The common p.Ile291Val variant of ERLIN1 enhances TM6SF2 function and is associated with protection against MASLD.

BACKGROUND: The ERLIN1 p.Ile291Val single-nucleotide polymorphism (rs2862954) is associated with protection from steatotic liver disease (SLD), but effects of this variant on metabolic phenotypes remain uncertain. METHODS: Metabolic phenotypes and outcomes associated with ERLIN1 p.Ile291Val were analyzed by using a genome-first approach in the UK Biobank (UKB), Penn Medicine BioBank (PMBB), and All of Us cohort. FINDINGS: ERLIN1 p.Ile291Val carriers exhibited significantly lower serum levels of alanine aminotransferase and aspartate aminotransferase as well as higher levels of triglycerides, low-density lipoprotein cholesterol, Apolipoprotein B, high-density lipoprotein cholesterol, and Apolipoprotein A1 in UKB, and these values were affected by ERLIN1 p.Ile291Val in an allele-dose-dependent manner. Homozygous ERLIN1 p.Ile291Val carriers had a significantly reduced risk of developing metabolic dysfunction-associated SLD (MASLD, adjusted odds ratio [aOR] = 0.92, 95% confidence interval [CI], 0.88-0.96). The protective effect of this variant was enhanced in patients with alcoholic liver disease. Our results were replicated in PMBB and the All of Us cohort. Strikingly, the protective effects of ERLIN1 p.Ile291Val were not apparent in individuals carrying the TM6SF2 p.Glu167Lys variant associated with increased risk of SLD. We analyzed the effects of predicted loss-of-function ERLIN1 variants and found that they had opposite effects, namely reduced plasma lipids, suggesting that ERLIN1 p.Ile291Val may be a gain-of-function variant. CONCLUSION: Our study contributes to a better understanding of ERLIN1 by investigating a coding variant that has emerged as a potential gain-of-function mutation with protective effects against MASLD development.

Microbiota modulation by dietary oat beta-glucan prevents steatotic liver disease progression.

Background & Aims: Changes in gut microbiota in metabolic dysfunction-associated steatotic liver disease (MASLD) are important drivers of disease progression towards fibrosis. Therefore, reversing microbial alterations could ameliorate MASLD progression. Oat beta-glucan, a non-digestible polysaccharide, has shown promising therapeutic effects on hyperlipidemia associated with MASLD, but its impact on gut microbiota and most importantly MASLD-related fibrosis remains unknown. Methods: We performed detailed metabolic phenotyping, including assessments of body composition, glucose tolerance, and lipid metabolism, as well as comprehensive characterization of the gut-liver axis in a western-style diet (WSD)-induced model of MASLD and assessed the effect of a beta-glucan intervention on early and advanced liver disease. Gut microbiota were modulated using broad-spectrum antibiotic treatment. Results: Oat beta-glucan supplementation did not affect WSD-induced body weight gain or glucose intolerance and the metabolic phenotype remained largely unaffected. Interestingly, oat beta-glucan dampened MASLD-related inflammation, which was associated with significantly reduced monocyte-derived macrophage infiltration and fibroinflammatory gene expression, as well as strongly reduced fibrosis development. Mechanistically, this protective effect was not mediated by changes in bile acid composition or signaling, but was dependent on gut microbiota and was lost upon broad-spectrum antibiotic treatment. Specifically, oat beta-glucan partially reversed unfavorable changes in gut microbiota, resulting in an expansion of protective taxa, including Ruminococcus, and Lactobacillus followed by reduced translocation of Toll-like receptor ligands. Conclusions: Our findings identify oat beta-glucan as a highly efficacious food supplement that dampens inflammation and fibrosis development in diet-induced MASLD. These results, along with its favorable dietary profile, suggest that it may be a cost-effective and well-tolerated approach to preventing MASLD progression and should be assessed in clinical studies. Impact and Implications: Herein, we investigated the effect of oat beta-glucan on the gut-liver axis and fibrosis development in a mouse model of metabolic dysfunction-associated steatotic liver disease (MASLD). Beta-glucan significantly reduced inflammation and fibrosis in the liver, which was associated with favorable shifts in gut microbiota that protected against bacterial translocation and activation of fibroinflammatory pathways. Together, oat beta-glucan may be a cost-effective and well-tolerated approach to prevent MASLD progression and should be assessed in clinical studies.

