Fungal lysozyme leverages the gut microbiota to curb DSS-induced colitis

Abstract

Colitis is characterized by colonic inflammation and impaired gut health. Both features aggravate obesity and insulin resistance. Host defense peptides (HDPs) are key regulators of gut homeostasis and generally malfunctioning in above-mentioned conditions. We aimed here to improve bowel function in diet-induced obesity and chemically induced colitis through daily oral administration of lysozyme, a well-characterized HDP, derived from Acremonium alcalophilum . C57BL6/J mice were fed either low-fat reference diet or HFD ± daily gavage of lysozyme for 12 weeks, followed by metabolic assessment and evaluation of colonic microbiota encroachment. To further evaluate the efficacy of intestinal inflammation, we next supplemented chow-fed BALB/c mice with lysozyme during Dextran Sulfate Sodium (DSS)-induced colitis in either conventional or microbiota-depleted mice. We assessed longitudinal microbiome alterations by 16S amplicon sequencing in both models. Lysozyme dose-dependently alleviated intestinal inflammation in DSS-challenged mice and further protected against HFD-induced microbiota encroachment and fasting hyperinsulinemia. Observed improvements of intestinal health relied on a complex gut flora, with the observation that microbiota depletion abrogated lysozyme’s capacity to mitigate DSS-induced colitis. Akkermansia muciniphila associated with impaired gut health in both models, a trajectory that was mitigated by lysozyme administration. In agreement with this notion, PICRUSt2 analysis revealed specific pathways consistently affected by lysozyme administration, independent of vivarium, disease model and mouse strain. Taking together, lysozyme leveraged the gut microbiota to curb DSS-induced inflammation, alleviated HFD-induced gastrointestinal disturbances and lowered fasting insulin levels in obese mice. Collectively, these data present A. alcalophilum- derived lysozyme as a promising candidate to enhance gut health.

Human Beta Defensin 2 Ameliorated Alcohol-Associated Liver Disease in Mice

“…However, microbiota-deficient mice, e.g., germ free mice, have altered immunity and ethanol metabolism which confound the protective effects of hBD-2 (Chen et al, 2015). A previous report regarding the use of another AMP, fungal lysozyme, showed that in an experimental colitis model the presence of gut microbiota was required for the therapeutic effects of the treatment (Larsen et al, 2021), suggesting that the effects of hBD-2 may similarly be microbiotadependent.…”

Sex-Biased Immune Responses to Antibiotics during Anti-PD-L1 Treatment in Mice with Colon Cancer

“…Olu et al confirmed that oral administration of Akkermansia muciniphila strain BAA-835 considerably ameliorated colitis by modulating intestinal microecology [ 45 ]. Larsen et al reported that lysozyme leveraged gut microbiota to inhibit DSS-induced colitis [ 46 ]. These findings indicate that restoring gut microbiota is conducive to alleviating colitis [ 47 ].…”

Rewiring host–microbe interactions and barrier function during gastrointestinal inflammation

“…Similarly, both genetic and diet-induced Paneth cell dysfunctions promote increased inflammatory reactions towards mutualistic bacteria, enhancing bacterial translocation and mucosal inflammation [ 101 , 109 , 112 , 113 ]. Further supporting the relevance of HDPs in maintaining and even re-establishing homeostasis, oral administration of fungal lysozyme enhances the bacterial lysis zone near the epithelium in HFD-fed mice, thereby shielding the mucosal immune system from microbial exposure [ 114 ]. Intriguingly, microbial lysis is not exclusively beneficial and the phenotypic trait of mammalian lysozyme activity is vastly influenced by the inflammatory tone and anatomical compartment.…”

“…Fungal lysozyme appears capable of leveraging the gut microbiota to dose-dependently alleviate experimental colitis. Diminished colitis was followed by increased colonic R. gnavus abundances in two genotypes, both sexes, and across three geographically and inter-continent separated facilities, pointing towards a markedly different microbiota imprinting ability of GH25 family lysozymes compared to GH22 family lysozymes [ 114 ].…”