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

Abstract

Alcohol-associated liver disease (ALD) is a prevalent liver disorder and significant global healthcare burden with limited effective therapeutic options. The gut-liver axis is a critical factor contributing to susceptibility to liver injury due to alcohol consumption. In the current study, we tested whether human beta defensin-2 (hBD-2), a small anti-microbial peptide, attenuates experimental chronic ALD. Male C57Bl/6J mice were fed an ethanol (EtOH)-containing diet for 6 weeks with daily administration of hBD-2 (1.2 mg/kg) by oral gavage during the final week. Two independent cohorts of mice with distinct baseline gut microbiota were used. Oral hBD-2 administration attenuated liver injury in both cohorts as determined by decreased plasma ALT activity. Notably, the degree of hBD-2-mediated reduction of EtOH-associated liver steatosis, hepatocellular death, and inflammation was different between cohorts, suggesting microbiota-specific mechanisms underlying the beneficial effects of hBD-2. Indeed, we observed differential mechanisms of hBD-2 between cohorts, which included an induction of hepatic and small intestinal IL-17A and IL-22, as well as an increase in T regulatory cell abundance in the gut and mesenteric lymph nodes. Lastly, hBD-2 modulated the gut microbiota composition in EtOH-fed mice in both cohorts, with significant decreases in multiple genera including Barnesiella, Parabacteroides, Akkermansia, and Alistipes, as well as altered abundance of several bacteria within the family Ruminococcaceae. Collectively, our results demonstrated a protective effect of hBD-2 in experimental ALD associated with immunomodulation and microbiota alteration. These data suggest that while the beneficial effects of hBD-2 on liver injury are uniform, the specific mechanisms of action are associated with baseline microbiota.

Human α-Defensin 51–9 and Human β-Defensin 2 Improve Metabolic Parameters and Gut Barrier Function in Mice Fed a Western-Style Diet

“…In vitro, hBD-2 has been found to reduce proinflammatory cytokines, such as interleukin 1-β (IL1-β) and TNF-α (TNF) in LPS-treated human peripheral blood mononuclear cells (PBMCs) [ 38 ]. Furthermore, oral administration of hBD-2 reduced both alcohol-induced liver injury and graft-versus-host disease, in numerous mouse strains, by improving barrier function and thereby modulating host–microbe interactions and immunoreactivity [ 40 , 41 ].…”

Akkermansia muciniphila and Alcohol‐Related Liver Diseases. A Systematic Review

“…They also reported an increased abundance of A. muciniphila in the absence of HIF‐a and suggest further studies to understand the relationship between Akkermansia levels and intestinal integrity in this context. [ 104 ] Similarly, Warner et al [ 3 ] studied the effect of the human beta‐defensin‐2, a small antimicrobial peptide, in male mice fed with a diet containing alcohol. They reported an amelioration of ALDs in mice by administration of the human beta‐defensin‐2, with a significant decrease in Akkermansia , associated with gut and liver immunomodulation.…”

“…They reported an amelioration of ALDs in mice by administration of the human beta‐defensin‐2, with a significant decrease in Akkermansia , associated with gut and liver immunomodulation. [ 3 ] Interestingly, ethanol consumption has been described as protective in some autoimmune diseases. For example, male mice fed moderate‐dose alcohol experienced significantly greater disease remission in a model system of autoimmune neuroinflammation, compared to alcohol‐fed females and control‐fed animals.…”

“…Several mechanisms may account for these reactions: translocation of gut‐derived endotoxins, up‐regulation of toll like receptor (TLR) expression, or production of chemokines/cytokines. [ 3 ] Altogether, these changes enhance responses of immune cells, leading to inflammation. Oxidative stress was also reported as a trigger of ethanol‐induced immune reactions.…”

Innate immunity and nonalcoholic fatty liver disease

“…The ability of hβD-2 to ameliorate liver inflammation by modification of gut microbiota requires further evidence. However, oral administration of hβD-2 in mice [ 34 ] attenuates the increase of certain microbial genera that comprise part of the typical gut microbiota signature in NASH and steatosis, while favoring a shift towards a more diverse phenotype, similar to healthy controls.…”