The intestinal microbiota

Intestinal microbiota comprises a wide variety of anaerobic bacteria. Here’s a close-up of its composition.

We’ve known for around a century that the digestive system is colonized by bacteria essential for proper digestion, metabolism and immunity. This bacterial ecosystem, which we call intestinal microbiota (or gut flora), is quantitatively and qualitatively unique to each individual. Each individual’s intestinal microbiota comprises a mean of 100,000 billion bacteria, which exceeds an organism’s total number of nerve cells. The bacteria belong to several hundred different species, mostly anaerobic or extremely sensitive to oxygen, but only 15 to 20 species form a shared foundation, derived from 7 phyla (branches of the classical classification of living organisms).

Very specific organisms

The intestinal microbiota is extremely diverse, but with dominant phyla, like Firmicutes and Bacteroidetes, which are its most important components,1 joined byActinobacteria, Proteobacteria, Verrucomicrobia, Fusobacteria and Cyanobacteria phyla. The Firmicutes are composed mostly of species belonging to Clostridia groups XIVa and IV (Ruminococcus and Faecalibacterium prausnitzii), while Bacteriodetes is represented by Bacteroides fragilis, Bacteroides ovatus and Bacteroides caccae. Other subdominant (enterococci, lactobacilli, streptococci) or transitory species (yeasts, etc.) complete the gut flora.2,3 This composition varies with age, diet and health, reaching maturity at 2 to 3 years of age. Any composition leads to metabolic, immune or digestive dysfunction in the affected individual.4

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Sources
1 - Qin et al. A human gut microbial gene catalogue established by metagenomic sequencing, Nature 2010;464(7285):59-65. http://www.nature.com/nature/journal/v464/n7285/full/nature08821.html
2. Chen J. et al. Contribution of the intestinal microbiota to human health: from birth to 100 years of age. Curr Top Microbiol Immunol 2013;358:323-346. https://www.ncbi.nlm.nih.gov/pubmed/22094893 
3. Lay C et al. Colonic microbiota signatures across five northern european countries. Appl Environ Microbiol 2005;71:4153-5. https://www.ncbi.nlm.nih.gov/pubmed/16000838
4. Cherbuy et al. Le microbiote intestinal : une composante santé qui évolue avec l'âge. Innovations agronomiques. 2013;33:37-46 https://www6.inra.fr/ciag/content/download/5203/40683/file/Vol33-4-Cherbuy.pdf 

 

Additional sources
- INSERM file http://www.inserm.fr/thematiques/physiopathologie-metabolisme-nutrition/dossiers-d-information/microbiote-intestinal-et-sante
- CNRS Article https://lejournal.cnrs.fr/articles/microbiote-des-bacteries-qui-nous-veulent-du-bien

Changes

Although researchers have known about the existence of the microbiota for a long time, it has only recently been the subject of successful genomic studies.

Roughly 100,000 billion bacteria of various species, as well as fungi, yeasts, and viruses, live hidden in the intestine. Some researchers agree that together they form their own organ, weighing about 2kg—heavier than a brain and just as complex. Although we’ve known about their existence for over a century, their exploration has only been relatively recent. For a long time, the only way to describe them was to grow them in vitro and study their biological properties, but only a small number of them can easily be grown in a lab. But now researchers can use their genome to hunt down their smallest details, thanks to the methods deployed by high-throughput sequencing and metagenomics, which study them in situ.

 

Finally known through DNA

As a result, the identification of these bacteria continues to progress, and we learn more about them through their genome. The international consortium project MetaHIT,1 run by INRA, has genomically identified almost 800 species of bacteria so far. Among them, 85% are “new specimens” of bacteria, which had been unknown until then. The same program has also sequenced 238 species of bacteria that are totally genetically identified. Little by little, MetaHIT is creating a genetic map of intestinal microbiota, which could eventually lead to the use of microbiota as a diagnostic tool to detect early stages of diseases3. The study of the microbiota will be able to go even further thanks to metatranscriptomics3 and metaproteomics4, which are currently being studied. They both encompass the products of transcription and translation of the bacterial genome, giving an overall bacterial profile including a functional analysis.

