Modeling alcohol-associated liver disease in a human Liver-Chip.
Ontology highlight
ABSTRACT:
SUBMITTER: Nawroth JC
PROVIDER: S-EPMC8342038 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The liver possesses a unique microenvironment with a complex internal vascular system and cell-cell interactions. Nonalcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease, and although much effort has been dedicated to building models to target NAFLD, most in vitro systems rely on simple models failing to recapitulate complex liver functions. Here, an in vitro system is presented to study NAFLD (steatosis) by coculturing human hepatocellular carcinoma (HepG2) cells and umbilical vein endothelial cells (HUVECs) into spheroids. Analysis of colocalization of HepG2-HUVECs along with the level of steatosis reveals that the NAFLD pathogenesis could be better modeled when 20% of HUVECs are presented in HepG2 spheroids. Spheroids with fat supplements progressed to the steatosis stage on day 2, which could be maintained for more than a week without being harmful for cells. Transferring spheroids onto a chip system with an array of interconnected hexagonal microwells proves helpful for monitoring functionality through increased albumin secretions with HepG2-HUVEC interactions and elevated production of reactive oxygen species for steatotic spheroids. The reversibility of steatosis is demonstrated by simply stopping fat-based diet or by antisteatotic drug administration, the latter showing a faster return of intracellular lipid levels to the basal level.
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Project description:Alcohol-associated liver disease (ALD) is a major cause of chronic liver disease worldwide, and comprises a spectrum of several different disorders, including simple steatosis, steatohepatitis, cirrhosis, and superimposed hepatocellular carcinoma. Although tremendous progress has been made in the field of ALD over the last 20 years, the pathogenesis of ALD remains obscure, and there are currently no FDA-approved drugs for the treatment of ALD. In this Review, we discuss new insights into the pathogenesis and therapeutic targets of ALD, utilizing the study of multiomics and other cutting-edge approaches. The potential translation of these studies into clinical practice and therapy is deliberated. We also discuss preclinical models of ALD, interplay of ALD and metabolic dysfunction, alcohol-associated liver cancer, the heterogeneity of ALD, and some potential translational research prospects for ALD.
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Project description:Background and aimsAlcohol consumption increased during the COVID-19 pandemic in 2020 in the United States. We projected the effect of increased alcohol consumption on alcohol-associated liver disease (ALD) and mortality.Approach and resultsWe extended a previously validated microsimulation model that estimated the short- and long-term effect of increased drinking during the COVID-19 pandemic in individuals in the United States born between 1920 and 2012. We modeled short- and long-term outcomes of current drinking patterns during COVID-19 (status quo) using survey data of changes in alcohol consumption in a nationally representative sample between February and November 2020. We compared these outcomes with a counterfactual scenario wherein no COVID-19 occurs and drinking patterns do not change. One-year increase in alcohol consumption during the COVID-19 pandemic is estimated to result in 8000 (95% uncertainty interval [UI], 7500-8600) additional ALD-related deaths, 18,700 (95% UI, 17,600-19,900) cases of decompensated cirrhosis, and 1000 (95% UI, 1000-1100) cases of HCC, and 8.9 million disability-adjusted life years between 2020 and 2040. Between 2020 and 2023, alcohol consumption changes due to COVID-19 will lead to 100 (100-200) additional deaths and 2800 (2700-2900) additional decompensated cirrhosis cases. A sustained increase in alcohol consumption for more than 1 year could result in additional morbidity and mortality.ConclusionsA short-term increase in alcohol consumption during the COVID-19 pandemic can substantially increase long-term ALD-related morbidity and mortality. Our findings highlight the need for individuals and policymakers to make informed decisions to mitigate the impact of high-risk alcohol drinking in the United States.
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Project description: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.
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Project description:The diagnosis of metabolic-associated fatty liver disease is based on the detection of liver steatosis together with the presence of metabolic dysfunction. According to this new definition, the diagnosis of metabolic-associated fatty liver disease is independent of the amount of alcohol consumed. Actually, alcohol and its metabolites have various effects on metabolic-associated abnormalities during the process of alcohol metabolism. Studies have shown improved metabolic function in light to moderate alcohol drinkers. There are several studies focusing on the role of light to moderate alcohol intake on metabolic dysfunction. However, the results from studies are diverse, and the conclusions are often controversial. This review systematically discusses the effects of alcohol consumption, focusing on light to moderate alcohol consumption, obesity, lipid and glucose metabolism, and blood pressure.
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Project description:The lung is the primary respiratory organ of the human body and has a complicated and precise tissue structure. It comprises conductive airways formed by the trachea, bronchi and bronchioles, and many alveoli, the smallest functional units where gas-exchange occurs via the unique gas-liquid exchange interface known as the respiratory membrane. In vitro bionic simulation of the lung or its microenvironment, therefore, presents a great challenge, which requires the joint efforts of anatomy, physics, material science, cell biology, tissue engineering, and other disciplines. With the development of micromachining and miniaturization technology, the concept of a microfluidics-based organ-on-a-chip has received great attention. An organ-on-a-chip is a small cell-culture device that can accurately simulate tissue and organ functions in vitro and has the potential to replace animal models in evaluations of drug toxicity and efficacy. A lung-on-a-chip, as one of the first proposed and developed organs-on-a-chip, provides new strategies for designing a bionic lung cell microenvironment and for in vitro construction of lung disease models, and it is expected to promote the development of basic research and translational medicine in drug evaluation, toxicological detection, and disease model-building for the lung. This review summarizes current lungs-on-a-chip models based on the lung-related cellular microenvironment, including the latest advances described in studies of lung injury, inflammation, lung cancer, and pulmonary fibrosis. This model should see effective use in clinical medicine to promote the development of precision medicine and individualized diagnosis and treatment.
