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The human ecosystem

Matthew Child and George Macfarlane explain the role of gastrointestinal microbiota

Genetic analysis shows that our gastrointestinal tracts are home to more than 100 000 billion (10¹⁴) individual micro-organisms of perhaps 36 000 different species. And more than 90% of the cells in our bodies are non-human.¹ These bacteria form a diverse and complex ecosystem with a total gene pool (microbiome) more than 100 times larger than the human genome—in effect we are hybrid “superorganisms.” The types and numbers of bacteria differ from the stomach to the distal colon, reflecting the changes in pH, concentration of oxygen, and availability of nutrients. Small numbers persist in the stomach (notably Helicobacter pylori, which causes ulcers) and the small intestine, but most of these organisms are found in the anaerobic environment of the large intestine (table).

Genus or family	Key role	Notable gastrointestinal members
Bacteroidetes	Polysaccharide breakdown4	Bacteroides fragilis, Bacteroides thetaiotaomicron
Bifidobacteria	Immunomodulation;anti-inflammatory; pathogen suppression5; biotin production6	Bifidobacterium.infantis, Bifidobacterium longum
Clostridium	Substrate breakdown7	C lostridium difficile
Atopobium	Cellulose fermentation8; host interactions	Atopobium parvulum
Enterobacteriaceae	Sugar fermentation; vitamin K production6	Escherichia coli
Enterococcus	Carbohydrate fermentation9	Enterococcus faecalis
Lactobacillus	Carbohydrate fermentation; immunomodulation; pathogen suppression10	Lactobacillus casei
Lachnospira	Pectin fermentation11	Lachnospira multiparous
Roseburia	Butyrate production12	Roseburia intestinalis
Ruminococcus	Cellulose fermentation13; biotin production6	Ruminococcus albus

Maintenance of this population of resident microbes, termed the gut microbiota, has several advantages. By competing for nutrients and epithelial receptors and producing bacteriocins (antibiotic peptides) and fermentation acids, microbiota can stop pathogenic micro-organisms from colonising the gastrointestinal tract.¹⁴ When the normal microbiota is destabilised, such as after the use of broad spectrum antibiotics, opportunistic pathogens can proliferate, often with acute health implications. A good example of this is diarrhoea associated with Clostridium difficile, which has become common in UK hospitals, especially among elderly people.¹⁵

Our resident bacteria can also salvage energy by fermenting dietary residues, such as plant polysaccharides and resistant starches, which the host does not have the ability to digest. One product of this action is butyrate, a short chain fatty acid that is used by colonic epithelial cells for most of their energy needs.¹⁶ Estimates show that 5-30% of the host’s daily energy requirements might be provided through bacterial fermentation, potentially important in some areas of the world where food sources are limited. Bacterial metabolism also provides essential vitamins and cofactors, such as biotin, folate, and vitamin K,⁶ which is needed to form several enzymes involved in blood clotting. Neonates in many developed countries are offered vitamin K supplements; one reason for this is that their gut microbiota has yet to become established.

Immune development and regulation

The gastrointestinal tract is the primary interface between the immune system and the environment and contains more than 75% of the body’s lymphatic system and 80% of its antibody producing B cells.¹⁷ Early bacterial colonisation seems essential for stimulating the physical development and subsequent functioning of the gut immune system. Experiments have shown that mice prevented from acquiring a gut microbiota have sparsely developed immune structures, have stunted epithelial growth, and are more prone to infections.¹⁸

One intriguing question is how does the gut immune system learn to tolerate most organisms and various food antigens, which would potentially initiate a strong response if encountered by the systemic immune system, while maintaining the ability to eliminate a minority of undesirable or pathogenic species? The answers are still being investigated; however, it seems to involve elements of the innate immune system, including specialised dendritic, T, and B cells and the insulation of the gut immune system from the systemic immune system.

