is an Adjunct Assistant Professor of Immunobiology at Yale School of Medicine, a US board-certified rheumatologist, and a Translational Physician Scientist at Roche. His NIH-funded laboratory at Yale dissects microbiota-host interactions in immune-mediated diseases with a translational focus to take basic discoveries from gnotobiotic models to patient-oriented research.
Contact
Martin Kriegel , MD PhD
Kriegel Lab
Amistad Street Building
10 Amistad Street
New Haven, CT 06519
USA
E: [email protected]
T: (+1) 203 737 2294 (Admin Assistant)
W: https://medicine.yale.edu/lab/kriegel/
W: Video on gut commensal translocation paper
W: Video on Ro60 ortholog cross-reactivity paper
W: Video on antiphospholipid syndrome, diet and microbiome studies in the lab


Promotion of pathogen invaders

Microbiota components modify the within-host environment

Metabolic environment.

Microbiota metabolites are beneficial to hosts in myriad ways. They help to prime the immune system, act as antimicrobials to combat infection, and aid host metabolism [24,80–82]. However, microbiota metabolites can also provide a convenient and easily attainable source of food for invading pathogens to exploit. Metabolic cross-feeding, in which a product of metabolism from one strain is used by another strain, generates novel niches that may benefit pathogens [83]. This assimilation of resources can enhance energy production within the pathogen, enabling increased virulence and rapid growth, and thus more severe disease. For example, the human gut commensal Bacteroides thetaiotaomicron (Bt) can exacerbate infection caused by enterohaemorrhagic Escherichia coli (EHEC) via metabolic cross-feeding [84]. Bt modifies the metabolic environment at the site of EHEC infection, increasing metabolites involved in gluconeogenesis which are then sensed by the virulence-regulating transcription factor Cra. Virulence is up-regulated as a result and, concurrent with invasion of the gut epithelial barrier (also facilitated by Bt), EHEC induces a greater degree of host pathology and higher risk of mortality.

Individual species of the microbiota cannot always be pinpointed for their role in facilitating infection. While Bt was specifically identified in the previous example as a contributor to EHEC infection [84], microbial metabolites from multiple components of the microbiota can also collectively enhance EHEC virulence [85]. A comparison between human and mouse microbiota metabolites illustrated that the increased severity of EHEC infection in humans, compared to that in mice, is driven by distinct human gut microbiota metabolites [29]. These metabolites specifically induce increased expression of flagellin in the pathogen, increasing its ability to invade host tissues. Distinct microbial communities can thus shape different infection outcomes via metabolite production.

The metabolic environment within a host is a crucial contributor to the pathogenesis of invading organisms. It can be extensively modified by components of the microbiota to both the detriment and the benefit of the host. Changes in host health can likewise alter the within-host metabolic environment, contributing to disease onset from resident commensals [62]. Given the diversity of species housed by the animal gut, there are complex interactions to pick apart. Research is moving towards characterising the functionality of the microbiome by holistically sampling its taxonomic and genomic repertoire in addition to the chemical phenotype. Progress has been made in uncovering pathogen-induced disease phenotypes that are enhanced by the microbiota through application of multi-omics strategies [86,87] (see Table 2). Nonetheless, data integration and interpreting meaningful biological signatures of infection (e.g., biomarkers of infection) remain a challenge [88].

Immunological environment.

Microbiota can prime the host immune response, altering their susceptibility to invading pathogens. Pathogen infectivity can be indirectly reduced by host microbiota this way [89–93]. Conversely, launching the immune response can inadvertently boost infection by some infectious agents [49]. Reynolds and colleagues [49] found that Lactobacillaceae species abundance in the mouse duodenum positively correlated with susceptibility to the nematode parasite Heligmosomoides polygyrus and heightened immunosuppressive regulatory T-cell and Th17 responses. Subsequent treatment of mice with Lactobacillus taiwanensis—a rodent commensal dominant in infected mice—elevated regulatory T-cell frequencies and promoted the establishment of H. polygyrus. The fact that microbiota composition changed after H. polygyrus exposure towards more “helpful” bacterial species suggests that parasites could actively modify the microbiota to improve their survival. This manipulation could occur directly via antimicrobials [94] or by pathogen-induced host inflammation [95]. Physical disruption of the host site might also cause changes in resource availability, shifting microbiota composition [96].

