The microbiota has an essential role in maintaining health. Its members assist in the metabolism of dietary constituents such as cellulose, as well as degrade toxins and produce essential cofactors such as vitamin K1. Short-chain fatty acids (SCFAs), such as acetate, propionate, and especially butyrate, produced by anaerobic metabolism of dietary carbohydrates by commensal bacteria are an essential source of energy for colonic enterocytes through their entry as substrates into the tricarboxylic acid (TCA) cycle. Surgical procedures, such as ileostomy, that remove the normal fecal flow to the colon can cause a syndrome called diversion colitis, in which enterocytes starved of SCFAs undergo inflammation and necrosis. Providing SCFAs to the affected colon segment can reverse this condition. Another important property of commensal organisms is that they interfere with the ability of pathogenic bacteria to colonize and invade the gut, partly by competing for space and nutrients. They can also directly inhibit the pro-inflammatory signaling pathways that pathogens stimulate in epithelial cells and that are needed for invasion. Perturbations in the balance between the various species of bacteria present in the microbiota (dysbiosis) have been found to increase susceptibility to a variety of diseases (see Sections 12-21 and 12-22).
The protective role of the commensal microbiota is dramatically illustrated by the adverse effects of broad-spectrum antibiotics. These antibiotics can kill large numbers of commensal gut bacteria, thereby creating an ecological niche for bacteria that would not otherwise be able to compete successfully. One example of a bacterium that grows in the antibiotic-treated gut and can cause a severe infection is Clostridium difficile (Fig. 12.20). This organism is an increasing problem in countries where broad-spectrum antibiotic use is prevalent, as it produces toxins that cause severe diarrhea and mucosal injury. Restoring the normal microbiota by a transplant of feces from healthy individuals can be used to treat C. difficile infection.
The importance of the local defense mechanisms against commensal bacteria for health is shown by experiments in animals that lack one or more of the factors involved. For instance, mice without secretory antibodies have increased numbers of commensal bacteria that have penetrated the intestinal mucosa and have disseminated beyond its draining lymphoid tissues. The composition of the microbiota in these mice is also altered, with increased numbers of bacteria, but decreased species diversity. Similar dysbiosis has been described in mice lacking FoxP3+ regulatory T cells or eosinophils.
while preventing inflammation without compromising the ability to react to invaders.
Despite their beneficial effects, commensal bacteria are a potential threat, as is shown when the integrity of the intestinal epithelium is damaged. In these circumstances, normally innocuous gut bacteria, such as nonpathogenic E. coli, can cross the mucosa, invade the bloodstream, and cause fatal systemic infection. Therefore, the immune system in the intestine has to mount some form of response to control commensal microbes (Fig. 12.21). Since inappropriate reactions may lead to chronic inflammation and damage to the intestine, the immune system must balance the recognition and response to commensal bacteria with the cost of damaging tissues from inflammation. Commensal bacteria elicit antigen-specific responses that maintain the local balance between host and microbiota and are largely confined to the intestine itself. Unlike soluble food antigens, commensal bacteria do not induce a state of systemic immune unresponsiveness, and when these organisms enter the bloodstream, they can stimulate a normal primary systemic immune response.