Aspirin is associated with a reduced incidence of liver disease in men.

BACKGROUND: The hepatoprotective effects of aspirin have been observed in individuals with viral hepatitis; however, its impact on the general population remains uncertain. Understanding the association between aspirin use and the development of liver diseases is crucial for optimizing preventive strategies. METHODS: We identified individuals with aspirin use in the UK Biobank and the Penn Medicine Biobank, as well as propensity-score-matched controls. Outcome measures included new liver disease development, diagnosed by MRI or "International Classification of Diseases and Related Health Problems" coding, and incidences of gastrointestinal bleeding and ulcers. RESULTS: In the UK Biobank cohort, regular aspirin use was associated with an 11.2% reduction in the risk of developing new liver diseases during the average 11.84 ± 2.01-year follow-up period (HR=0.888, 95% CI = 0.819-0.963; p = 4.1 × 10-3). Notably, the risk of metabolic dysfunction-associated steatotic liver disease (ICD-10 K76.0) and MRI-diagnosed steatosis was significantly lower among aspirin users (HR = 0.882-0.911), whereas no increased risk of gastrointestinal bleeding or ulcers was observed. These findings were replicated in the Penn Medicine Biobank cohort, in which the protective effect of aspirin appeared to be dependent on the duration of intake. The greatest risk reduction for new liver disease development was observed after at least 1 year of aspirin use (HR = 0.569, 95% CI = 0.425-0.762; p = 1.6 × 10-4). Intriguingly, when considering general risk factors, only men exhibited a lower risk of MRI-confirmed or ICD-coded steatosis with aspirin use (HRs = 0.806-0.906), while no significant protective effect of aspirin was observed in females. CONCLUSION: This cohort study demonstrated that regular aspirin use was associated with a reduced risk of liver disease in men without an elevated risk of gastrointestinal bleeding or ulcers. Further investigation is warranted to elucidate potential sex-related differences in the effects of aspirin and to inform tailored preventive strategies for liver diseases.

Omega-3 intake is associated with liver disease protection.

Background: Non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease are among the most common liver diseases worldwide, and there are currently no Food and Drug Administration (FDA)-approved treatments. Recent studies have focused on lifestyle changes to prevent and treat NAFLD. Omega-3 supplementation is associated with improved outcomes in patients with chronic liver disease. However, it is unclear whether Omega-3 supplementation can prevent the development of liver disease, particularly in individuals at an increased (genetic) risk. Methods: In this UK Biobank cohort study, we established a multivariate cox proportional hazards model for the risk of incident liver disease during an 11 year follow up time. We adjusted the model for diabetes, prevalent cardiovascular disorders, socioeconomic status, diet, alcohol consumption, physical activity, medication intake (insulin, biguanides, statins and aspirin), and baseline characteristics. Results: Omega-3 supplementation reduced the risk of incident liver disease (HR = 0.716; 95% CI: 0.639, 0.802; p = 7.6 × 10-9). This protective association was particularly evident for alcoholic liver disease (HR = 0.559; 95% CI: 0.347, 0.833; p = 4.3 × 10-3), liver failure (HR = 0.548; 95% CI: 0.343, 0.875; p = 1.2 × 10-2), and non-alcoholic liver disease (HR = 0.784; 95% CI: 0.650, 0.944; p = 1.0 × 10-2). Interestingly, we were able to replicate the association with reduced risk of NAFLD in a subset with liver MRIs (HR = 0.846; 95% CI: 0.777, 0.921; p = 1.1 × 10-4). In particular, women benefited from Omega-3 supplementation as well as heterozygous allele carriers of the liver-damaging variant PNPLA3 rs738409. Conclusions: Omega-3 supplementation may reduce the incidence of liver disease. Our study highlights the potential of personalized treatment strategies for individuals at risk of metabolic liver disease. Further evaluation in clinical trials is warranted before Omega-3 can be recommended for the prevention of liver disease.

Association of Statin Use With Risk of Liver Disease, Hepatocellular Carcinoma, and Liver-Related Mortality.

