Project description:The intestinal mucus layer produced by goblet cells is a critical component of innate immunity. The key host factors and regulatory mechanisms controlling goblet cell function in mucus layer formation remain poorly understood. This study identifies a function for the microprotein FXYD domain-containing transport regulator 3 (FXYD3) in goblet cells in regulating mucus layer formation to maintain intestinal homeostasis. Deficiency of FXYD3 in mouse intestinal epithelial cellsresults in a damaged mucus barrier, leading to microbiota dysbiosis and increased susceptibility to colitis. Mechanistically, FXYD3 interacts with endoplasmic reticulum Ca2+-ATPase SERCA2 to enhances its pump activity. FXYD3 deficiency causes defects in ER Ca2+ homeostasis and mucin glycosylation, impairing mucus layer integrity. Furthermore, metabolites of gut microbiota, propionate and butyrate promoteFXYD3 expression. In ulcerative colitis (UC) patients, FXYD3 expression is significantly downregulated and correlats with disease severity. These findings indicat FXYD3 is a key mediator of host-microbiota interactions for intestinal health.
Project description:Two C57BL/6 mice colonies maintained in two rooms in the same specific pathogen free (SPF) facility were found to have different gut microbiota and a mucus phenotype specific for each colony. The thickness and growth of the colon mucus was similar in the two colonies, but one colony had mucus not penetrable to bacteria or bacterial-sized beads, similar to what occurs in free-living wild mice. On the other hand, the other colony had an inner mucus layer that was penetrable to bacteria and beads. These different properties of the mucus in the two rooms were dependent on the microbiota, as the phenotypes were transmissible by transfer of ceacal microbiota to germ-free mice. Mice with an impenetrable mucus layer had increased amounts of Erysipelotrichi, while mice with a penetrable mucus layer had higher levels of Proteobacteria and TM7 bacteria in the distal colon mucus. Thus bacteria affect mucus barrier properties in ways that can have implications for health and disease.
Project description:Dietary intake of fruits and vegetables (FV) has been inversely associated with lower risk of ulcerative colitis. A pig model was used to evaluate the impact of feeding FV on the host response to dextran sulfate sodium (DSS)-induced colitis. Methods: Six-week-old pigs were fed a grower diet alone or supplemented with lyophilized FV equivalent to the half (half-FV) or full (full-FV) daily levels recommended for humans by the Dietary Guidelines for Americans (DGA). Pigs were fed a 1) grower diet alone (negative control), 2) grower diet and orally treated with 4% DSS for 10 days to induce colitis (positive control), 3) half-FV diet treated with 4% DSS or 4) full-FV diet treated with 4% DSS. Pigs were monitored for the development of clinical signs of colitis. Proximal colon (PC) contents and mucosa (PCM) were collected for gut metagenome, tissue transcriptome and histopathological analysis. Results: Pigs fed the full-FV diet did not exhibit diarrhea, showed less fecal occult blood (FOB), PCM crypt hyperplasia but with no differential expressed genes (DEG) or changes in PC microbiome diversity (p < 0.05). Pigs within the half-FV group exhibited increased group FOB and DEG associated with tissue remodeling, crypt and goblet cell hyperplasia in the PCM and no changes in PC microbiome diversity and two pigs exhibiting diarrhea (p < 0.05). Pigs within the DSS positive control group exhibited a reduced DEG involved with intestinal immune response and PC microbiome diversity with altered metagenome, increased group PCM erosion and FOB with persistent diarrhea in one pig (p < 0.05) Conclusions: Overall, our results showed that pigs fed a three-week full-FV supplemented diet, were resistant to DSS-induced colitis with a differential dose-dependent protective effect on host intestinal tissue and gut metagenome when exposed to an inflammatory challenge.