Microbiomics, Metabolomics, Predicted Metagenomics, and Hepatic Steatosis in a Population‐Based Study of 1,355 Adults

Abstract

Background and Aims Previous small studies have appraised the gut microbiome (GM) in steatosis, but large‐scale studies are lacking. We studied the association of the GM diversity and composition, plasma metabolites, predicted functional metagenomics, and steatosis. Approach and Results This is a cross‐sectional analysis of the prospective population‐based Rotterdam Study. We used 16S ribosomal RNA gene sequencing and determined taxonomy using the SILVA reference database. Alpha diversity and beta diversity were calculated using the Shannon diversity index and Bray–Curtis dissimilarities. Differences were tested across steatosis using permutational multivariate analysis of variance. Hepatic steatosis was diagnosed by ultrasonography. We subsequently selected genera using regularized regression. The functional metagenome was predicted based on the GM using Kyoto Encyclopedia of Genes and Genomes pathways. Serum metabolomics were assessed using high‐throughput proton nuclear magnetic resonance. All analyses were adjusted for age, sex, body mass index, alcohol, diet, and proton‐pump inhibitors. We included 1,355 participants, of whom 472 had steatosis. Alpha diversity was lower in steatosis (P = 1.1∙10−9), and beta diversity varied across steatosis strata (P = 0.001). Lasso selected 37 genera of which three remained significantly associated after adjustment (Coprococcus3: β = −65; Ruminococcus Gauvreauiigroup: β = 62; and Ruminococcus Gnavusgroup: β = 45, Q‐value = 0.037). Predicted metagenome analyses revealed that pathways of secondary bile‐acid synthesis and biotin metabolism were present, and D‐alanine metabolism was absent in steatosis. Metabolic profiles showed positive associations for aromatic and branched chain amino acids and glycoprotein acetyls with steatosis and R. Gnavusgroup, whereas these metabolites were inversely associated with alpha diversity and Coprococcus3. Conclusions We confirmed, on a large‐scale, the lower microbial diversity and association of Coprococcus and Ruminococcus Gnavus with steatosis. We additionally showed that steatosis and alpha diversity share opposite metabolic profiles.

Activation of the gut microbiota-kynurenine-liver axis contributes to the development of nonalcoholic hepatic steatosis in nondiabetic adults

“…Clinical and animal studies have shown that dysbiosis of the gut microbiota represents an independent risk factor for NHS [ 1 , 5 ]. Indeed, since alterations the gut microbiota can contribute to insulin resistance, chronic inflammation, and disorders of glucose, lipid, and amino acid metabolism, the gut microbiota is considered an important target for NHS treatment [ 1 , 18 ].…”

“…Nonalcoholic hepatic steatosis (NHS) is the most common liver disease in the world and is associated with increased the risk of cardiovascular disease, type-2 diabetes, and liver-related complications such as hepatocellular carcinoma [ 1 – 3 ]. The occurrence and progression of NHS result from a combination of multiple genetic and environmental factors [ 1 ]. However, the factors that are currently known represent only a small fraction of those involved in disease onset and progression.…”

“…Several studies have explored the characteristics of the gut microbiota in patients with NHS [ 1 , 4 ]. Compared to healthy individuals, a consistently altered microbiome signature, characterized by increased abundance of Proteobacteria , Enterobacteriaceae , Dorea , and Escherichia and decreased abundance of Ruminococcaceae , Rikenellaceae , and Coprococcus , is found in NHS patients [ 4 – 9 ].…”

Long-term association between diet quality and characteristics of the gut microbiome in the multiethnic cohort study

“…The positive association of diet quality with the Eubacterium eligens group agrees with its higher abundance among those with a vegetarian diet in Thailand (40) . Although we are not aware of any connections with diet for Ruminococcus gnavus, it is known that this organism is involved in non-alcoholic fatty liver disease (41) . Also diets rich in animal products have been associated with Collinsella and Ruminococcus gnavus, two pro-inflammatory genera (42) .…”

Applying artificial intelligence in the microbiome for gastrointestinal diseases: A review

“…Second, the gene‐targeted amplicons and metagenomics big data could support the integration of novel microbiome signatures. On the one hand, a large‐scale study on thousands of participants has revealed the association of gut bacterial diversity and composition, plasma metabolites, predicted functional pathways, and steatosis by 16S ribosomal RNA gene sequencing 29 . On the other hand, by shotgun sequencing, an integration study on the basis of fecal metagenomes, hepatic transcriptomes, and plasma and urine metabolomes has revealed hepatic steatosis‐associated molecular networks underlying the interaction between gut microbiome and the host phenome 30 .…”