# The Gut–Liver Axis in MASLD: From Host–Microbiome Crosstalk to Precision Therapeutics

**Authors:** Ji Zhou, Bowen Zhu, Ziqian Bing, Tingting Wang, Yue Zhao

PMC · DOI: 10.3390/microorganisms14020471 · Microorganisms · 2026-02-14

## TL;DR

This review explores how gut microbiota influences liver disease and suggests microbiome-based treatments could lead to personalized therapies.

## Contribution

The paper introduces a precision framework linking gut microbiome mechanisms to non-invasive biomarkers for MASLD treatment.

## Key findings

- Gut microbiota modifies MASLD through metabolic dysbiosis and immune activation.
- Three core mechanisms drive MASLD progression via gut-liver interactions.
- Microbiome-based interventions may align with biomarkers for personalized treatment.

## Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is an emerging global health challenge with limited effective therapeutic options. The gut microbiota, at the interface of host metabolism and immunity, acts as a critical disease modifier via the gut–liver axis. This review goes beyond cataloging its associations and synthesizes how intrinsic and extrinsic factors sculpt a permissive microbial ecosystem. These factors likely converge to establish a state of “metabolic dysbiosis”, fueling MASLD progression through three core mechanisms: compromised intestinal barrier integrity with immune activation, dysregulation of key microbial metabolite axes, and direct hepatic insult from gut-derived products. Next, we evaluate the translational landscape through a mechanism-informed precision framework, with an emphasis on how microbiome-based interventions could be aligned with non-invasive biomarkers increasingly used for MASLD risk stratification and treatment monitoring. By integrating evidence across scales, this review aims to frame a roadmap from microbiome correlations to causality-driven, personalized therapeutic strategies for MASLD.

## Linked entities

- **Diseases:** metabolic dysfunction-associated steatotic liver disease (MONDO:0013209), MASLD (MONDO:0013209)