Innate immune system

Mucus secreted by goblet cells coats the surface of the gut epithelium and traps bacteria, and in the small intestine waves of peristalsis move organisms quickly along before they can become established. Consequently, most micro-organisms and antigens remain in the gut lumen and do not contact the epithelial surface.

The small intestine and large bowel are both lined with a single layer of intestinal epithelial cells. Initially they were thought to be specialised solely for nutrient absorption, but intestinal epithelial cells are also important in the control of the immune response to the gut microbiota. They do this partly through the expression of Toll-like receptors and production of defensin.¹⁹ Toll-like receptors are an evolutionary conserved part of the innate immune system that are present in the animal and plant kingdoms. Ten have been identified in humans. They are activated when they encounter structures associated with pathogens, such as lipopolysaccharide (found on the surface of Gram negative bacteria); flagellin (a component of bacterial flagella); and the double stranded RNA common to many viruses.²⁰

When these receptors are stimulated the cells produce cytokines, chemical messengers that induce an appropriate immune response, such as inflammation or macrophage recruitment. Toll-like receptors are located either intracellularly or on the basal membranes of intestinal epithelial cells, therefore, they are not stimulated unless the physical integrity of the epithelium is compromised. Consequently, only pathogenic bacteria that attack and breach the epithelium stimulate an immunological response.²¹

Defensins are genome encoded antibiotic agents that are active against certain bacteria, protozoa, and fungi.²² More than 50 have been identified in humans, and they are important in the gastrointestinal tract, where their secretion can be induced by inflammation and infection. Defensins, as the name suggests, are thought to be important in the defence against food and waterborne pathogens, and they have been shown to have bactericidal activities against common pathogens, such as Salmonella typhimurium, Listeria monocytogenes,²³ and the yeast Candida albicans.²⁴ Low levels of expression of defensin may cause necrotising enterocolitis, a devastating disease of the small intestine that occurs in premature infants.²⁵

Adaptive immune system

The adaptive immune system also plays a major role in controlling the gut microbiota. IgA is the predominant immunoglobulin expressed by B cells in the gut immune system, indeed it has been estimated that the daily production of IgA in the gut exceeds the production of all other immunoglobulins combined.²⁶ These B cells are induced to secrete IgA after help from specialised populations of T cells and dendritic cells, located in lymphoid structures, such as Peyer’s patches and mesenteric lymph nodes, which continually sample the contents of the gastrointestinal tract. IgA is secreted constantly onto the epithelial surface and helps to shape gastrointestinal bacterial diversity and neutralise foreign proteins and toxins. Mice deficient in the ability to produce IgA have a different distribution of species, with more anaerobic bacteria, resulting in hyperactivity and deregulation of the gut immune system.²⁷

Some gut bacteria can directly influence host gene expression and dampen inflammatory responses.^{28 29} Organisms such as Bacteroides thetaiotaomicron and Lactobacillus casei have been shown to inhibit pro-inflammatory signalling by intestinal epithelial cells. The anti-inflammatory properties of some of these organisms are the rationale behind the use of popular “probiotic” food products. These products contain live bacteria, which, despite the absence of conclusive supporting evidence, manufacturers claim can help to promote gut health.

Microbiota in health and disease

Given the importance of the colonic microbiota for immune development and the delicate homoeostatic balance that needs to be maintained, it is unsurprising that alterations in bacterial diversity or immune regulation have been linked to numerous health problems throughout life (box).

