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Associations of the gut microbiome and hepatic adiposity

From the Johanna Lampe Group

Over 30% of the US population is affected by nonalcoholic fatty liver disease (NAFLD); NAFLD increases the risk of cardiovascular disease, metabolic syndrome, type 2 diabetes (T2D), and malignancy.  Recently, NAFLD has been shown to influence the risk of hepatocellular carcinoma (HCC).  The gut microbiome and its metabolites, genetics, and ethnicity are all risk factors for NAFLD. According to the Multiethnic Cohort Study (MEC), NAFLD is a common risk factor for chronic liver disease (CLD) among five ethnic groups. Because the liver is exposed to gut microbial metabolites and endotoxins, inflammation can occur and encourage the development of NAFLD.  Also, the gut microbiome along with its microbial metabolic pathways may promote oxidative stress and systemic and liver inflammation and altered host metabolism. Although NAFLD prevalence varies for ethnic groups, how variation in the gut microbiome is associated with NAFLD has not been examined across ethnic groups, until now. Meredith Hullar, PhD, Principal Staff Scientist in the JLampe Group in the Division of Public Health Sciences, examined the associations between NAFLD and gut microbiome composition and bacterial metabolic pathways in a cross-sectional subset of the MEC. This study measured the association between microbiome structure and function that could potentially link pathophysiologic pathways of clinical importance and reduce the racial/ethnic disparity associated with NAFLD. This paper was published in Gut Microbes.

The MEC-Adiposity Phenotype Study (MEC-APS) recruited men and postmenopausal women aged 60-77 years from five main MEC ethnic groups: African American, Japanese American, White, Latino, and Native Hawaiian participants  In one of two affiliated clinical facilities, from 2013 and 2016, participants underwent dual X-ray absorptiometry (DXA) and abdominal magnetic resonance imaging (MRI) scans, anthropometric and resting metabolism measurements, fasting blood and stool sample collections, and completion of a food frequency questionnaire with specific ethnic foods. The study consisted of a total of 1,544 MEC-APS participants. Liver fat and NAFLD was assessed by measuring percent liver fat using the abdominal MRI and total body fatness via the DXA scan.  Blood biomarkers were collected after an overnight fast (>8 hours). The microbiome was analyzed in stool samples using 16S rRNA gene and metagenomic sequencing. Lipopolysaccharide binding protein (LBP), a measure of bacterial lipopolysaccharide linked to innate immune inflammation response, was measured in plasma. Linear regression was utilized to assess the Shannon alpha diversity by NAFLD status and its interaction with ethnicity. Beta-binomial regression models evaluated each genus and phylum associated with % liver fat. Linear regression was utilized to examine the association of microbial metabolic pathways, both bioinformatically imputed and measured using metagenomics, with liver fat. Lastly, mediation analysis determined whether the association between percent liver fat and a marker of systemic inflammation (C-reactive protein, CRP) was mediated by LBP.  These models were adjusted for sex and percent total fat mass. 

Graphical Representation of  Figure 1.  Forest plot of the abundance (incidence rate ratio, IRR) and prevalence (odds ratio, OR) of the genera significantly enriched in individuals with and without NAFLD in the MEC-APS. The IRR and ORs, adjusted for sex, ethnicity and total fat mass, relative to the non-NAFLD group are presented on a multiplicative scale.
Figure 1. Forest plot of the abundance (incidence rate ratio, IRR) and prevalence (odds ratio, OR) of the genera significantly enriched in individuals with and without NAFLD in the MEC-APS. The IRR and ORs, adjusted for sex, ethnicity and total fat mass, relative to the non-NAFLD group are presented on a multiplicative scale. Image from Dr. Lampe

The demographics table reported that sedentary lifestyle and smoking were significantly higher among participants with NAFLD. The JLampe Group identified 10 phyla, 152 genera, and 1,311 operational taxonomic units (OTUs) in the microbiome.  Alpha diversity was inversely associated with overall NAFLD status; ethnicity and NAFLD were significantly associated in an interaction model and in stratified analysis among African Americans, whites, and Latinos. Overall, 40% of the genera were associated with % liver fat. Although there was a significant interaction between NAFLD status and ethnicity, no single genera associated with NAFLD was found in common across ethnicities. A measure of liver damage was also associated with genera. Liver fat was associated with the microbial metabolism of carbohydrates and secondary bile acids, overall. Butyrate, branched chain amino acids, and fatty acid synthesis were uniquely significantly enriched in Native Hawaiian women.  In mediation models, plasma LBP concentrations mediated 22% of liver fat’s effect on CRP.

The JLampe Group concludes, “Microbial-associated mechanisms may provide insight into the development of NAFLD. Once replicated in other studies, ethnic-specific microbial composition and pathophysiologic pathways can provide the basis for targeted therapies, such as narrow spectrum antibiotics, diet, fecal transplants, or phage therapies, for future clinical treatment specific to the microbiome. Microbiome-mediated pathways may provide an actionable ethnic-specific target to reduce inflammation and reduce the transition from simple steatosis to advanced liver disease.”

This research was supported by the National Cancer Institute  

Fred Hutch/UW Cancer Consortium members Timothy Randolph and Johanna Lampe contributed to this work.

Meredith A. J. Hullar, Isaac C. Jenkins  , Timothy W. Randolph , Keith R. Curtis , Kristine R. Monroe ,Thomas Ernst, John A. Shepherd,  Daniel O. Stram, Iona Cheng, Bruce S. Kristal, Lynne R. Wilkens, Adrian Franke, Loic Le Marchand, Unhee Lim, and Johanna W. Lampe Associations of the gut microbiome with hepatic adiposity in the Multiethnic Cohort Adiposity Phenotype Study. Gut Microbes. 2021 Jan 1;13(1):1965463.