Invading pathogens might evolve in response to host microbiota

Microbes can evolve quickly [100] because of their large population sizes and rapid generation times. Microbiota components can evolve within their host’s lifetime with consequences for host health [101]. For example, a mildly pathogenic strain of the gut microbiota component Enterococcus faecalis has been shown in nematode hosts to evolve to become more protective due to competitive interactions with a virulent pathogen [23]. Likewise, the pathogen Candida albicans was shown to evolve towards protective mutualism when introduced to a new host in a mouse model [102].

Invading pathogens, in turn, may evolve to overcome or exploit the host microbiota. They can readily overcome barriers to their establishment, including from host resistance [103], antibiotic treatments [104], and vaccines [105]. Theory has shown that pathogens can evolve virulence factors to overcome commensals in the host microbiota, either directly killing their competitors [106] or inducing host inflammation as a form of “proactive invasion” [95]. Experimental evolution approaches in animal model systems have produced mixed evidence on the ability of evolving pathogens to escape suppression by protective microbes. Martinez and colleagues [107] found that niche blocking by Wolbachia in Drosophila melanogaster effectively suppressed the pathogen Drosophila C virus (DCV), which did not evolve to overcome the protective symbiont. In contrast, Rouchet and Vorburger [108] found the parasitoid wasp, Lysiphlebus fabarum, readily counteradapted to the protection given by sympatric Hamiltonella defensa in aphids. A variety of pathogens may have evolved to exploit host microbiota for replication and transmission. Poliovirus and Trichuris muris, for example, have been empirically found to depend on interactions with mouse intestinal microbiota to trigger replication and hatching, respectively, at key host sites [47,48]. Poliovirus was able to better associate with host cells, and its replication was enhanced by up to 500% after binding lipopolysaccharide on enterobacterial surfaces [48]. Similarly, fimbriae on the surface of gut colonisers E. coli and Salmonella typhimurium were found to bind to proteins at the poles of eggs of the parasitic nematode, T. muris. This interaction with enterobacteria provides an essential cue, triggering the emergence of infective larvae [47].

Microbiome-mediated protection can drive the evolution of increased [109] and decreased [110] pathogen virulence. McNally and colleagues [109] found that manipulating the microbiota generated increased competition between commensal competitors and increased the intensity of bacterial warfare. Using theory, they found that stronger competition selected for increased expression of pathogen weapons (virulence factors). Enhanced production of virulence factors by many pathogenic bacteria can inadvertently harm the host. For example, release of Shiga toxin-encoding phage by shigatoxinagenic E. coli [111], and similarly TcdA released by Clostridioides difficile, can clear commensals both directly and via provocation of host inflammation [112,113].

Host microbiota has the potential to influence the evolutionary trajectory of invading pathogens. Manipulating host microbiota offers a promising route to treat or prevent infection, but such approaches should be scrutinised in light of the evolutionary potential of target pathogens.

Harmful infection from within

Transitions of commensal microbes to pathogens.

Commensals in the microbiota can transition along the parasite–mutualist continuum [66,76,114]. Transitions towards pathogenicity can be influenced by changes to the within-host environment—onset of illness or compromised immunity [7], diet [26], antibiotic treatment [115], or stress [28,116]—as well as changes in the external environment [28]. Infection by invading pathogens can also induce otherwise commensal bacteria to become pathogenic [33,117].

A well-studied example of a transition to pathogenicity is that of C. difficile, the causative agent of colitis. C. difficile can be at very low abundance in the human gastrointestinal tract. A healthy gut microbiota usually provides colonisation resistance against C. difficile expansion [52]. However, following a period of antibiotic treatment which diminishes the protective power of the microbiota, this bacterium can proliferate extensively to dominate the intestinal niche [71]. In this context, it is a highly problematic pathogen which can cause recurrent disease. Faecal microbiota transplants have proven useful in such cases, whereby the dysbiotic gut microbiota of a C. difficile patient is replaced with that of a healthy donor to eliminate the infection [118].

