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

Objective: Overnutrition is the principal cause of insulin resistance (IR) and dyslipidemia, which drive non-alcoholic 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 alpha-defensin-5 (HD-5), and have shown repressed secretory capacity in human obesity.

Methods: Mice were fed a 60%HFD for 13 weeks and subsequently treated with physiologically relevant amounts of HD-5 (0,001%) or vehicle for 10 weeks. 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. Fresh fecal samples were collected immediately before and after intervention. Small intestine samples were harvested at necropsy. Plasma and liver lipid and protein profiles were determined by biochemical analyses.

Results: 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, whichcorrelated inversely with metabolic dysfunctions.

Conclusion: 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.