Human Paneth cell α-defensin-5 treatment reverses dyslipidemia and improves glucoregulatory capacity in diet-induced obese mice

Abstract

Overnutrition is the principal cause of insulin resistance (IR) and dyslipidemia, which drive nonalcoholic fatty liver disease (NAFLD). Overnutrition is further linked to disrupted bowel function, microbiota alterations, and change of function in gut-lining cell populations, including Paneth cells of the small intestine. Paneth cells regulate microbial diversity through expression of antimicrobial peptides, particularly human α-defensin-5 (HD-5), and have shown repressed secretory capacity in human obesity. Mice were fed a 60% high-fat diet for 13 wk and subsequently treated with physiologically relevant amounts of HD-5 (0.001%) or vehicle for 10 wk. The glucoregulatory capacity was determined by glucose tolerance tests and measurements of corresponding insulin concentrations both before and during intervention. Gut microbiome composition was examined by 16S rRNA gene amplicon sequencing. HD-5-treated mice exhibited improved glucoregulatory capacity along with an ameliorated plasma and liver lipid profile. This was accompanied by specific decrease in jejunal inflammation and gut microbiota alterations including increased Bifidobacterium abundances, which correlated inversely with metabolic dysfunctions. This study provides proof of concept for the use of human defensins to improve host metabolism by mitigating the triad cluster of dyslipidemia, IR, and NAFLD.

Lysates ofMethylococcus capsulatusBath induce a lean-like microbiota, intestinal FoxP3+RORγt+IL-17+Tregs and improve metabolism

“…16S rRNA gene amplification, library preparation and sequencing were performed as previously described 22 . Initial data processing was performed as described elsewhere 23 . Data was rarefied to 23,107 reads per sample.…”

Does an Apple a Day Also Keep the Microbes Away? The Interplay Between Diet, Microbiota, and Host Defense Peptides at the Intestinal Mucosal Barrier

“…However, as discussed above, the overall impact of HDPs on gut microbiota community structure is expected to be reflected by the potential antimicrobial effect against gut commensals. And indeed, administration of HD5 increased Bifidobacterium relative abundance (17), while transgenic expression of HD5 on top of the own mouse antimicrobial arsenal led to increased relative abundance of Bacteroidetes (9). This suggests that defensins can promote the growth of selected microbial taxa by specifically eliminating other microbes.…”

“…Interestingly, a fragment produced after proteolysis of HD5 (HD5 1−9 ), shifted the fecal microbiota composition and influenced the microbial diversity in the small intestine, specifically increasing Akkermansia and a member of the Ruminococcaceae family and decreasing Intestimonas from the Clostridiaceae family (154). Furthermore, administration of HD5 in a murine model of diet-induced obesity reversed dyslipidemia and improved the overall glucose regulation (17). The latter was partly attributed to HD5-induced changes in the fecal microbiota, namely an increase in Bifidobacterium and Alloprevotella abundance, that correlated with improved metabolic parameters (17).…”

“…Furthermore, administration of HD5 in a murine model of diet-induced obesity reversed dyslipidemia and improved the overall glucose regulation (17). The latter was partly attributed to HD5-induced changes in the fecal microbiota, namely an increase in Bifidobacterium and Alloprevotella abundance, that correlated with improved metabolic parameters (17). However, the effect on microbiota composition in the small intestine was less marked.…”

“…On the contrary, much less is known about how HDPs affect commensal bacteria, and several studies suggest that antimicrobial activity against the resident microbiota is comparably low or even absent (14)(15)(16)). Yet, two independent studies demonstrated that transgenic intestinal expression or oral application of human alpha-defensin 5 (HD5) in mice could shape the intestinal microbiota composition in vivo (9,17). It is therefore possible that previous activity testings of HDPs in in vitro assays did not appropriately reflect the in vivo conditions, as already demonstrated for human beta-defensins 1 (HBD1) and the Paneth cell-derived human alpha defensin 6 (HD6), which gained activity under adjusted conditions that reflected the intestinal microenvironment (18,19).…”