How can these transitions to pathogenicity occur among pathobionts? Metabolic changes in components of the microbiota can underpin the transition. Recent work on the Drosophila gut microbiome demonstrates that catabolism of host gut luminal uridine by pathobionts drives the generation of uracil and ribose. These metabolites respectively trigger an inflammatory host immune response and increased expression of virulence genes in pathobionts. Quorum sensing regulates both processes and is therefore necessary for a transition to virulence. Deletion of genes involved in nucleotide metabolism in strains of enteric Drosophila pathobionts blocked quorum sensing and thus the commensal-to-pathogen transition. Metabolites such as uracil and ribose may therefore act as pathogen-specific indicators, used by metazoan hosts to distinguish good from bad within the gut. Recognition of these indicators equips hosts to modulate immunity and gut-microbe homeostasis in response to changes within the microbiota [58].

In polymicrobial infections, metabolic cross-feeding can be an essential source of nutrients, enhancing the ability of commensal microbes to establish infection. The pathobiont Aggregatibacter actinomycetemcomitans, for example, requires L-lactate produced by the commensal bacterium Streptococcus gordonii to establish polymicrobial periodontal infection in a murine abscess model [119]. A. actinomycetemcomitans also exhibits enhanced respiratory metabolism in the presence of S. gordonii [120], as the latter increases the bioavailability of oxygen to the opportunist by providing electron acceptors. A. actinomycetemcomitans uses these electron acceptors to increase energy yield in the form of ATP production, which promotes increased virulence. With more energy available, the pathobiont can invest in the production of toxins, adhesins, and immunomodulatory proteins, among many other virulence factors [120].

Pathobionts have an array of tools available to adapt to environmental change within their niche [69,121–123]. Factors which contribute to the commensal bacterial lifestyle can be repurposed upon immune compromisation in the host or upon nutrient limitation or community disruption of the microbiota. Such changes within the host environment can lead to pathobionts proliferating beyond their niche to invade host tissues [69,123]. Adhesive proteins, for example, are required for asymptomatic colonisation of a new host, yet are also important in attaching to host cells to initiate invasion [123,124]. They can additionally contribute to the development of bacterial biofilms [69,70] to facilitate persistence of an infection under adverse conditions (e.g., antibiotic treatment). Likewise, toxins play a significant destructive role in the onset of disease. Toxins induce host cell lysis and stimulate inflammation, and they are recognised as major drivers of the symptoms of bacterial infection [125]. Recent research has also highlighted the contribution of toxins to pathobiont colonisation or persistence in different niches within the host during asymptomatic carriage, thus they aid both the commensal and pathogenic lifestyles of pathobionts [126]. Gene expression changes underpin transitions to pathogenicity and are driven by the need to adapt to changing conditions [121,122]. Infection can therefore be instigated by pathobionts within the host microbiota, following a transition from commensalism to a pathogenic state.

Costly protective symbionts.

In wild animal systems, beneficial microbiota components otherwise known as defensive/protective symbionts have been shown to prevent pathogen establishment and reproduction [127]. They are so effective at defending that the evolution of host resistance is slowed in the face of pathogen infection [128]. Many of these symbionts can, however, impose a physiological burden upon their host that is measured in the absence of an invading threat. [127]. For example, while the endosymbiont Wolbachia in numerous arthropod hosts defends against parasitic viruses [129], bacteria [130], and nematodes [131], Wolbachia in Drosophila fruit flies can cause a reduction in colonised host fertility, fecundity, and egg hatch rates, mediated by high symbiont densities [31]. A trade-off emerges in many host-microbe systems whereby increased conferred protection means the symbiont can become more pathogenic [34,35] (albeit, see Cayetano and colleagues [132]). Mathé-Hubert and colleagues [133] further showed that the cost of carrying a protective symbiont (Spiroplasma) in pea aphids can be alleviated by concurrent colonisation with a second symbiont (Regiella insecticola), as co-colonisation improves host lifetime reproduction and population growth.

