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RegIIIβ and RegIIIγ are antimicrobial peptides expressed in intestinal epithelial cells. Expression of these peptides is reportedly decreased by high-fat diet (HFD) and increased by indigestible oligosaccharides in mice. Clearly, these dietary regimens change the structure of intestinal microbiota. We employed an intestinal microbiota transplantation (IMT) to test whether diet-induced changes in the expression of these peptides are mediated by gut microbiota. C57BL/6J mice were fed either a normal-fat diet (NFD), a HFD, or a NFD supplemented with or without 1-kestose (KES), an indigestible oligosaccharide. Ileal RegIIIβ and RegIIIγ mRNA levels were lower in mice receiving IMT from HFD-fed mice than in those receiving NFD-fed mice and higher in mice receiving IMT from KES-supplemented mice than in those receiving the mice without KES supplementation. Western blot analysis showed that serum RegIIIβ levels changed in parallel with the ileal mRNA levels. We propose that HFD- and KES-induced changes in the ileal RegIIIβ and RegIIIγ expression and in the circulating RegIIIβ levels are mediated, at least in part, by intestinal microbiota. • How diet affects intestinal expression of antimicrobial RegIII peptides is unclear. • Mice receiving microbiota transplantation reproduced diet-induced changes. • Previously known regulator IL-22 is not involved in the diet-induced changes. • We propose that diet-induced changes are mediated by intestinal microbiota. [ABSTRACT FROM AUTHOR]

Summary The bactericidal lectin RegIIIβ is inducibly produced by intestinal epithelial cells as a defense against infection by enteropathogens. In the gut lumen, RegIIIβ kills not only certain enteropathogens, but also some commensal bacteria; thus, RegIIIβ is also thought to be an innate immune effector shaping microbiota composition and establishing intestinal homeostasis. Using the streptomycin mouse model for Salmonella colitis, we show that RegIIIβ can promote sustained gut colonization of Salmonella Typhimurium and prolong enteropathy. RegIIIβ expression was associated with suppression of Bacteroides spp. in the gut lumen, prolonged disease-associated alterations in colonic metabolism, and reduced luminal vitamin B6 levels. Supplementation with Bacteroides spp. or vitamin B6 accelerated pathogen clearance from the gut and remission of enteropathy. Our findings indicate that interventions at the level of RegIIIβ and supplementation with Bacteroides spp. or vitamin B6 might open new avenues for therapeutic intervention in the context of Salmonella colitis. [ABSTRACT FROM AUTHOR]

In the inflamed gut, the bactericidal lectin RegIIIβ is massively produced by intestinal mucosa. RegIIIβ binds peptidoglycan and lipid A respectively, and thus can kill certain Gram-positive and Gram-negative bacteria, including the gut commensal microbiota and enteropathogenic bacteria. Considering the expression pattern and bactericidal activity, RegIIIβ is believed to be a host defense factor for protecting against the infection with enteropathogenic bacteria. However, it was poorly understood how RegIIIβ recognizes the target bacteria and kill them, and how RegIIIβ plays role(s) in infectious diarrhea. Therefore, our recent study has focused on RegIIIβ-target recognition, killing of Gram-negative bacteria, and host protective functions of RegIIIβ for infectious diarrhea inflicted by Salmonella Typhimurium. Here, we discuss novel insights into the protective role of RegIIIβ in infectious diarrhea, and propose avenues towards novel therapeutic interventions for Salmonella diarrhea.