The influence of the gut microbiota on host mucosal immunity and its impact on gastrointestinal inflammation

In healthy individuals the intestinal microbiota, a complex microbial ecosystem, and the host maintain a mutually beneficial relationship. A balanced composition of the microbiota is crucial to provide its beneficial functions to the hostÕs health. In contrast, alterations of the balanced gut microbiota have been associated to worse or recover disease outcomes. Specifically, studies have demonstrated that alteration in the composition of gut microbiota can dramatically affect host immunity and are frequently associated to common gastrointestinal diseases. Therefore it is essential to investigate and identify the key players that tip the balance between pathogenic or homeostatic host-microbiota interactions to eventually develop novel microbiome-centered therapeutics to modulate inflammatory diseases. Here we demonstrated that alterations in gut microbial communities are able to directly enhance the disease severity in a mouse model of human inflammatory bowel disease (IBD). Specifically, we unveiled that distinct microbial communities utilized opposing arms of host immunity to promote disease severity. While one community required microbiota-specific CD4+ T cell responses, another community triggered severe intestinal inflammation even in the absence of adaptive immunity. Intriguingly, an overexpansion in the Proteobacteria over the Firmicutes phylum was associated to pathogenic CD4+ T cell response. Next, we elucidated beneficial CD4+ T cell responses driven by specific commensals during intestinal inflammation. Specifcally, we explored a previously reported immunomodulatory bacteria, segmented filamentous bacteria (SFB) and its effect on Salmonella induced gastroenteritis. While this bacterium is known to induce proinflammatory cells, SFB specific CD4+ T cells served as 'innate-like' source of antibacterial cytokines rapidly after infection. Importantly, SFB colonized mice displayed reduced pathogen invasion in the cecum suggesting that modulation of CD4 T cells by SFB is associated with improved immune defense. Together our studies demonstrate that the intestinal microbiota can directly influence host immunity to exert both pathogenic and beneficial disease outcome. Further studies are needed to explore specific interactions among distinct microbial members and host factors to drive different disease pathogenicity. Elucidation of similar microbiota induced effects in human may help to develop personalized therapies.