Abstract LB-062: Deficiency of dietary fiber in Slc5a8-null mice promotes bacterial dysbiosis and inflammatory milieu in colon

Abstract

Abstract Inflammatory bowel disease (IBD) is characterized by chronic inflammation in the intestinal tract due to disruption of the symbiotic relationship between the host immune system and microbiota. Various factors alter the composition of the gut microbiota which lead to dysbiosis; in particular, diet and dietary fiber constitute important determinants. Dietary fiber protects against IBD; bacteria ferment these dietary fibers in colon and generate short chain fatty acids (SCFAs), which mediate the anti-inflammatory actions of dietary fiber. SLC5A8 is a sodium-coupled transporter in the apical membrane of colonic epithelium which mediates the entry of SCFAs from the lumen into cells. Due to the unique transport kinetics, the function of the transporter becomes important only under conditions of low dietary fiber intake. We have shown previously that deficiency of dietary fiber increased susceptibility to colitis and colon cancer in Slc5a8-null mice. This effect was primarily due to deficiency of regulatory T cells (Treg) and increased pro-inflammatory cytokines. Now we have examined the impact of dietary fiber deficiency on luminal microbial composition and transcriptomic profile in colonic epithelium in wild type (WT) and Slc5a8-null (KO) mice. We fed WT and KO mice with fiber-containing diet (FC) or fiber-free diet (FF) and analyzed the luminal bacterial composition by sequencing 16S rRNA gene in feces. Markedly altered luminal microbiota was observed when fiber was deficient in the diet and also when Slc5a8 was absent. Decreased diversity of microbiota was observed in WT mice fed FF diet; similarly, KO mice showed decreased microbial diversity compared to WT mice even when fed FC diet. Interestingly, the impact of dietary fiber on microbial composition was lost when Slc5a8 was not present. The Principal Coordinate Analysis (PCoA) showed samples were separated into four clusters based on the mouse genotype and dietary fiber condition. These results suggest that there are significant differences in the microbial community depending on dietary fiber content and on the presence or absence of the SCFA transporter Slc5a8. Decreased abundance of Bacteroidetes and Firmicutes was observed in WT mice fed FF-diet and in KO mice fed FC-diet compared to WT mice fed FC-diet. We observed increased abundance of well-known microbial biomarkers of active colitis and also the mucin-degrading Vercomicrobia and Akkermansia and the sulfate-reducing Desulfovibrio in KO mice fed FF-diet. Further, KO mice had decreased abundance of Oscilospira species, which is known to be preset at lower abundance in IBD patients. There was also marked differences in the transcriptomic profile of the colonic epithelium depending on the dietary fiber content and on the presence or absence of Slc5a8. We conclude that absence of fiber in diet in KO mice causes bacterial dysbiosis and promotes inflammation in colon. Citation Format: Sathish Sivaprakasam, Pramodh K. Ganapathy, Sabarish Ramachandran, Kameswara Rao Kottapalli, Ganapathy Vadivel. Deficiency of dietary fiber in Slc5a8-null mice promotes bacterial dysbiosis and inflammatory milieu in colon [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-062.