 

Sources

1- http://www.metahit.eu: the consortium unites 13 research centers in 8 countries.
2- Li J et al. An integrated catalog of reference genes in the human gut microbiome. Nat  Biotechnol. 2014; 32: 834-41. http://www.nature.com/nbt/journal/v32/n8/full/nbt.2942.html
3- Turnbaugh PJ, et  al. Organismal, genetic, and transcriptional variation in the deeply sequenced gut microbiomes of identical twins. PNAS 2010; 107: 7503-8. https://www.ncbi.nlm.nih.gov/pubmed/20363958
4- Wilmes P, Heintz-Buschart A, Bond PL. A decade of meta-proteomics: Where we stand and what the future holds. Proteomics 2015; 15 (20): 3409-17. https://www.ncbi.nlm.nih.gov/pubmed/26315987

The intestinal microbiota forms as of the first moments of life under the influence of various factors and evolves over the first few years before stabilizing.

An individual’s microbiota is constituted during birth: after having been nestled in their mother’s womb, the newborn is suddenly confronted with a multitude of bacteria that will determine the composition of his/her intestinal microbiota. Recent data even suggest that microbial colonization begins before birth, upending the dogma of in utero sterility.1 During vaginal birth, the neonatal microbiota is formed by contact with the mother’s vaginal and fecal flora, whereas after caesarian section birth, the baby’s gut flora forms more slowly under the influence of the external ecosystem and its microorganisms.2 Gestational age at birth, the external environment and feeding method (breast milk or infant formula) also affect its development. This colonization takes place progressively, in a well-established order, even though the mechanisms have not yet been completely elucidated. The first colonizing bacteria are facultative anaerobes – enterococci and staphylococci – which require oxygen to multiply. They create a new environment that promotes the subsequent implantation of obligate anaerobes, like Bacteroides, Clostridium and Bifidobacterium.3

 

External influences

The microbiota then evolves quantitatively and qualitatively, influenced by food, hygiene conditions, potential medical treatments received and the environment. Among the well-studied factors, breastfeeding holds a significant place in the establishment of an individual’s favorable microbiota, with dominant Bifidobacterium implantation3 and delayed colonization by Clostridium and Bacteroides, compared with infant formula. Moreover, early antibiotic use4,5 was shown to negatively influence gut flora development (later appearance of allergies, asthma, diabetes, overweight, etc.). Once the microbiota is established, it evolves gradually, diversifying in response to environmental exposure and food eaten, finally stabilizing around the age of 3 years.6 Nevertheless, it remains sensitive throughout life to many of the organism’s inherent factors (genetics, circadian rhythm) or environmental factors (the role of food), even to periods of stress during antibiotic treatments, which can lead to dysbiosis.

 

Sources
1. JM Rodriguez et al. The composition of the gut microbiota throughout life, with an emphasis on early life. Microbial Ecology in Health and Disease 2015;[S.l.]26:26050
2 Jakobsson HE et al. Decreased gut microbiota diversity, delayed Bacteroidetes colonisation and reduced Th1 responses in infants delivered by caesarean section. Gut 2014;63:559-66.
3.. Guaraldi Fet al. Effect of breast and formula feeding on gut microbiota shaping in newborns. Front Cell Infect Microbiol 2012;2:94.
4. Tanaka S et al. Influence of antibiotic exposure in the early postnatal period on the development of intestinal microbiota. FEMS Immunol Med Microbiol 2009;56:80-7.
5. Fouhy F et al. High-throughput sequencing reveals the incomplete, short-term recovery of infant gut microbiota following parenteral antibiotic treatment with ampicillin and gentamicin. Antimicrob Agents Chemother 2012;56:5811-20.
6. Yatsunenko T et al. Human gut microbiome viewed across age and geography. Nature 2012;486:222-7.

Baby

From 0 to 3 years, children’s microbiota diversifies.

Adult

Until adult age, intestinal microbiota diversifies, then stabilizes.

Senior

As we age, microbiota becomes slightly impoverished.

Functions

Intestinal microbiota is essential to our bodies’ proper development and function, particularly because of the numerous metabolites it provides.

The presence of an intestinal microbiota after birth is essential to the proper development of the body, -and of the intestinal tract in particular, as it is not fully developed in newborns. This has been shown by numerous studies, for the most part conducted in rodents without any intestinal bacteria.

Maturation of the gastrointestinal tract

The tract of these animals, called “axenic,” has numerous alterations compared with those raised in normal conditions: an enlarged cecum1, reduced villus thickness and vascularization 2,3, decreased intestinal crypt depth 4, reduced mucus5 production, etc.

Strengthening of tight junctions

Intestinal microbiota also influences the permeability of intestinal epithelium. For example, certain strains of lactobacilli and probiotics strengthen tight junctions that are formed between epithelial6 cells.

