Submitted Abstract
BackgroundThe health benefits of fiber consumption have been purported for decades, yet the influence of many different chemical and physical forms of fiber polysaccharides on the gut microbiome, and ways through which gut bacteria catabolize these nutrients, are just now being unraveled. Aside from loss of beneficial short-chain fatty acid (SCFA) production, microbiome-mediated mechanisms that connect low fiber intake to poor gastrointestinal health have not been described. Using a gnotobiotic mouse model, we have recently found a mechanism by which a diet deficient in complex plant fiber triggers a fiber-deprived human gut microbiota to alternatively feed on the host-secreted colonic inner mucus layer that serves as a primary barrier against invading pathogens (Desai et al., under review in Cell). Our findings reveal important implications regarding how immediate history of human diet may modify immune status of the host and susceptibility to some enteric diseases. Project objectives•Since the colonic mucus barrier is an important first line of defense of the host, we further hypothesize that erosion of the mucus barrier would negatively impact the colonic regulatory T cells (Tregs) and other cells involved in the immune responses (e.g., other Th subsets, macrophages and epithelial cells such as M cells). In order to reach this objective, we will employ our innovative mouse model and low- and high-fiber diets. •A recent study published in Cell showed that commensal bacteria that are responsible for driving the pathogenesis of Inflammatory Bowel Disease (IBD) get coated with significantly higher amounts of Immunoglobulin A (IgA) (Palm, et al., Cell, 158: 1000-1010). Other reports have observed reduced or abnormal mucus production in IBD patients and even an increase in mucolytic bacteria. Therefore, we intend to study changes in IgA coating during a fiber deprived-gut microbiota driven colonic mucus degradation. We hypothesize that the mucus-degrading activity of the bacteria in our model would lead to increased IgA coating. •Since the colonic mucus layer is the first anatomical structure that an enteric pathogen encounters, our next goal is to understand how the erosion of the mucus barrier together with the microbiota-produced SCFAs and organic acids would lead to changes in the susceptibility to an enteric pathogen (such as Citrobacter rodentium). Justification for INTER Mobility The current research objectives will be achieved over a period of 3 years. To successfully execute the necessary experiments, certain key expertise would be required, which are lacking in the PI’s laboratory or in Luxembourg. The PI, who has recently started his research group in Luxembourg, has expertise in gut microbiome’s role in dietary carbohydrate metabolism as well as hands-on experience on employing C. rodentium as a model pathogen to study mechanisms of intestinal pathogenesis. On the other hand, the PI lacks vital expertise that are essential to reach the current research objectives such as conceptual knowledge and technical know-how about the connection between microbiome and Tregs/IgA. A world-leading laboratory that possesses all these expertise is Dr. Hiroshi Ohno’s group at RIKEN Center for Integrative Medical Sciences (IMS) in Japan. Moreover, in order to gain expertise on dietary fiber-mediated impact on the interaction of the gut microbiome and enteric pathogens, a scientist from RIKEN-IMS will visit the PI’s research group in Luxembourg. The current INTER Mobility application would allow the PI and the scientist from RIKEN to perform three research visits each to RIKEN-IMS and the PI’s group in Luxembourg, respectively. Through these research visits, high-impact publications and a long-standing collaboration are envisaged. Additionally, the proposal would strengthen other FNR-funded projects of the PI, such as CORE and AFR bilateral with RIKEN-IMS.