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A Perspective Of Intestinal Immune-Microbiome Interactions In Alcohol-Associated Liver Disease.

ABSTRACT: Uncovering the intricacies of the gut microbiome and how it interacts with the host immune system has opened up pathways in the search for the treatment of disease conditions. Alcohol-associated liver disease is a major cause of death worldwide. Research has shed light on the breakdown of the protective gut barriers, translocation of gut microbes to the liver and inflammatory immune response to microbes all contributing to alcohol-associated liver disease. This knowledge has opened up avenues for alternative therapies to alleviate alcohol-associated liver disease based on the interaction of the commensal gut microbiome as a key player in the regulation of the immune response. This review describes the relevance of the intestinal immune system, the gut microbiota, and specialized and non-specialized intestinal cells in the regulation of intestinal homeostasis. It also reflects how these components are altered during alcohol-associated liver disease and discusses new approaches for potential future therapies in alcohol-associated liver disease.

SUBMITTER: Bruellman R

PROVIDER: S-EPMC7757023 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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A Perspective Of Intestinal Immune-Microbiome Interactions In Alcohol-Associated Liver Disease.

Bruellman Ryan R Llorente Cristina C

International journal of biological sciences 20210101 1

Uncovering the intricacies of the gut microbiome and how it interacts with the host immune system has opened up pathways in the search for the treatment of disease conditions. Alcohol-associated liver disease is a major cause of death worldwide. Research has shed light on the breakdown of the protective gut barriers, translocation of gut microbes to the liver and inflammatory immune response to microbes all contributing to alcohol-associated liver disease. This knowledge has opened up avenues fo ...[more]

PMID: 33390852

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Project description:BACKGROUND:Relationships between specific microbes and proper immune system development, composition, and function have been reported in a number of studies. However, researchers have discovered only a fraction of the likely relationships. "Omic" methodologies such as 16S ribosomal RNA (rRNA) sequencing and time-of-flight mass cytometry (CyTOF) immunophenotyping generate data that support generation of hypotheses, with the potential to identify additional relationships at a level of granularity ripe for further experimentation. Pairwise linear regressions between microbial and host immune features provide one approach for quantifying relationships between "omes", and the differences in these relationships across study cohorts or arms. This approach yields a top table of candidate results. However, the top table alone lacks the detail that domain experts such as microbiologists and immunologists need to vet candidate results for follow-up experiments. RESULTS:To support this vetting, we developed VOLARE (Visualization Of LineAr Regression Elements), a web application that integrates a searchable top table, small in-line graphs illustrating the fitted models, a network summarizing the top table, and on-demand detailed regression plots showing full sample-level detail. We applied VOLARE to three case studies-microbiome:cytokine data from fecal samples in human immunodeficiency virus (HIV), microbiome:cytokine data in inflammatory bowel disease and spondyloarthritis, and microbiome:immune cell data from gut biopsies in HIV. We present both patient-specific phenomena and relationships that differ by disease state. We also analyzed interaction data from system logs to characterize usage scenarios. This log analysis revealed that users frequently generated detailed regression plots, suggesting that this detail aids the vetting of results. CONCLUSIONS:Systematically integrating microbe:immune cell readouts through pairwise linear regressions and presenting the top table in an interactive environment supports the vetting of results for scientific relevance. VOLARE allows domain experts to control the analysis of their results, screening dozens of candidate relationships with ease. This interactive environment transcends the limitations of a static top table.

Project description:Alcohol liver disease (ALD) is a major cause of liver-related mortality globally, yet there remains an unmet demand for approved ALD drugs. The pathogenesis of ALD involves perturbations to the intestinal barrier and subsequent translocation of bacterial endotoxin that, acting through toll-like receptor 4 (TLR4), promotes hepatic inflammation and progression of ALD. In the present study we investigated the ability of fenretinide (Fen) [N-(4-hydroxyphenyl) retinamide], a synthetic retinoid with known anti-cancer and anti-inflammatory properties, to modulate intestinal permeability and clinical hallmarks of ALD in a mouse model of chronic ethanol (EtOH) exposure. Our results show that EtOH-treated mice had reductions in mRNA and protein expression of intestinal tight junction proteins, including claudin one and occludin, and increases in intestinal permeability and endotoxemia compared to pair-fed mice. Also, EtOH-treated mice had marked increases in hepatic steatosis, liver injury, and expression of pro-inflammatory mediators, including TNF-α, and TLR4-positive macrophages, Kupffer cells, and hepatocytes in the intestines and liver, respectively. In contrast, EtOH + Fen-treated mice were resistant to the effects of EtOH on promoting intestinal permeability and had higher intestinal protein levels of claudin one and occludin. Also, EtOH + Fen-treated mice had significantly lower plasma levels of endotoxin, and reductions in expression of TNF-α and TLR4 positive macrophages, Kupffer cells, and hepatocytes in the intestine and liver. Lastly, we found that EtOH + Fen-treated mice exhibited major reductions in hepatic triglycerides, steatosis, and liver injury compared to EtOH-treated mice. Our findings are the first to demonstrate that Fen possesses anti-ALD properties, potentially through modulation of the intestinal barrier function, endotoxemia, and TLR4-mediated inflammation. These data warrant further pre-clinical investigations of Fen as a potential anti-ALD drug.

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.

Dataset Information

A Perspective Of Intestinal Immune-Microbiome Interactions In Alcohol-Associated Liver Disease.

Publications

A Perspective Of Intestinal Immune-Microbiome Interactions In Alcohol-Associated Liver Disease.

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