Changes in the abiotic environment can also reveal the costs of these resident protectors in the microbiota. One extreme example is a species of the nematode-infecting bacterium Leucobacter, which under dry laboratory conditions is a protective bacterium against another highly virulent Leucobacter species, but in aqueous conditions causes hosts to become irreversibly fused by their tails leading to death [134]. The abiotic environment can therefore mediate host-associated microbe function to both favour and oppose pathogenicity.

Microbiota community structure as an early warning signal

Healthy microbiota community compositions can differ between individuals and population groups and also within individuals over time [135]. It is consequently not always feasible to establish what a “typical” dysbiotic microbiota looks like during infectious disease. However, a recent study in apiculture has demonstrated how early microbiota perturbations can have sustained negative consequences on host development and increase pathogen susceptibility within a population [116]. Schwarz and colleagues administered the commensal species Snodgrassella alvi to newly emerged worker bees as a potential probiotic therapy to protect against the parasite Lotmaria passim. Yet, despite S. alvi being part of the usual core microbiota of bees, inoculation of this species alone in young hosts led to microbiota perturbation, possibly reducing the protective benefits normally conferred and ultimately increasing parasite susceptibility [116].

While microbiota dysbiosis in general may correlate with infectious disease onset, microbial taxonomic signatures for specific infections may not always be a reliable indicator of disease [136]. The Anna Karenina principle [137] (“all happy families look alike, but each unhappy family is unhappy in its own way”) has been applied to explain observations in which microbiota community composition varies more between diseased individuals than healthy individuals. Nonetheless, in some instances, pathologies may be predicted by a specific reduction in certain key taxa. Bacterial vaginosis (BV) in humans is one such example, a condition caused by dysbiosis within the vaginal microbiota that affects approximately one-third of reproductive age women [138]. Vaginal microbiota composition varies across demographics [139], but onset of BV is typically associated with a reduction in Lactobacillus species, accompanied by the dominance of anaerobes and increased alpha diversity [140]. In these lactobacilli-depleted communities, the presence of biogenic amines can increase [141]. These amines, and the microbial community composition with which they are associated, could be useful biomarkers of disease in the early stages of BV development. Indeed, multi-omic approaches have been used to characterise the metabolic profiles corresponding to different symptomatic BV types [142]. Yeoman and colleagues [142] took this approach and identified distinct microbial taxa and metabolites which correlated to 2 different symptomatic BV types (and also to host behaviour). The characteristic odour of BV infection was linked to Dialister spp., the presence of discharge was linked with Mobiluncus spp., and Gardnerella spp. were linked with the symptom of pain. These findings provide both potential diagnostic markers for the onset of disease and insights into the determinants of BV.

Moving beyond correlative relationships between microbes and infections to establishing causation remains a major challenge [143–146]. Due to the complexities of microbial communities within a host, including the high species richness within a niche and the multitude of microbe–microbe and host–microbe interactions, it is often difficult to attribute specific microbes to a causative role in disease. Furthermore, in some cases, infection may not be attributable to one species, but to polymicrobial interactions which are difficult to pick apart [30]. Host heterogeneity in genotype, lifestyle, and diet further compounds the ability to infer causality. Not all components of the microbiota are culturable in the laboratory setting and are only identifiable as members of the community through sequencing. They are thus often excluded from culture-dependent laboratory experiments aiming to determine causality [86,147–150].

To bridge this gap between correlation and causation in elucidating the relationship between microbiota and infection, current research is benefitting from combining laboratory experiments with multidisciplinary and multi-omic approaches (see Table 2). Tractable, controlled experimental models of defined microbial communities will be important in this transition [151]. Synthetic microbial communities composed of native microbiota components are now being developed for use in model organisms [147,152–154]. Such resources will allow in-depth dissection of host–microbiota interactions in model organisms, using tools which are easily controlled while remaining representative of natural systems. The combination of experimental models with corresponding omics data will further allow functional verification of bacterial phenotypes within the microbiota [155] this mechanistic insight will be essential in determining causality in microbial infections.

Microbiota manipulation: Always a silver bullet?

