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Background and Aims Triggering receptor expressed on myeloid cells-1 [TREM-1] is known to amplify inflammation in several diseases. Autophagy and endoplasmic reticulum [ER] stress, which activate the unfolded protein response [UPR], are closely linked and defects in these pathways contribute to the pathogenesis of inflammatory bowel disease [IBD]. Both autophagy and UPR are deeply involved in host-microbiota interactions for the clearance of intracellular pathogens, thus contributing to dysbiosis. We investigated whether inhibition of TREM-1 would prevent aberrant inflammation by modulating autophagy and ER stress and preventing dysbiosis. Methods An experimental mouse model of colitis was established by dextran sulphate sodium treatment. TREM-1 was inhibited, either pharmacologically by LR12 peptide or genetically with Trem-1 knock-out [KO] mice. Colon tissues and faecal pellets of control and colitic mice were used. Levels of macroautophagy, chaperone-mediated autophagy [CMA], and UPR proteins were evaluated by western blotting. The composition of the intestinal microbiota was assessed by MiSeq sequencing in both LR12-treated and KO animals. Results We confirmed that inhibition of TREM-1 attenuates the severity of colitis clinically, endoscopically and histologically. We observed an increase in macroautophagy [ATG1/ULK-1, ATG13, ATG5, ATG16L1, and MAP1LC3-I/II] and in CMA [HSPA8 and HSP90AA1], whereas there was a decrease in the UPR [PERK, IRE-1α, and ATF-6α] protein expression levels in TREM-1 inhibited colitic mice. TREM-1 inhibition prevented dysbiosis. Conclusions TREM-1 may represent a novel drug target for the treatment of IBD, by modulating autophagy activity and ER stress. [ABSTRACT FROM AUTHOR]

In genetically susceptible individuals, an altered mucosal immune response against some commensal bacteria of the gut ecosystem appears to be the principal mechanism leading to intestinal lesions in inflammatory bowel disease (IBD). The information currently available does not provide an exact explanation about the origin of this important dysfunction of the interaction between host and commensal bacteria, but an altered microbial composition has been detected in the gut ecosystem of patients with Crohn's disease or ulcerative colitis. Prebiotics are food ingredients not digested nor absorbed in the upper intestinal tract that are fermented by intestinal bacteria in a selective way promoting changes in the gut ecosystem. Experimental and human studies have shown that inulin and oligofructose stimulate saccharolysis in the colonic lumen and favour the growth of indigenous lactobacilli and bifidobacteria. These effects are associated with reduced mucosal inflammation in animal models of IBD. Strong experimental evidence supports the hypothesis that inulin and oligofructose can offer an opportunity to prevent or mitigate intestinal inflammatory lesions in human Crohn's disease, ulcerative colitis, and pouchitis. Encouraging results have been obtained in preliminary clinical trials. [ABSTRACT FROM PUBLISHER]