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Project description:Consumption of alcohol in excess leads to substantial medical, economic, and societal burdens. Approximately 5.3% of all global deaths may be attributed to alcohol consumption. Moreover, the burden of alcohol associated liver disease (ALD) accounts for 5.1% of all disease and injury worldwide. Alcohol use disorder (AUD) affects men more than women globally with significant years of life loss to disability in low, middle and well-developed countries. Precise data on global estimates of alcohol related steatosis, alcohol related hepatitis, and alcohol related cirrhosis have been challenging to obtain. In the United States (US), alcohol related steatosis has been estimated at 4.3% based on NHANES data which has remained stable over 14 years. However, alcohol-related fibrotic liver disease has increased over the same period. In those with AUD, the prevalence of alcohol related hepatitis has been estimated at 10-35%. Globally, the prevalence of alcohol-associated cirrhosis has been estimated at 23.6 million individuals for compensated cirrhosis and 2.46 million for those with decompensated cirrhosis. The contribution of ALD to global mortality and disease burden of liver related deaths is substantial. In 2016 liver disease related to AUD contributed to 50% of the estimated liver disease deaths for age groups 15 years and above. Data from the US report high cost burdens associated with those admitted with alcohol-related liver complications. Finally, the recent COVID-19 pandemic has been associated with marked increase in alcohol consumption worldwide and will likely increase the burden of ALD.
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Project description:The fungal microbiota plays an important role in the pathogenesis of alcohol-associated liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD). In this study, we aimed to compare changes of the fecal fungal microbiota between patients with ALD and NAFLD and to elucidate patterns in different disease stages between the two conditions. We analyzed fungal internal transcribed spacer 2 (ITS2) sequencing using fecal samples from a cohort of 48 patients with ALD, 78 patients with NAFLD, and 34 controls. The fungal microbiota differed significantly between ALD and NAFLD. The genera Saccharomyces, Kluyveromyces, Scopulariopsis, and the species Candida albicans (C. albicans), Malassezia restricta (M. restricta), Scopulariopsis cordiae (S. cordiae) were significantly increased in patients with ALD, whereas the genera Kazachstania and Mucor were significantly increased in the NAFLD cohort. We identified the fungal signature consisting of Scopulariopsis, Kluyveromyces, M. restricta, and Mucor to have the highest discriminative ability to detect ALD vs NAFLD with an area under the curve (AUC) of 0.93. When stratifying the ALD and NAFLD cohorts by fibrosis severity, the fungal signature with the highest AUC of 0.92 to distinguish ALD F0-F1 vs NAFLD F0-F1 comprised Scopulariopsis, Kluyveromyces, Mucor, M. restricta, and Kazachstania. For more advanced fibrosis stages (F2-F4), the fungal signature composed of Scopulariopsis, Kluyveromyces, Mucor, and M. restricta achieved the highest AUC of 0.99 to differentiate ALD from NAFLD. This is the first study to identify a fungal signature to differentiate two metabolic fatty liver diseases from each other, specifically ALD from NAFLD. This might have clinical utility in unclear cases and might hence help shape treatment approaches. However, larger studies are required to validate this fungal signature in other populations of ALD and NAFLD.
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Project description:The goal of this study was to assess RNA expression in human primary hepatocytes in response to ethanol exposure compared to control. The hepatocytes were cultured in co-culture on a Liver-Chip model with Kupffer cells and Liver sinusoidal endothelial cells (LSECs) and treated with 0.08% to 0.16% ethanol for 48h.
2021-05-25 | GSE175396 | GEO
Project description:Background and aimsIn some states, liver transplantation (LT) for alcohol-associated liver disease (ALD) is covered by Medicaid only with documentation of abstinence and/or alcohol rehabilitation. Different Medicaid policies may affect the distribution of LT for ALD, particularly post-2011, as centers have adopted early (i.e., specific abstinence period not required) LT practices.Approach and resultsWe surveyed Medicaid policies in all states actively performing LT and linked state policies to prospectively collected national registry data on LT recipients from 2002 to 2017 with ALD as the primary listing diagnosis. We categorized Medicaid policies for states as "restrictive" (requiring documentation of a specific abstinence period and/or rehabilitation) versus "unrestrictive" (deferring to center eligibility policies). Difference-of-differences analysis, comparing 2002-2011 versus 2012-2017, evaluated whether restrictive policies were associated with decreased proportion of LTs paid by Medicaid among patients with ALD post-2011. We performed sensitivity analyses to account for any differences by diagnosis of hepatocellular carcinoma, hepatitis C virus, nonalcoholic steatohepatitis, or Medicare insurance. We also performed a sensitivity analysis to account for any difference by prevalence of ALD among restrictive versus unrestrictive states. Of 10,836 LT recipients in 2002-2017, 7,091 were from 24 states in the restrictive group and 3,745 from 14 states in the unrestrictive group. The adjusted proportion (95% confidence interval) of LTs paid by Medicaid among restrictive versus unrestrictive states between 2002 and 2011 was 17.6% (15.4%-19.8%) versus 18.9% (15.4%-22.3%) (P = 0.54) and between 2012 and 2017, 17.2% (14.7%-19.7%) versus 23.2% (19.8%-26.6%) (P = 0.005). In difference-of-differences analysis, restrictive (versus unrestrictive) policies were associated with a 4.7% (0.8%-8.6%) (P = 0.02) absolute lower adjusted proportion of LTs for ALD paid by Medicaid post-2011.ConclusionsRestrictive Medicaid policies are present in most states with active LT centers and are associated with lower proportions of LTs for ALD paid by Medicaid post-2011 compared to states with unrestrictive Medicaid policies. Reevaluation of Medicaid alcohol use policies may be warranted, to align more closely with contemporary center-level practices.
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