Microbial approaches to managing disease in both humans and animals are gaining traction. The application of protective microbes directly to a host, or into a host’s habitat or food source, has been investigated for the control of infectious disease in endangered amphibians [36], aquaculture [156], and apiculture [157] as well as in the prevention and treatment of infectious and noninfectious human disease [38].

Microbe-based solutions have huge potential as alternatives to synthetic drugs [156,158,159]. However, they can sometimes have off-target effects. Studies on amphibian infection reveal the need for identification of these effects associated with probiotic use. Inhibition of the amphibian fungal pathogen Batrachochtyrium dendrobatidis (Bd) by bacteria can differ based on pathogen genotype and microbial community composition [160,161]. Single bacterial strains show both growth inhibition or promotion depending on Bd genotype. Becker and colleagues [37] exposed the critically endangered Panamanian golden frog, Atelopus zeteki, to fungal Bd and candidate probiotic bacteria identified based on their Bd inhibitory activity in vitro. Results of the in vivo study showed no difference in Bd-induced mortality in probiotic-treated versus untreated groups. Several probiotics, however, showed a (nonsignificant) trend towards exacerbating Bd-induced mortality when compared to Bd alone. More recently, a probiotic treatment for the emerging fungal pathogen of amphibians Batrachochytrium salamandrivorans (Bsal) was shown to slow disease progression, but did not improve individual survival within populations [36]. A longer period of infection resulting from treatment was suggested to likely extend the shedding period of Bsal into the environment, increasing its transmission. Research has also shown that colonisation resistance of the native skin microbiota can be metabolically costly and cause amphibians to lose body mass during probiotic treatment for chytridiomycosis [162]. These amphibian studies demonstrate the difficulty in applying protective microbes in the natural environment. There could be a mismatch between in vitro and in vivo outcomes, genetic variation in the effectiveness of protective microbes, or probiotic treatment could alter the infection dynamics in a way that benefits transmission.

Transplantation of entire microbial communities has shown promise in treating human disease. Faecal microbiota transplants are currently used to successfully treat recurrent C. difficile infection [118]. However, the long-term and off-target effects of this intervention remain unknown [158]. One potential side effect is the unintentional transfer of pathobionts from donor to recipient [163], for which follow-up studies are lacking [164]. Evidence is also emerging of extra-intestinal and systemic effects of intestinal microbiota replacement [165], including obesity [166], autoimmune disorders [167], and depression [168]. Observations of such varied off-target effects reveal the complex and systemic consequences which microbiota manipulation may have on hosts.

The use of known protective microbes as probiotics also needs to be monitored for unexpected consequences. Bifidobacterium longum subsp. longum has been investigated for its potential to prevent lethal infection from enteric pathogens. This bacterium is a component of the human gut microbiota which positively modifies the metabolic environment within the gut to inhibit translocation of invading EHEC from the gut to the blood [169]. Severe and ultimately lethal infection is prevented in this manner, but cases of infection caused by this species have been reported [30]. Tena and colleagues [30] reflected that B. longum may often be overlooked as a cause of disease in polymicrobial infections due to being labelled as a commensal.

Administration of protective microbes used clinically as probiotics could be particularly problematic for immunocompromised, critically ill, or otherwise vulnerable hosts [170]. Safety concerns include the potential for a probiotic to cause infection by translocation [171], to pass antibiotic resistance genes or other virulence-associated genes onto other microbiota components, and the possibility for production of metabolites that can be toxic [172]. There is also the possibility of permanent colonisation [173] and long-term side effects. Such safety concerns will be essential to account for in cases where probiotic treatments are being investigated to treat vulnerable hosts. Furthermore, the applied probiotic will interact with host microbiota and invading pathogens. As probiotics are inherently “live microorganisms” [174], they retain the ability to evolve, and it is largely unclear how they might change in a new host [175].


Disrupted gut microbiome makes children more susceptible to amoebic dysentery

Children with lower diversity of microbial species in their intestines are more susceptible to severe infection with the Entamoeba histolytica parasite, according to a new study published in PLOS Pathogens.

