Microbiome as a therapeutic target in alcohol-related liver disease

Sarin, Shiv Kumar; Pande, Apurva; Schnabl, Bernd

doi:10.1016/j.jhep.2018.10.019

Cited by 197 publications

(182 citation statements)

References 132 publications

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“…Growing evidence suggests a key role of excessive alcohol use in changing the composition of the gut microbiota. 26,27 In the present study, we describe the loss of Akkermansia and the excess of This detrimental effect of AUD on the intestinal environment was confirmed by our study. We observed high serum levels of LPS and pro-inflammatory cytokines/chemokines in the AUD patients compared to the control group as well as a decreased microbial alpha diversity with the prevalence of potentially pathogenic bacteria, such as Enterobacteriaceae, a finding consistent with previous works in human and animal models.…”

Section: Discussionsupporting

confidence: 84%

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Gut microbiota compositional and functional fingerprint in patients with alcohol use disorder and alcohol‐associated liver disease

Addolorato

Ponziani

Dionisi

et al. 2020

Liver International

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Background & aims Alcohol use disorder (AUD) represents the most common cause of liver disease. The gut microbiota plays a critical role in the progression of alcohol‐related liver damage. Aim of this study was to characterize the gut microbial composition and function in AUD patients with alcohol‐associated liver disease (AALD). Methods This study included 36 AUD patients (14 with cirrhosis) who were active drinkers and an equal number of matched controls. Stool microbial composition, serum levels of lipopolysaccharide, cytokines/chemokines and gut microbiota functional profile were assessed. Results AUD patients had a decreased microbial alpha diversity as compared to controls (0.092 vs 0.130, P = .047) and a specific gut microbial signature. The reduction of Akkermansia and the increase in Bacteroides were able to identify AUD patients with an accuracy of 93.4%. Serum levels of lipopolysaccharide (4.91 vs 2.43, P = .009) and pro‐inflammatory mediators (tumour necrosis factor alpha 60.85 vs 15.08, P = .001; interleukin [IL] 1beta 4.43 vs 1.72, P = .0001; monocyte chemoattractant protein 1 225.22 vs 16.43, P = .006; IL6 1.87 vs 1.23, P = .008) were significantly increased in AUD patients compared to controls and in cirrhotic patients compared to non‐cirrhotic ones (IL6 3.74 vs 1.39, P = .019; IL8 57.60 vs 6.53, P = .004). The AUD‐associated gut microbiota showed an increased expression of gamma‐aminobutyric acid (GABA) metabolic pathways and energy metabolism. Conclusions AUD patients present a specific gut microbial fingerprint, associated with increased endotoxaemia, systemic inflammatory status and functional alterations that may be involved in the progression of the AALD and in the pathogenesis of AUD.

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Section: Discussionsupporting

confidence: 84%

“…Growing evidence suggests a key role of excessive alcohol use in changing the composition of the gut microbiota . In the present study, we describe the loss of Akkermansia and the excess of Bacteroides as the compositional signature of the human gut microbiota in patients with AUD.…”

Section: Discussionmentioning

confidence: 70%

Gut microbiota compositional and functional fingerprint in patients with alcohol use disorder and alcohol‐associated liver disease

Addolorato

Ponziani

Dionisi

et al. 2020

Liver International

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“…Wei Zhong, 1,2 Xiaoyuan Wei, 3 Liuyi Hao, 1 Tai-Du Lin, 1,4 Ruichao Yue, 1 Xinguo Sun, 1 Wei Guo, 1 Haibo Dong, 1 Tianjiao Li, 2 Ali R. Ahmadi, 5 Zhaoli Sun, 5 Qibin Zhang, 1,4 Jiangchao Zhao, 3…”

Section: Paneth Cell Dysfunction Mediates Alcohol-related Steatohepatmentioning

confidence: 99%

“…Translocation of pathogen-associated molecular patterns (PAMPs) (e.g., bacterial endotoxin) from the intestinal tract to the circulation represents a crucial inflammatory signaling that triggers hepatic proinflammatory response and subsequent injury. (2) Accumulating evidence demonstrates that alcoholperturbed gut microbiota composition (dysbiosis) promotes ALD and that treatment with commensal bacterial species, such as Lactobacillus spp. or Akkermansia muciniphila, or antibiotics (Abx) protects against alcohol-induced liver damage.…”

Section: And Zhanxiang Zhou 12mentioning

confidence: 99%

“…or Akkermansia muciniphila, or antibiotics (Abx) protects against alcohol-induced liver damage. (2,3) Early studies reveal that alcohol disrupts the intestinal barrier and increases intestinal permeability, which facilitates the leakage of PAMPs. Emerging data suggest that alcohol-impaired intestinal immune function, such as antimicrobial peptides (AMPs), also influences the development of ALD.…”

Section: And Zhanxiang Zhou 12mentioning

confidence: 99%

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Paneth Cell Dysfunction Mediates Alcohol‐related Steatohepatitis Through Promoting Bacterial Translocation in Mice: Role of Zinc Deficiency

