The human intestinal microbiome includes all of the commensal bacteria that normally reside in the intestines, discussed earlier, as well as thousands of species of viruses, fungi, and protozoans. Humans and their intestinal microbiome have coevolved mechanisms for mutual benefit, including mechanisms to defend against invasion by these organisms and to maintain equilibrium by minimizing unneeded proinflammatory immune responses to the commensal organisms. One consequence of this coevolution is a profound influence of the microbiome on the immune system. The microbiome changes with age, diet, and disease, and experimental studies indicate that these changes affect immune function locally in the gut and systemically.
Commensal organisms in the intestines induce and regulate innate immune responses in the gut and also influence systemic innate immunity. Studies in mice have shown that commensal bacteria are needed for proliferation and repair of the intestinal epithelial barrier after injury, an effect mediated by bacterial cell wall PAMPs and the TLRs to which they bind on the epithelial cells. As mentioned earlier, microflora in the gut stimulate the expression of mucins and antimicrobial molecules (including defensins and REGIIIγ) that prevent bacterial colonization. In addition, several studies in mice have shown that products of commensal bacteria in the gut influence the way circulating neutrophils and macrophages function systemically. For example, short-chain fatty acids from gut bacteria dampen neutrophil inflammatory responses, whereas fragments of intestinal bacterial peptidoglycan enhance the ability of circulating neutrophils to kill gram-positive bacteria. Gut bacteria also appear to be required for systemic antiviral functions of macrophages, DCs, and natural killer (NK) cells.
Intestinal commensal organisms influence local and systemic adaptive immune responses. In mice, the production of IgA in the intestinal mucosa, which is a major adaptive immune mechanism for protection against microbial invasion through the intestinal epithelial barrier, is dependent on the presence of a subset of small bowel luminal bacterial flora. Commensal bacterial anti gens activate specific IgA responses by inducing the expression of BAFF, APRIL, and retinoic acid, which are IgA switch factors required for T-dependent and T-independent B-cell class switching to IgA (discussed earlier). By preventing commensals from reaching the barrier epithelium, IgA in the gut reduces innate responses to these organisms, and limits B-cell activation and antibody responses locally and systemically. Certain species of commensal organisms are also required for accumulation of Th17 cells in the gut, as discussed earlier, and the presence of these species increases resistance to some gut pathogens, but may also increase susceptibility to autoimmune disease outside the gut. Other commensal species contribute to the development of Tregs.
In humans, the impact of gut microflora on local and systemic immune responses is inferred from many clinical observations and experimental therapies. Normal flora appears to be required to prevent harmful intestinal innate responses and inflammation induced by pathogenic bacteria. For example, antibiotic treatment for infections outside the gut will invariably alter the makeup of the gut microflora, and this is associated with increased risk for pathologic bacterial infections in the colon, especially with Clostridium difficile. Patients with chronic C. difficile infection benefit from orally administered fecal transplants, which repopulate the gut with flora from healthy individuals.
It has been suggested that alterations in the intestinal micro biome, which is sometimes called dysbiosis, may underlie the development of numerous disorders, but how human commensal gut flora influence systemic immunologic health is largely unknown. The risk for developing allergic disease, including asthma, has been linked to variations in microflora acquired during early childhood as a consequence of mode of birth (vaginal vs. cesarean section), breast-feeding, and antibiotic use. Currently, the microbiomes of various normal and patient populations are being characterized by genetic methods. Although this work may lead to a better understanding of how the human immune system is regulated by gut bacteria, a major challenge in interpreting the data is the significant variation of the human microbiome among individuals and over time even in one person.
