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

Abstract

Fatty liver disease is the most common liver disease in the world. Its connection with the gut microbiome has been known for at least 80 y, but 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 of 6,269 Finnish participants. We based our models on biometric covariates and gut microbiome compositions from shallow metagenome sequencing. Our classification models could discriminate between individuals with a high FLI (≥60, indicates likely liver steatosis) and low FLI (<60) in internal cross-region validation, consisting of 30% of the data not used in model training, with an average AUC of 0.75 and AUPRC of 0.56 (baseline at 0.30). In addition to age and sex, our models included differences in 11 microbial groups from class Clostridia, mostly belonging to orders Lachnospirales and Oscillospirales. Our models were also predictive of the high FLI group in a different Finnish cohort, consisting of 258 participants, with an average AUC of 0.77 and AUPRC of 0.51 (baseline at 0.21). Pathway analysis of representative genomes of the positively FLI-associated taxa in (NCBI) Clostridium subclusters IV and XIVa indicated the presence of, e.g., ethanol fermentation pathways. These results support several findings from smaller case-control studies, such as the role of endogenous ethanol producers in the development of the fatty liver.

Keywords: Metagenomics; fatty liver; fatty liver index; human gut; population sample.

Figure 1.

Distribution of FLI (a), its components (b), and FLI in quantiles of the first three PC components of the fecal bacterial composition of the participants (c). The cutoff at FLI = 60 used to divide the participants is indicated with a dashed line in panels a and c

Figure 2.

Relative effects of predictive balances and covariates on the FLI < 60 and FLI ≥ 60 classification model (AUC = 0.75) predictions. Nodes of the balances are indicated in the cladogram and the relative effect sizes of their clades (opposite sides of each balance) are shown in the associated heatmap. The relative effect sizes of the covariates (age and sex) are shown below the legend with a heatmap on the same scale as was used for the balances. The two liver-specific balances associated with triglyceride and GGT levels are indicated with bold font. Clades with redundant information have been collapsed but their major genera are indicated. The complete tree is included in Figure S8.