Production of short-chain fatty acids

This effect is due to the fact that intestinal microbiota produces numerous molecules that are useful to the proper functioning of the intestines, particularly SCFAs, such as butyrate, which are energy substrates for colonocytes and are therefore essential to the growth and differentiation of the epithelium in the colon7. A study suggests, furthermore, that taking the probiotic yeast Saccharomyces boulardii reduces symptoms of diarrhea8 by increasing production of SCFAs in the intestines of patients under parenteral nutrition.

Maturation of the immune system

However, intestinal microbiota is not only necessary for the proper development of the intestines. The immune system is also disrupted in its absence: for instance, mesenteric ganglia are atrophied, lymphoid follicles are rare, and Peyer’s patches (aggregated lymphoid nodules) remain in an immature form.

Sources
1- Smith Karen et al. Use of axenic animals in studying the adaptation of mammals to their commensal intestinal microbiota. Semin Immunol. 2007;19:59–69. doi: 10.1016/j.smim.2006.10.002. https://www.ncbi.nlm.nih.gov/pubmed/?term=Use+of+axenic+animals+in+studying+the+adaptation+of+mammals+to+their+commensal+intestinal+microbiota
2- Reinhardt C et al. Tissue factor and PAR1 promote microbiota-induced intestinal vascular remodelling. Nature 483, 627–631 (2012). An investigation which demonstrates that bacteria promote vessel formation in the intestinal epithelium by modulating tissue factor signalling. http://www.nature.com/nature/journal/v483/n7391/full/nature10893.html
3- Stappenbeck TS et al. Developmental regulation of intestinal angiogenesis by indigenous microbes via Paneth cells. Proc. Natl Acad. Sci. USA 99, 15451–15455 (2002). http://www.pnas.org/content/99/24/15451.full.pdf
4- Sommer Felix et al. The gut microbiota--masters of host development and physiology. Nat Rev Microbiol. 2013;11:227–238.  2013 https://www.ncbi.nlm.nih.gov/pubmed/?term=The+gut+microbiota--masters+of+host+development+and+physiology
5- Johansson Malin et al. Normalization of host intestinal mucus layers requires long-term microbial colonization. Cell Host Microbe. 2015;18(5):582–592. http://www.cell.com/cell-host-microbe/pdf/S1931-3128(15)00417-5.pdf
6- Lutgendorff F et al. The role of microbiota and probiotics in stress-induced gastro-intestinal damage. Curr. Mol. Med. 8, 282–298 (2008)  https://www.ncbi.nlm.nih.gov/pubmed/?term=The+role+of+microbiota+and+probiotics+in+stress-induced+gastro-intestinal+damage
7- Linares Daniel M. et al. Beneficial microbes: the pharmacy in the gut. Bioengineered. 2016;7:11–20.  http://www.tandfonline.com/doi/full/10.1080/21655979.2015.1126015
8- Schneider  Stéphane et al. Effects of Saccharomyces boulardii on fecal short-chain fatty acids and microflora in patients on long-term total enteral nutrition. World J Gastroenterol 2005;11(39):6165-6169

 

A direct or indirect barrier effect, maturation of the immune system, the intestinal microbiota protects its host against pathogens in many ways.

The intestines are a preferred portal for invasion by pathogenic organisms and toxic molecules, meaning the intestinal microbiota is our first line of defense against these attacks. This gut flora acts in many ways.

Direct competition 

Via a competitive exclusion mechanism, commensal bacteria passively protect the body against infection by other strains, by competing with them for adhesion sites and the nutrients essential to their survival. They also act more directly by producing metabolites that are harmful to their competitors, such as antibacterial peptides.

Reinforcement of natural defenses

Commensal bacteria also protect us  by reinforcing the intestinal barrier. They stimulate the production of mucus and defensive molecules, such as IgA antibodies, and activate intestinal epithelial cell replacement and the formation of tight junctions between them, maintaining the impermeability of the physical barrier.1,2,3

Effect on the intestinal immune system

Lastly, during the first years of our lives, the intestinal microbiota participates in immune-system maturation. For example, the gut flora stimulates the development of T-helper 17 (Th17) cells,4 through a process based on the secretion of molecules that can cross the intestinal epithelium and interact with specific cell surface receptors. This action is not limited to immune defense around the intestines; the microbiota seems to be able to influence responses to all kinds of threats (for example, respiratory infections).5

