High-fat high-calorie-fed wild-type mice exhibit a gut microbiota dysbiosis and an increased permeability of the intestinal epithelium partly due to a lowered expression of the tight junction proteins but also to a decrease of the integrity of the mucus layer in relation to endoplasmic reticulum stress. This intestinal hyperpermeability facilitates the crossing of LPS leading to low-grade inflammation observed in obese individual. Conversely, we evidenced that fat-1 mice are protected against dysbiosis and intestinal hyperpermeability by a higher expression of tight junction proteins and an unaltered colonic mucus layer, which might be explained at least by the fact that a prevention of the reticulum stress and a higher proportion of Akkermansia muciniphila were observed in fat-1 mice which display a lean phenotype. In addition, the ceacal microbiome transplantation of fat-1 mice to wild-type mice totally prevented high-fat-induced alteration of the colonic mucus layer and endoplasmic reticulum stress in colonic tissues. FFA: free fatty acids; HF/HS: high fat/high sucrose; LPS: lipopolysaccharides; MUC2: mucin 2; OCLN: occludine; ER: endoplasmic reticulum; UPR: unfolded protein response; WT: wild-type; ZO-1: zonula occludens-1.