E. histolytica is an amoeba that typically spreads via food, water, or hands that have been contaminated with feces. Some infected people have no symptoms, but others experience symptoms of varying severity, from mild abdominal symptoms to life-threatening disease. The factors that influence severity are unclear, but previous studies suggest an important role for the gut microbiome.

In the new study, Koji Watanabe of the University of Virginia and colleagues collected and analyzed stool samples from children in an urban slum in Dhaka, Bangladesh. They found that children who experienced colon inflammation because of E. histolytica infection had lower diversity of microbes in their stool than children with asymptomatic infection.

To better understand these findings, the researchers used antibiotics to disrupt the gut microbiome in mice. They then exposed the mice to E. histolytica to see whether they were more susceptible to infection. The researchers found that mice treated with antibiotics had more severe colon inflammation than untreated mice.

Mouse tissue and gene expression analysis showed that disruption of the gut microbiome decreased the activity of infection-fighting white blood cells known as neutrophils. The surface of neutrophils in these mice had lower amounts of a protein known as CXCR2 than in untreated mice. CXCR2 plays a role in the recruitment of neutrophils to fight infection in the gut, so decreased CXCR2 levels likely resulted in the observed decreased neutrophil activity.

The analysis also showed that disruption of the mouse gut microbiome decreased production of a protein known as interleukin-25, which aids the function of the mucosal barrier that acts as the intestine's first line of defense against infection.

These findings suggest a molecular mechanism by which disruption of the gut microbiome increases severity of E. histolytica infection, but further research will be needed to determine if similar molecular effects occur in humans. Meanwhile, the finding that disruption of the mouse gut microbiome can interfere with neutrophil activity may be of broader interest in research of other infectious diseases.

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Why is the microbial ecosystem of the gut so susceptible to disruption by pathogens? - Biology

Inside your gastrointestinal (GI) tract are trillions of micro-organisms, including bacteria, fungi and viruses. You have roughly the same number of micro-organisms in there, mostly in the large intestine, as you do human cells in your entire body. But only 10% to 20% of the bacteria you have in your gut will be shared with anyone else.

These microbiomes differ hugely from person to person, depending on diet, lifestyle and other factors, and they influence everything from our health to our appetites, weight and moods. But despite being one of the most-researched parts of the body, there's still a long way to go to fully understanding our guts. BBC Future reviewed the findings of some of the science so far.

Our diets have a huge influence the gut microbiome. Research has found links between Western diet, typically high in animal fat and protein and low in fibre, with increased production of cancer-causing compounds and inflammation. The Mediterranean diet, on the other hand, which is typically high in fibre and low in red meat, has been likened to increased levels of faecal short-chain fatty acids, which have been found to have anti-inflammatory effects and improve the immune system.

Scientists hope that population-wide research will advance existing findings. One such project, the ongoing American Gut Study, is collecting and comparing the gut microbiomes of thousands of people living in the US. So far, research suggest those whose diets include more plant-based foods have a more diverse microbiome, and one that is "extremely different" from those who don't, says Daniel McDonald, the project's scientific director.

"We can't say one end is healthy or unhealthy yet, but we suspect that those who are eating a diet rich in fruits and vegetables have very healthy microbiomes," he says. However, McDonald adds, it's unclear if and how radically switching from a diet high in plant-based food to a diet low in healthy food would change the microbiome.

There has been a lot of hype around the health benefits of prebiotics and probiotics in recent years, but while they're increasingly used in treatments including inflammatory bowel diseases such as Crohn’s disease and ulcerative colitis, several reviews suggest there needs to be further research on which strains and dosages are effective.

Eran Elinav, an immunologist at the Weizmann Institute of Science in Israel, has recently found that some people are immune to probiotics – although he did this in a relatively small study that would require future research to come to any concrete answers. He gave 25 healthy individuals either 11 strains of probiotics or placebos, and tested their microbiomes and gut function with colonoscopies and endoscopies before and three weeks after the intervention.

Siome people have a gut biome which welcomes probiotic supplements (Credit: Getty Images)


Watch the video: Ch 20 Microbial Ecosystems (July 2022).


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