hPepT1 is an apical transporter expressed in intestinal epithelial cells and responsible for the uptake of a broad range of di/tri-peptides. Colonic hPepT1 is over-expressed in patients with inflammatory bowel disease (IBD) and colorectal cancer. Our previous studies have shown that colonic hPepT1 overexpression exacerbate colitis in mice, while PepT1 deficiency is sufficient to protect mice from DSS-induced colitis and colitis-associated cancer. The microbial community living in the gastrointestinal tract, referred as the gut microbiota, is the most abundant and diverse niche of the human body. Increasing evidences show that the disruption of this symbiosis between the intestine and the gut microbiota may lead to pathologies such as IBD. With intestinal microbiota being the key player in intestinal inflammation, our aim is to investigate the role played by the microbiota and its interaction with the host mucosa in mediating the protection observed in PepT1-KO.Methods:
Microbiota composition and diversity and mucus layer were analyzed in PepT1-KO and WT mice. In order to investigate any functional role played by the microbiota, and in order to prevent any genotype-driven differences, microbiota from PepT1-KO and matched WT animals were transferred to WT germ-free mice, which were the recipient mice subsequently subjected to DSS.Results:
We observed an altered microbiota composition in PepT1-KO mice compared to WT mice, characterized by an increased diversity and species richness, a decreased pro-inflammatory potential, and a distant localization from the monolayer epithelium. Microbiota from PepT1-KO and matched WT animals were transferred to WT germ-free recipient in order to analyze the functional role played by such altered microbiota composition. Colitis was induced by DSS in the recipient mice. We demonstrated that, compared to WT-microbiota, PepT1-KO microbiota was sufficient to protect recipient animals from colitis, as attested by various parameters (spleen weight, colon weight, colon length, MPO, and fecal LCN-2). We also observed that mice receiving PepT1-KO microbiota harbor a lower microbiota-associated pro-inflammatory potential. We are currently investigating whether the benefits ensued by altered microbiota composition can be protective against colitis-associated cancer, as well as testing the hypothesis that a greater microbiota-dependent production of mucus and anti-bacterial peptides in PepT1-KO might explain the protective phenotype observed in these animals.Conclusions:
This study demonstrates that PepT1-KO mice are protected against colitis in a microbiota sufficient manner, and identifying microbiota members that drive such protection might be a potent therapeutic approach for the treatment of IBD.