Importance: Given the burden of chronic liver disease on the health care system, more information on the hepatoprotective association of statins in the general population is needed. Objective: To examine whether regular statin use is associated with a reduction in liver disease, particularly hepatocellular carcinoma (HCC) and liver-related deaths, in the general population. Design, Setting, and Participants: This cohort study used data from the UK Biobank (UKB) (individuals aged 37-73 years) collected from baseline (2006-2010) to the end of follow-up in May 2021, from the TriNetX cohort (individuals aged 18-90 years) enrolled from baseline (2011-2020) until end of follow-up in September 2022, and from the Penn Medicine Biobank (PMBB) (individuals aged 18-102 years) with ongoing enrollment starting in 2013 to the end of follow-up in December 2020. Individuals were matched using propensity score matching according to the following criteria: age, sex, body mass index, ethnicity, diabetes with or without insulin or biguanide use, hypertension, ischemic heart disease, dyslipidemia, aspirin use, and number of medications taken (UKB only). Data analysis was performed from April 2021 to April 2023. Exposure: Regular statin use. Main Outcomes and Measures: Primary outcomes were liver disease and HCC development as well as liver-associated death. Results: A total of 1 785 491 individuals were evaluated after matching (aged 55 to 61 years on average, up to 56% men, and up to 49% women). A total of 581 cases of liver-associated death, 472 cases of incident HCC, and 98 497 new liver diseases were registered during the follow-up period. Individuals were aged 55-61 years on average, with a slightly higher proportion of men (up to 56%). In UKB individuals (n = 205 057) without previously diagnosed liver disease, statin users (n = 56 109) had a 15% lower hazard ratio (HR) for the association of developing a new liver disease (HR, 0.85; 95% CI, 0.78-0.92; P < .001). In addition, statin users demonstrated a 28% lower HR for the association with liver-related death (HR, 0.72; 95% CI, 0.59-0.88; P = .001) and a 42% lower HR for the development of HCC (HR, 0.58; 95% CI, 0.35-0.96; P = .04). In TriNetX individuals (n = 1 568 794), the HR for the association of HCC was reduced even further for statin users (HR, 0.26; 95% CI, 0.22-0.31; P = .003). The hepatoprotective association of statins was time and dose dependent, with a significant association in PMBB individuals (n = 11 640) for incident liver diseases after 1 year of statin use (HR, 0.76; 95% CI, 0.59-0.98; P = .03). Taking statins was particularly beneficial in men, individuals with diabetes, and individuals with a high Fibrosis-4 index at baseline. Carriers of the heterozygous minor allele of PNPLA3 rs738409 benefited from statin use and had a 69% lower HR for the association with HCC (UKB HR, 0.31; 95% CI, 0.11-0.85; P = .02). Conclusions and Relevance: This cohort study indicates substantial preventive associations of statins against liver disease, with an association with duration and dose of intake.

Comorbidities, biomarkers and cause specific mortality in patients with irritable bowel syndrome: A phenome-wide association study.

BACKGROUND: Irritable bowel syndrome (IBS) is one of the most common functional digestive disorders. Our understanding about its comorbidities, biomarkers, or long-term risks is still incomplete. OBJECTIVE: To characterize comorbidities and biomarkers for IBS and establish the effect of IBS on overall- and cause specific mortality. METHODS: We analyzed data from the population-based cohort of the UK Biobank (UKB) with 493,974 participants, including self-reported physician-diagnosed (n = 20,603) and ICD-10 diagnosed (n = 7656) IBS patients, with a mean follow-up of 11 years. We performed a phenome-wide association study (PheWAS) and competing risk analysis to characterize common clinical features in IBS patients. RESULTS: In PheWAS analyses, 260 PheCodes were significantly overrepresented in self-reported physician-diagnosed IBS patients, 633 in patients with ICD-10 diagnosed IBS (ICD-10-IBS), with 221 (40%) overlapping. In addition to gastrointestinal diseases, psychiatric, musculoskeletal, and endocrine/metabolic disorders represented the most strongly associated PheCodes in IBS patients. Self-reported physician-diagnosed IBS was not associated with increased overall mortality and the risk of death from cancer was decreased (hazard ratio [HR] = 0.78 [95% CI = 0.7-0.9]). Lastly, we evaluated changes in serum metabolites in IBS patients and identified glycoprotein acetyls (GlycA) as a potential biomarker in IBS. One standard deviation increase in GlycA raised the risk of self-reported IBS/ICD-10 coded by 9%-20% (odds ratio [OR] = 1.09 [95% CI = 1.1-1.1]/OR = 1.20 [95% CI = 1.1-1.3]) and the risk of overall mortality in ICD-10-IBS patients by 28% (HR = 1.28 [95% CI = 1.1-1.5]). CONCLUSION: Our large-scale association study determined IBS patients having an increased risk of several different comorbidities and that GlycA was increased in IBS patients.

