Table 1.
NAFLD, gut microbiome and metabolites.
| Author, Year | Study Descriptive (Population; Follow-up; Weight Loss) | Method | Microbiome | Metabolites |
|---|---|---|---|---|
| Belgaumkar, 2016 [84] | Prospective analysis; SG (n = 18) NAFLD defined by serum cytokeratin 18 (n = 14, 78% NAFL) FU 6 months; TWL-39.9 kg |
Bile acids: LC/MS | Not described. | ↑ primary glycine- and ↑ taurine-conjugated BA, ↓ cholic acid decreased, and ↑ secondary BA, ↑ glycine-conjugated urodeoxycholic acid No change in total BA. |
| Boursier, 2016 [64] | Biopsy-proven NAFLD (n = 57) F0/FI n = 30 vs. F3/F4 n = 27 |
Fecal microbiome: 16 S RNA sequencing analysis | Increased NAFLD severity: ↑ Bacteroidaceae, ↓ Prevotellacea; ↓ Erysipelotrichaceae. NASH (compared to no NASH): ↑ Bacteroides; ↓ Prevotella Significant fibrosis (F3/4) compared to F0/F1: ↑ Bacteroides; ↑ Ruminococcus; ↓ Prevotella. |
Not described. |
| Loomba, 2017 [53] | Prospective analysis biopsy-proven NAFLD (n = 86): comparison mild/moderate (n = 72;) vs. advanced fibrosis (n = 14); | Fecal microbiome: whole-genome shotgun sequencing | NAFLD—mild/moderate: ↑ abundance Firmicutes; most abundant Eubacterium rectale, Bacteroides vulgates NAFLD-AF: ↑ abundance Proteobacteria; most abundant B. vulgates, Escherichia coli. ↓ Ruminococcus obeum CAG:39; R. obeum; E. rectale. |
NAFLD—mild/moderate: serum: ↑ Hypoxanthine, ↑ Inosine; Stool: ↑ L-lactate; ↑ Acetate ↑ formate; NAFLD-AF: serum: ↑ Succinate; ↑ Malatae; ↑ alfa-ketoglutarate; ↑ Serine; ↑ Glutamine; ↑ Fumarate; ↑ Glutamate; ↑ Lactate; stool: ↑ butyrate, D-lactate, propionate, succinate |
| Caussy, 2018 [85] | Cross-sectional analysis twin family cohort, n = 156 validation cohort, n = 156 hepatic steatosis, n = 57 |
Fecal microbiome: whole-genome shotgun metagenomic sequencing; Liver: MRI/MRE; Metabolites CG/MS and LC/MS/MS | Proteobacteria, Firmicutes, Bacteroidetes correlated with 3-(4-hydroxyphenyl)lactate and phenyllactate. | 6 microbial origins: 3-(4-hydroxyphenyl)lactate, N-formylmethionine, phenyllactate, mannitol, allantoine, N-(2-furoyl)glycine. 3-(4-hydroxyphenyl)lactate gut microbiome-linked metabolite assosated with liver fibrosis. |
| Caussy, 2019 [62] | Cross-sectional; n = 203 NAFLD-cirrhosis, NAFLD, without advanced fibrosis non-NAFLD controls |
Fecal microbiome: 16S RNA sequencing analysis Liver: MRI/MRE. |
NAFLD–cirrhosis: ↑ Streptococcus; ↑ Megashaera; most enriched abundance of family Enterobacteriaceae, genera Streptococci and Gallibacterium. NAFLD-AF: ↑ Streptococcus; ↑ Bacillus; ↑ Lactococcus Non-NAFLD: ↑ Bacillus; ↑ Lactococcus; ↑ Pseudomonas; ↑ Faecalibacterium prausnitzii, ↑ genus Catenibacterium; families ↑ Rikenellaceae, ↑ Mogibacterium, ↑ Peptostreptococcaceae |
Not described. |
| Puri, 2018 [77] | Cross-sectional analysis biopsy-proven NAFLD and bile acids; n = 86 (controls n = 24. NAFL n = 25; NASH n = 37; BMI 31.9) |