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Sources
1. Jakobsson HE, Rodriguez-Pineiro AM, Schutte A, et al. The composition of the gut microbiota shapes the colon mucus barrier. EMBO Rep 2015;16:164-77.
2. Seth A, Yan F, Polk DB, Rao RK. Probiotics ameliorate the hydrogen peroxide-induced epithelial barrier disruption by a PKC- and MAP kinase-dependent mechanism. Am J Physiol Gastrointest Liver Physiol 2008;294:G1060-1069.
3. Reikvam DH, Erofeev A, Sandvik A, et al. Depletion of murine intestinal microbiota: effects on gut mucosa and epithelial gene expression. PLoS One 2011;6:e17996.
4. Caballero S, Pamer EG. Microbiota-mediated inflammation and antimicrobial defense in the intestine. Annu Rev Immunol. 2015;33:227–56. 10.
5. Denny JE, Powell WL and Schmidt NW (2016) Local and Long-Distance Calling: Conversations between the Gut Microbiota and Intra and Extra-Gastrointestinal Tract Infections. Front. Cell. Infect. Microbiol. Année;6:41.

Starting with the food we eat, the intestinal microbiota performs a vital function by producing essential nutrients.

The primary function of the intestine is to recover nutrients from food to supply metabolic functions that generate the energy needed for vital processes. The intestinal microbiota participates very actively in metabolism. To do so, the gut flora uses components from food that arrive in the colon (primarily carbohydrates and proteins not digested in the small intestine). It breaks them down into smaller molecules, some of which the organism can assimilate (catabolism), or use them as building blocks to synthesize new molecules, which can also be useful (anabolism).

Vitamins, fatty acids, amino acids...

Bacteria in the intestinal microbiota provide vitamins, such as menaquinone (vitamin K2), cobalamin (vitamin B12) and biotin (vitamin B7), short-chain fatty acids (acetate, propionate, butyrate), which serve many functions (for example, acetate is a cholesterol precursor), and the essential amino acids, which are branched-chain amino acids (leucine, isoleucine, and valine).1
All of these metabolites are partially absorbed through the intestinal wall, then transported through the bloodstream to the organs that need them.
Not all these bacteria have the same anabolic and catabolic abilities. The composition of the intestinal microbiota, which varies among individuals, contributes to the diversity of human metabolisms and the variety of effects of different dietary programs.2

 

Sources
1. Turroni F, Ribbera A, Foroni E, van Sinderen D, Ventura M. Human gut microbiota and bifidobacteria: from composition to functionality. Antonie Van Leeuwenhoek. 2008;94(1):35–50
2. Sonnenburg J.L., Backhed F. Diet-microbiota interactions as moderators of human metabolism. Nature. 2016;535(7610):56–64

Pathologies

Dysbiosis can cause multiple pathologies with repercussions on different organs.

Affecting the microbiota

There are 5 ways to affect the equilibrium of microbiota. Each of them has its own specific features.

  • Probiotics

    The WHO defines probiotics as “live microorganisms which, when administered in adequate amounts, confer a health benefit on the host”.
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  • Prebiotics

    Prebiotics are substrates that promote the growth of bacteria. They are thus essential for a balanced microbiota.
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  • Synbiotics

    Synbiotics are products that combine prebiotics and probiotics to improve the benefits for the microbiota.
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  • Fecal transplants

    Fecal transplant consists of implanting a healthy microbiota through natural passages into a patient to restore their microbial ecosystem.
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  • Nutritional modulation

    The composition of intestinal microbiota depends on what food is ingested and has consequences on overall metabolism.
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The various microbiota

Intestinal

The intestinal microbiota is an organ in its own right.
Better characterized thanks to metagenomics, it is gradually giving up its secrets. Highly diversified, it lives in close relationship with its host. Formed from birth, it is specific to each individual and fulfills different functions within the body: barrier effect, trophic, metabolic and immune functions, etc., as well as others that remain to be elucidated.

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Vaginal

The vaginal microbiota is an ecosystem constituted of microorganisms, where the genus Lactobacillus predominates. Its equilibrium is fragile and changes in its composition cause infections.

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ENT

The ENT microbiota is an extremely diverse microbiota which is assumed to include at least 700 different species.

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Cutaneous

Cutaneous microbiota is extremely diverse. Its composition varies according to the cutaneous zone and between individuals, and its imbalance is associated with skin diseases.

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Pulmonary

The pulmonary microbiota was unknown for a long time, since it was commonly accepted that healthy lungs are sterile. This paradigm was cast into doubt with the discovery of the various human microbiota.

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Urinary

The urinary microbiota was discovered very recently and has only begun to be described. Imbalances in this flora may be associated with problems in the urinary tract.

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