Imbalanced gut microbiota fuels hepatocellular carcinoma development by shaping the hepatic inflammatory microenvironment.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide, and therapeutic options for advanced HCC are limited. Here, we observe that intestinal dysbiosis affects antitumor immune surveillance and drives liver disease progression towards cancer. Dysbiotic microbiota, as seen in Nlrp6-/- mice, induces a Toll-like receptor 4 dependent expansion of hepatic monocytic myeloid-derived suppressor cells (mMDSC) and suppression of T-cell abundance. This phenotype is transmissible via fecal microbiota transfer and reversible upon antibiotic treatment, pointing to the high plasticity of the tumor microenvironment. While loss of Akkermansia muciniphila correlates with mMDSC abundance, its reintroduction restores intestinal barrier function and strongly reduces liver inflammation and fibrosis. Cirrhosis patients display increased bacterial abundance in hepatic tissue, which induces pronounced transcriptional changes, including activation of fibro-inflammatory pathways as well as circuits mediating cancer immunosuppression. This study demonstrates that gut microbiota closely shapes the hepatic inflammatory microenvironment opening approaches for cancer prevention and therapy.

Gut microbiota depletion exacerbates cholestatic liver injury via loss of FXR signalling.

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease of unknown aetiology for which there are no approved therapeutic options. Patients with PSC display changes in gut microbiota and in bile acid (BA) composition; however, the contribution of these alterations to disease pathogenesis remains controversial. Here we identify a role for microbiota-dependent changes in BA synthesis that modulates PSC pathophysiology. In a genetic mouse model of PSC, we show that loss of microbiota-mediated negative feedback control of BA synthesis results in increased hepatic BA concentrations, disruption of bile duct barrier function and, consequently, fatal liver injury. We further show that these changes are dependent on decreased BA signalling to the farnesoid X receptor, which modulates the activity of the rate-limiting enzyme in BA synthesis, CYP7A1. Moreover, patients with advanced stages of PSC show suppressed BA synthesis as measured by serum C4 levels, which is associated with poor disease prognosis. Our preclinical data highlight the microbiota-dependent dynamics of BA metabolism in cholestatic liver disease, which could be important for future therapies targeting BA and gut microbiome interactions, and identify C4 as a potential biomarker to functionally stratify patients with PSC and predict disease outcomes.

Intestinal Dysbiosis Amplifies Acetaminophen-Induced Acute Liver Injury.

BACKGROUND & AIMS: Acute liver failure (ALF) represents an unmet medical need in Western countries. Although the link between intestinal dysbiosis and chronic liver disease is well-established, there is little evidence for a functional role of gut-liver interaction during ALF. Here we hypothesized that intestinal dysbiosis may affect ALF. METHODS: To test this hypothesis, we assessed the association of proton pump inhibitor (PPI) or long-term antibiotics (ABx) intake, which have both been linked to intestinal dysbiosis, and occurrence of ALF in the 500,000 participants of the UK BioBank population-based cohort. For functional studies, male Nlrp6-/- mice were used as a dysbiotic mouse model and injected with a sublethal dose of acetaminophen (APAP) or lipopolysaccharide (LPS) to induce ALF. RESULTS: Multivariate Cox regression analyses revealed a significantly increased risk (odds ratio, 2.3-3) for developing ALF in UK BioBank participants with PPI or ABx. Similarly, dysbiotic Nlrp6-/- mice displayed exacerbated APAP- and LPS-induced liver injury, which was linked to significantly reduced gut and liver tissue microbiota diversity and correlated with increased intestinal permeability at baseline. Fecal microbiota transfer (FMT) from Nlrp6-/- mice into wild-type (WT) mice augmented liver injury on APAP treatment in recipient WT mice, resembling the inflammatory phenotype of Nlrp6-/- mice. Specifically, FMT skewed monocyte polarization in WT mice toward a Ly6Chi inflammatory phenotype, suggesting a critical function of these cells as sensors of gut-derived signals orchestrating the inflammatory response. CONCLUSIONS: Our data show an important yet unknown function of intestinal microbiota during ALF. Intestinal dysbiosis was transferrable to healthy WT mice via FMT and aggravated liver injury. Our study highlights intestinal microbiota as a targetable risk factor for ALF.