Abstract
Family with sequence similarity 96 member A (FAM96A) is an evolutionarily conserved intracellular protein that is involved in the maturation of the Fe/S protein, iron regulatory protein 1 (IRP1), and the mitochondria-related apoptosis of gastrointestinal stromal tumor cells. In this study, we used a mouse model of chemically induced colitis to investigate the physiological role of FAM96A in intestinal homeostasis and inflammation. At baseline, colons from Fam96a−/− mice exhibited microbial dysbiosis, dysregulated epithelial cell turnover, an increased number of goblet cells, and disordered tight junctions with functional deficits affecting intestinal permeability. After cohousing, the differences between wild-type and Fam96a−/− colons were abrogated, suggesting that FAM96A affects colonic epithelial cells in a microbiota-dependent manner. Fam96a deficiency in mice resulted in increased susceptibility to dextran sulfate sodium (DSS)-induced colitis. Importantly, the colitogenic activity of Fam96a−/− intestinal microbiota was transferable to wild-type littermate mice via fecal microbial transplantation (FMT), leading to exacerbation of DSS-induced colitis. Taken together, our data indicate that FAM96A helps to maintain colonic homeostasis and protect against DSS-induced colitis by preventing gut microbial dysbiosis. This study used gene knockout animals to help to understand the in vivo effects of the Fam96a gene for the first time and provides new evidence regarding host–microbiota interactions.
Highlights
Inflammatory bowel disease (IBD) is a collection of chronic remittent inflammatory disorders that are associated with a variety of factors such as host genetics, the environment, and intestinal microbes (Wlodarska et al, 2015)
The commensal microbiota is a key part of the intestinal barrier system, and microbial dysbiosis often leads to increased pathological responses in the gut (Thomas, 2018)
Real-time PCR revealed increased levels of inflammation-promoting bacteria in Fam96a−/− feces, such as Helicobacter and Clostridium perfringens, and a decreased level of the probiotic Lactobacillus/Lactococcus. This indicates that Fam96a−/− mice may harbor pro-inflammatory gut microbiota profiles. 16S rDNA sequencing indicated an overall microbial dysbiosis in the Fam96a−/− gut
Summary
Inflammatory bowel disease (IBD) is a collection of chronic remittent inflammatory disorders that are associated with a variety of factors such as host genetics, the environment, and intestinal microbes (Wlodarska et al, 2015). IBD is prevalent in Western countries, affecting approximately 0.5% of the total population (Molodecky et al, 2012). It mainly consists of two clinically defined chronic disorders: Crohn’s disease (CD) and ulcerative colitis (UC). Patients with IBD have a higher risk of colon cancer; about 7–8% of IBD patients eventually develop colon cancer within 20 years (Gillen et al, 1994). There are several animal models that help to understand IBD pathogenesis and to develop novel therapeutic approaches. Dextran sulfate sodium (DSS) administration is a commonly used method, which can induce reproducible acute colitis characterized by bloody diarrhea, ulcerations, and leukocyte infiltration (Perše and Cerar, 2012)
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