LC/MS | Not described. | NASH: ↑ total primary BAs; ↓ secondary BAs. NASH vs. NAFL, vs. controls: ↑ Total conjugated primary BAs ↑ conjugated/unconjugated chenodeoxycholate; ↑ cholate; ↑ total primary BAs. NAFL: ↑ Total cholate/chenodeoxycholate ratio ↑ total secondary/primary BA ratio -> ↓ likelihood of significant fibrosis (F ≥ 2) ↑ conjugated cholate -> ↑ likelihood of significant fibrosis (F ≥ 2). |
| Hoyles, 2018 [29] | Prospective analysis; obese women n= 105; liver biopsy (histology), NAFLD (n = 56); fecal microbiome (n =56, | Fecal microbiome: shotgun metagenomic sequencing; serum and urine Metabolites: LC/MS | Steatosis: ↑ Proteobacteria, ↑ Actinobacteria, Verrucomicrobia ↑ correlated Firmicutes and Euryarchaeta ↓ correlated. Species: ↑ Acidaminococcus, ↑ Escherichia; ↓ Lachnospiraceae, ↓ Ruminococcaceae Functional analysis: ↑ LPS and peptidoglycan biosynthesis. |
Steatosis: Serum BCAAs: ↑ leucine, ↑ valine, ↑ isoleucine. ↑ phenylacetic acid (PAA) Urine: ↑ choline No-NAFLD: ↑ acetate; ↑ TMAO |
| Lee, 2020 [67] | Prospective analysis Non-obese NAFLD |
Fecal metabolites: 16S RNA sequencing analysis | Elevated Ruminococcaceae and Veillonellaceae associated with fibrosis severity. | Fecal metabolites: bile acids and propionate elevated (especially with significant fibrosis). |
| Adams, 2020 [75] | Prospective analysis liver biopsy n = 122 (as part of clinical care or during bariatric surgery) |
Fecal microbiome: 16S RNA sequencing analysis Metabolies: serum + fecal BA analysis: LCMS. | NAFLD-AF (F3/4): ↑ Firmicutes, ↑ Proteobacteria; ↑ Actinobacteria; ↓ Bacteriodetes. Family: ↑ Actinomycetaceae; ↑ Lachnospiraceae; ↓ Bacteroidaceae; ↓ unclassifiable of order Bacteroidales. | Progressive ↑ total serum BAs from controls, F0–2 NAFLD to F3/4 NAFLD. ↑ GCA (glycocholic acid); ↑ GDCA (glycodeoxycholic acid) Fecal BA: ↑ DCA (deoxycholic acid); ↑ LC (lithocholic acid). |
| Masarone, 2021 [68] | Cross-sectional analysis cohort biopsy-proven NAFLD n = 144 steatosis, n = 76, NASH n = 23, cirrhosis, n = 43 (NASH–cirrhosis n = 15, HCV n = 8, cryptogenic n = 20) | Serum metabolites GC/MS; machine learning model. | Not described. | Lower in controls and increase with disease progression: isocitric acid, isoleucine, not identified metabolite Higher in controls and decrease with disease progression: xanthine, glutathione, glycolic acid Valine, asparagine, 4-deoxy erythronic acid, propanoic acid, palmitic acid, butanoic acid, stearic acid, phenylalanine, taurocholic acid NASH-related cirrhosis, increased concentration of galactose, uric acid, glyceric acid, butanoic acid, histidine, phenylalanine, stearic acid, threonine and palmitic acid |
| Nimer, 2021 [76] | Prospective analysis; NAFLD n = 102 (30% simple steatosis, 43% borderline NASH, 27% NASH); controls n = 50 Liver biopsy; BMI 32.8 kg/m2 |
Plasma bile acid profile: quantitative stable isotope dilution LC/MS/MS | Not described. | NAFLD vs. controls: ↑ almost all circulating BAs Fibrosis vs. NAFLD: ↑ glycine-conjugated primary BAs (↑ GCDCA, ↑ GCA), secondary BAs ↑ 7-keto-DCA, ↑ GUDCA NASH vs. simple steatosis: ↑ 7-keto-DCA, ↑ 7-keto, LCA |