The neonatal gut

After birth the human gut is first colonised by opportunistic bacteria acquired from maternal (faecal, vaginal) or environmental sources, before a more stable adult-like microbiota develops after weaning.³⁰ The composition of the gut microbiota in the neonatal period can be influenced by antibiotic treatment, whether infants are breast fed or bottle fed, or whether the delivery was vaginal or by caesarean section.³¹ Studies show that bottle fed children harbour higher proportions of potentially pathogenic Clostridia compared with their breastfed counterparts. Babies delivered by caesarean section also have more potential pathogens, possibly because they were not exposed to the maternal vaginal flora and the use of prophylactic antibiotics during the procedure. Research has shown that antibiotic use can affect gene expression in the host and disrupt the gastrointestinal microbial balance for years afterward.^{32 33} Given the importance of neonatal exposure to bacterial antigens for the development and priming of the immune system, it has been suggested that changes in the number and diversity of bacteria may be linked to specific diseases and allergies in childhood and throughout life. This “hygiene hypothesis” suggests that the increase in urban living has resulted in less microbial and antigen exposure during early life. This lack of antigen sensitisation has been used to explain increases in atopic diseases such as childhood asthma in developed countries.³⁴

The adult gut

Ulcerative colitis and Crohn’s disease are two idiopathic inflammatory conditions in the gut. The diseases differ in development, prognosis, and treatment, but both are characterised by chronic or episodic inflammation of the gastrointestinal mucosa. Genetically predisposed people are thought to mount a chronic inflammatory reaction to non-pathogenic bacteria, which are ignored in a healthy host. Evidence has shown that inflammatory lesions predominate in the areas of most bacterial exposure and that the gut microbiota differs between patients with disease and healthy controls.⁵ Several genes concerned with immune function have been found to be linked to the development of ulcerative colitis and Crohn’s disease and mainstay treatments involve the use of anti-inflammatory and immunosuppressant drugs.³⁵ Some people have responded to antibiotic and probiotic therapies, further supporting the link between the colonic microbiota and inflammatory bowel disease.³⁶

Butyrate formed by bacterial fermentation has been found to have anti-cancer properties. It promotes cell cycle arrest and apoptosis, and evidence from animal and tissue culture studies have shown the preventive effects of butyrate on colon cancer and adenoma development.³⁷ When colon transit times are prolonged, as can occur in people who eat low fibre diets or in elderly people, butyrate may be consumed in the proximal regions of the colon and not produced in the distal colon. It is theorised that diets rich in both fermentable substrates and non-digestible fibre may help to protect against distal colon cancer by improving the supply of butyrate to the distal regions of the bowel.

Many other health concerns are being linked to the microbial residents of the digestive tract. The gut microbiota has been reported to differ between obese and lean people, and it has been suggested that the metabolic activities of the gut microbiota of obese people facilitates the extraction of extra calories from ingested dietary substances, leading to greater formation of adipose tissue.³⁸ It has also been speculated that the breakdown of various environmental agents by atypical gut bacteria could liberate toxins implicated in conditions as diverse as attention deficit hyperactivity disorders, Tourette’s syndrome, and type 1 diabetes.³⁹

Conclusion

As multicellular organisms with an internal digestive system, humans have to balance the need to absorb nutrients with the risk of giving access to the numerous potentially pathogenic micro-organisms which share our environment. Evolution has favoured a trade off whereby certain microbes are tolerated in order to liberate energy sources and essential compounds, stop pathogenic bacteria from proliferating and stimulate immune development. However, when privileged access to the body’s internal environment is given to 100 trillion foreign organisms, it is unsurprising that loss of immune regulation or changes in the composition of bacterial species can have significant health implications. Currently, knowledge of the pathogenesis of many of these conditions remains incomplete, but with new health concerns being increasingly linked to alterations of the gut microbiota, a greater understanding of the interplay between ourselves and our bacterial residents is essential.

Competing interests: None declared.

Provenance and peer review: Not commissioned; externally peer reviewed.

See “Live yoghurt drinks” (Student BMJ 2001;9:390, http://student.bmj.com/back_issues/1001/life/390.html).

Matthew Childfourth year medical student Faculty of Medicine, Liverpool University, Liverpool L69 3GE
m.w.child@liv.ac.uk
George Macfarlane professor Dundee University Gut Group, Ninewells Hospital and Medical School, Dundee DD1 9SY
Student BMJ 2008;16:425468-ISSN 0966-6494 | December

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