Links between gut microbiome composition and fatty liver disease in a large population sample

Abstract

Background. Fatty liver disease is the most common liver disease in the world. It is characterized by a build-up of excess fat in the liver that can lead to cirrhosis and liver failure. The link between fatty liver disease and gut microbiome has been known for at least 80 years. However, this association remains mostly unstudied in the general population because of underdiagnosis and small sample sizes. To address this knowledge gap, we studied the link between the Fatty Liver Index (FLI), a well-established proxy for fatty liver disease, and gut microbiome composition in a representative, ethnically homogeneous population sample in Finland. We based our models on biometric covariates and phylogenetically transformed gut microbiome compositions from shallow metagenome sequencing. Results. Our classification models were able to discriminate between individuals with a high FLI (≥ 60, indicates likely liver steatosis) and low FLI (< 60) in our validation set, consisting of 30% of the data not used in model training, with an average AUC of 0.75. In addition to age and sex, our models included differences in 11 microbial groups from class Clostridia, mostly belonging to orders Lachnospirales and Oscillospirales. Pathway analysis of representative genomes of the FLI-associated taxa in (NCBI) Clostridium subclusters IV and XIVa indicated the presence of e.g., ethanol fermentation pathways. Conclusions. Through modeling the fatty liver index, our results provide with high resolution associations between gut microbiota composition and fatty liver in a large representative population cohort. Our results lend further support to the role of endogenous ethanol producers in the development of fatty liver.

Xylo-Oligosaccharides in Prevention of Hepatic Steatosis and Adipose Tissue Inflammation: Associating Taxonomic and Metabolomic Patterns in Fecal Microbiomes with Biclustering

“…In this process, the relative abundances of the phyla Firmicutes and Bacteroidetes increased 32 pp and decreased 45 pp, respectively. In previous studies Firmicutes accounted for most taxa predictive of liver disease [ 32 , 33 ] and in our case the dropped genera had low overall significance.…”

“…First, we fitted a classification model with metabolites and genera from the whole dataset and then from each bicluster separately to predict overall diet, diet fat content or XOS ingestion. We used XGBoost [ 44 ] as the classifier, as we previously demonstrated its suitability for microbiological dataset [ 32 , 33 ]. Our model was fitted with raw metabolite abundances without standardization, as XGBoost is a decision-tree based classifier.…”

“…The associations between fecal metabolomes, taxonomic composition, and metabolic health are less well characterized, however. Using classification and regression models, we recently explored the GM as a supplement to conventional risk factors to predict prevalent and incident liver disease occurrence and severity with improved accuracy in a large prospective population cohort [ 32 , 33 ]. Biclustering algorithms are a commonly utilized technique in gene expression studies that provide possibilities to detect associations between taxonomic and metabolomic variation by grouping the rows and columns of a 2-dimensional matrix [ 34 , 35 ].…”

Combined effects of host genetics and diet on human gut microbiota and incident disease in a single population cohort

“…Taxonomic profiling of FR02 metagenomes has been described elsewhere 100,106 . Briefly, raw shotgun metagenomic sequencing reads were mapped using the k -mer-based metagenomic classification tool Centrifuge 107 to an index database custom-built to encompass reference genomes that followed the taxonomic nomenclature introduced and updated in the GTDB release 89 93-95 .…”

Associations of the gut microbiome with hepatic adiposity in the Multiethnic Cohort Adiposity Phenotype Study

“…13Adults with NAFLD have altered bile acid metabolism as shown in small case control studies and in larger, although ethnically homogenous, cohort studies. 54 , 62 , 63 Imputed secondary bile acid synthesis pathways were significantly increased in all participants with NAFLD ( Figure 3 ; Supplemental Table 5). In an ethnic-specific manner, ALT, a clinical measure of liver dysfunction, was positively associated with secondary bile acid producing bacteria and support this microbial-driven pathophysiologic link to NAFLD ( Figure 2 ).…”