Zhong

Wei²,

Hao

et al. 2020

Hepatology

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Background and Aims Microbial dysbiosis is associated with alcohol‐related hepatitis (AH), with the mechanisms yet to be elucidated. The present study aimed to determine the effects of alcohol and zinc deficiency on Paneth cell (PC) antimicrobial peptides, α‐defensins, and to define the link between PC dysfunction and AH. Approach and Results Translocation of pathogen‐associated molecular patterns (PAMPs) was determined in patients with severe AH and in a mouse model of alcoholic steatohepatitis. Microbial composition and PC function were examined in mice. The link between α‐defensin dysfunction and AH was investigated in α‐defensin‐deficient mice. Synthetic human α‐defensin 5 (HD5) was orally given to alcohol‐fed mice to test the therapeutic potential. The role of zinc deficiency in α‐defensin was evaluated in acute and chronic mouse models of zinc deprivation. Hepatic inflammation was associated with PAMP translocation and lipocalin‐2 (LCN2) and chemokine (C‐X‐C motif) ligand 1 (CXCL1) elevation in patients with AH. Antibiotic treatment, lipopolysaccharide injection to mice, and in vitro experiments showed that PAMPs, but not alcohol, directly induced LCN2 and CXCL1. Chronic alcohol feeding caused systemic dysbiosis and PC α‐defensin reduction in mice. Knockout of functional α‐defensins synergistically affected alcohol‐perturbed bacterial composition and the gut barrier and exaggerated PAMP translocation and liver damage. Administration of HD5 effectively altered cecal microbial composition, especially increased Akkermansia muciniphila, and reversed the alcohol‐induced deleterious effects. Zinc‐regulated PC homeostasis and α‐defensins function at multiple levels, and dietary zinc deficiency exaggerated the deleterious effect of alcohol on PC bactericidal activity. Conclusions Taken together, the study suggests that alcohol‐induced PC α‐defensin dysfunction is mediated by zinc deficiency and involved in the pathogenesis of AH. HD5 administration may represent a promising therapeutic approach for treating AH.

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A Randomized Clinical Trial of Fecal Microbiota Transplant for Alcohol Use Disorder

et al. 2021

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BaCKgRoUND aND aIMS: Alcohol use disorder (AUD) is associated with microbial alterations that worsen with cirrhosis. Fecal microbiota transplant (FMT) could be a promising approach.appRoaCH aND ReSUltS: In this phase 1, doubleblind, randomized clinical trial, patients with AUD-related cirrhosis with problem drinking (AUDIT-10 > 8) were randomized 1:1 into receiving one placebo or FMT enema from a donor enriched in Lachnospiraceae and Ruminococcaceae. Six-month safety was the primary outcome. Alcohol craving questionnaire, alcohol consumption (urinary ethylglucuronide/creatinine), quality of life, cognition, serum IL-6 and lipopolysaccharide-binding protein, plasma/stool short-chain fatty acids (SCFAs), and stool microbiota were tested at baseline and day 15. A 6-month follow-up with serious adverse event (SAE) analysis was performed. Twenty patients with AUD-related cirrhosis (65 ± 6.4 years, all men, Model for End-Stage Liver Disease 8.9 ± 2.7) with similar demographics, cirrhosis, and AUD severity were included. Craving reduced significantly in 90% of FMT versus 30% in placebo at day 15 (P = 0.02) with lower urinary ethylglucuronide/ creatinine (P = 0.03) and improved cognition and psychosocial quality of life. There was reduction in serum IL-6 and lipopolysaccharide-binding protein and increased butyrate/ isobutyrate compared with baseline in FMT but not placebo. Microbial diversity increased with higher Ruminococcaceae and other SCFAs, producing taxa following FMT but not placebo, which were linked with SCFA levels. At 6 months, patients with any SAEs (8 vs. 2, P = 0.02), AUD-related SAEs (7 vs. 1, P = 0.02), and SAEs/patient (median [interquartile range], 1.5 [1.25] vs. 0 [0.25] in FMT, P = 0.02) were higher in placebo versus FMT. CoNClUSIoNS:This phase 1 trial shows that FMT is safe and associated with short-term reduction in alcohol craving and consumption with favorable microbial changes versus placebo in patients with alcohol-associated cirrhosis with alcohol misuse. There was also a reduction in AUD-related events over 6 months in patients assigned to FMT. (Hepatology 2021;73:1688-1700.A lcohol use disorder (AUD) and alcoholassociated cirrhosis are major causes of morbidity and mortality. (1) Continued alcohol misuse in the setting of end-organ damage, such as cirrhosis, can hasten disease progression. Therefore, therapies that encourage alcohol abstinence or reduce alcohol misuse are relevant. Pharmaco-therapies for craving in alcohol-associated cirrhosis have yielded partial success and focus largely on neuromodulation. (2) AUD is associated with major changes in the gut-brain axis, which is worsened with the occurrence of cirrhosis. (3) In addition, other studies

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Microbiome as a therapeutic target in alcohol-related liver disease

Cited by 197 publications

References 132 publications

Gut microbiota compositional and functional fingerprint in patients with alcohol use disorder and alcohol‐associated liver disease

Gut microbiota compositional and functional fingerprint in patients with alcohol use disorder and alcohol‐associated liver disease

Paneth Cell Dysfunction Mediates Alcohol‐related Steatohepatitis Through Promoting Bacterial Translocation in Mice: Role of Zinc Deficiency

A Randomized Clinical Trial of Fecal Microbiota Transplant for Alcohol Use Disorder

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