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.
Highlights
Alcohol consumption is a major global health burden and key etiological factor in the development of alcohol-associated liver disease (ALD), which is responsible for nearly half of liver cirrhosis deaths (Seitz et al, 2018)
To determine the potential mechanisms underlying the beneficial effects of human beta defensin-2 (hBD-2) on EtOH-associated liver injury, we first analyzed the immunomodulatory effects of hBD-2, focusing on well-known cytokines that play an important role in ALD pathogenesis and innate immunity
We demonstrated the beneficial effects of hBD-2 in an experimental model of chronic ALD. hBD-2, administered orally on each of the last 7 days of the chronic EtOH feeding, attenuated liver injury as evidenced by a significant reduction in ALT levels
Summary
Alcohol consumption is a major global health burden and key etiological factor in the development of alcohol-associated liver disease (ALD), which is responsible for nearly half of liver cirrhosis deaths (Seitz et al, 2018). In addition to the liver, alcohol induces alterations in other organs, such as the intestine In both the liver and the gut, alcohol consumption has marked immunomodulatory effects on innate and adaptive immunity, including alterations in the antiinflammatory response, increased pro-inflammatory cytokine production, and impaired antigen presentation and T cell responses (Szabo and Saha, 2015). Alcohol exposure can impair gut barrier function (Kirpich et al, 2013; Bishehsari et al, 2017; Warner et al, 2019), alter intestinal anti-microbial defense (Szabo and Saha, 2015), and induce changes in the gut microbiota composition and function, contributing to alcohol-induced liver pathology via the gut-liver axis (Engen et al, 2015; Sarin et al, 2019). The host gut microbiota is a target of alcohol toxicity and may modulate susceptibility to alcohol-associated liver and intestinal damage (Llopis et al, 2016; Ferrere et al, 2017)
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