The gut microbiota shapes intestinal immune responses during health and disease

Abstract

Germ-free mice have many immunological defects in the intestine, including smaller mesenteric lymph nodes and Peyer's patches, decreased numbers of interleukin-17 (IL-17)-producing T helper 17 (T_H17) cells and defects in regulatory T (T_Reg) cells. In addition, germ-free mice have impaired immune responses to certain pathogens, including Shigella and Listeria species. These findings indicate that the intestinal microbiota might influence both pro- and anti-inflammatory responses. Intestinal homeostasis depends on maintaining a proper balance between pro- and anti-inflammatory pathways that are mediated by T_H17 and T_Reg cells, respectively. Improper regulation of inflammatory pathways can lead to diseases such as inflammatory bowel disease (IBD). IBD results from the breakdown in immune tolerance to gut bacteria. Indeed, spontaneous disease does not occur in many mouse models of experimental colitis, including IL-2- and IL-10-deficient mice, when raised under germ-free conditions. Susceptibility to IBD is influenced by many factors, including genetic and dietary factors. However, recent studies have shown that the intestinal microbiota could be an important factor in driving disease. Similar to observations made in animal models, changes in the microbiota of humans have been implicated in disease. Numerous studies have revealed a significant alteration in the microbiota of patients with IBD compared with healthy individuals, although whether changes in the intestinal microbiota are the cause or effect of disease still needs to be determined. Several species of bacteria that peacefully reside in the intestine have been shown to have a protective role during IBD. These bacteria are referred to as probiotic bacteria and include species such as Lactobacillus casei and Bifidobacteria longum. The mechanisms by which these bacteria protect from disease are thought to involve modulation of T_Reg cell responses. A product of B. fragilis, polysaccharide A, elicits IL-10 production by CD4⁺ T cells and mediates protection from IBD, demonstrating that symbiotic intestinal bacteria have developed strategies to influence the host immune system. Does harbouring certain strains of bacteria predispose an individual to disease or protect from it? As symbiotic bacteria seem to have evolved mechanisms to promote protection from potentially pathogenic bacteria in the microbiota, disease may result from the absence of these symbiotic organisms and their beneficial molecules. Therefore, dysbiosis (a shift in the composition of the intestinal microbiota) could be an underlying factor in the development of IBD.