## Full-text entities

- **Genes:** NFE2L2 (NFE2 like bZIP transcription factor 2) [NCBI Gene 4780] {aka IMDDHH, NRF2, Nrf-2}, PDCD1 (programmed cell death 1) [NCBI Gene 100533201], FMO3 (flavin containing dimethylaniline monoxygenase 3) [NCBI Gene 2328] {aka FMOII, TMAU, dJ127D3.1}, Il33 (interleukin 33) [NCBI Gene 77125] {aka 9230117N10Rik, Il-33, Il1f11, NF-HEV}, FFAR2 (free fatty acid receptor 2) [NCBI Gene 2867] {aka FFA2R, GPR43}, HDAC9 (histone deacetylase 9) [NCBI Gene 9734] {aka HD7, HD7b, HD9, HDAC, HDAC7B, HDAC9B}, Il22 (interleukin 22) [NCBI Gene 50929] {aka IL-22, IL-22a, ILTIFa, If2b1, Iltif}, CASP1 (caspase 1) [NCBI Gene 834] {aka ICE, IL1BC, P45}, CYP2E1 (cytochrome P450 family 2 subfamily E member 1) [NCBI Gene 1571] {aka CPE1, CYP2E, P450-J, P450C2E}, MTOR (mechanistic target of rapamycin kinase) [NCBI Gene 2475] {aka FRAP, FRAP1, FRAP2, RAFT1, RAPT1, SKS}, NLRP3 (NLR family pyrin domain containing 3) [NCBI Gene 114548] {aka AGTAVPRL, AII, AVP, C1orf7, CIAS1, CLR1.1}, PYY (peptide YY) [NCBI Gene 5697] {aka PYY-I, PYY1}, NR1H4 (nuclear receptor subfamily 1 group H member 4) [NCBI Gene 9971] {aka BAR, FXR, HRR-1, HRR1, PFIC5, RIP14}, PTK2B (protein tyrosine kinase 2 beta) [NCBI Gene 2185] {aka CADTK, CAKB, FADK2, FAK2, PKB, PTK}, SLC2A2 (solute carrier family 2 member 2) [NCBI Gene 6514] {aka GLUT2}, Ppara (peroxisome proliferator activated receptor alpha) [NCBI Gene 19013] {aka 4933429D07Rik, Nr1c1, PPAR-alpha, PPARalpha, Ppar}, Dio2 (iodothyronine deiodinase 2) [NCBI Gene 65162] {aka 5DII, DIOII}, MYD88 (MYD88 innate immune signal transduction adaptor) [NCBI Gene 4615] {aka IMD68, MYD88D, WM1}, PRKAA2 (protein kinase AMP-activated catalytic subunit alpha 2) [NCBI Gene 5563] {aka AMPK, AMPK2, AMPKa2, PRKAA}, PIK3CB (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta) [NCBI Gene 5291] {aka P110BETA, PI3K, PI3KBETA, PIK3C1}, Gpt (glutamic pyruvic transaminase, soluble) [NCBI Gene 76282] {aka 1300007J06Rik, 2310022B03Rik, ALT, ALT1, Gpt-1, Gpt1}, IL1B (interleukin 1 beta) [NCBI Gene 3553] {aka IL-1, IL1-BETA, IL1F2, IL1beta}, Gcg (glucagon) [NCBI Gene 24952] {aka GLP-1, Glp1, Glp2}, Tlr4 (toll-like receptor 4) [NCBI Gene 21898] {aka Lps, Ly87, Ran/M1, Rasl2-8}, INS (insulin) [NCBI Gene 3630] {aka IDDM, IDDM1, IDDM2, ILPR, IRDN, MODY10}, Nr1h4 (nuclear receptor subfamily 1, group H, member 4) [NCBI Gene 60351] {aka Fxr}, CYP7A1 (cytochrome P450 family 7 subfamily A member 1) [NCBI Gene 1581] {aka CP7A, CYP7, CYPVII}, FFAR3 (free fatty acid receptor 3) [NCBI Gene 2865] {aka FFA3R, GPR41}, AKT1 (AKT serine/threonine kinase 1) [NCBI Gene 207] {aka AKT, PKB, PKB-ALPHA, PRKBA, RAC, RAC-ALPHA}, TLR4 (toll like receptor 4) [NCBI Gene 7099] {aka ARMD10, CD284, TLR-4, TOLL}, Smpd3 (sphingomyelin phosphodiesterase 3, neutral) [NCBI Gene 58994] {aka 4631433G07Rik, Nsm2, fro, nSMase2}, Cers6 (ceramide synthase 6) [NCBI Gene 241447] {aka 4732462C07Rik, Lass6, T1L}, IL18 (interleukin 18) [NCBI Gene 3606] {aka IGIF, IL-18, IL-1g, IL1F4}, TLR9 (toll like receptor 9) [NCBI Gene 54106] {aka CD289}, Mtor (mechanistic target of rapamycin kinase) [NCBI Gene 56718] {aka Frap1, RAFT1}, NR0B2 (nuclear receptor subfamily 0 group B member 2) [NCBI Gene 8431] {aka SHP, SHP1}, SLC10A1 (solute carrier family 10 member 1) [NCBI Gene 6554] {aka FHCA2, NTCP}, FGF19 (fibroblast growth factor 19) [NCBI Gene 9965], Gcg (glucagon) [NCBI Gene 14526] {aka GLP-1, Glu, PPG}, NFKB1 (nuclear factor kappa B subunit 1) [NCBI Gene 4790] {aka CVID12, EBP-1, KBF1, NF-kB, NF-kB1, NF-kappa-B1}
- **Diseases:** toxicity (MESH:D064420), hypercholesterolemic (MESH:D006938), Insulin Resistance (MESH:D007333), infection (MESH:D007239), gastrointestinal (MESH:D005767), lipid metabolism disorders (MESH:D052439), HCC (MESH:D006528), time-restricted eating (MESH:D002313), hepatic lipid accumulation (MESH:D011017), hepatitis (MESH:D056486), hepatic pathology (MESH:D005598), constipation (MESH:D003248), liver injury (MESH:D017093), type 2 diabetes (MESH:D003924), liver fibrosis (MESH:D008103), chronic kidney disease (MESH:D051436), NAFLD (MESH:D065626), Dysbiosis (MESH:D064806), cancer (MESH:D009369), mitochondrial dysfunction (MESH:D028361), injury to (MESH:D014947), ileum (MESH:D007078), disease (MESH:D004194), gastrointestinal symptoms (MESH:D012817), Inflammation (MESH:D007249), MASLD (MESH:D008107), cirrhosis (MESH:D005355), hyperlipidemia (MESH:D006949), metabolic syndrome (MESH:D024821), itch (MESH:D011537), metabolic abnormalities (MESH:D008659), stroke (MESH:D020521), MASH (MESH:D005234), obese (MESH:D009765)
- **Chemicals:** CDCA (MESH:D002635), propionate (MESH:D011422), LCA (MESH:D008095), carbohydrate (MESH:D002241), fatty acid (MESH:D005227), Nicotine (MESH:D009538), butyrate (MESH:D002087), MTTs (MESH:C070243), unsaturated fatty acids (MESH:D005231), HDA (MESH:C012346), L-carnitine (MESH:D002331), INT-777 (MESH:C545501), T4 (MESH:D013974), Branched-chain short-chain fatty acids (-), olive oil (MESH:D000069463), BAs (MESH:D001647), 5-HT (MESH:D012701), glucose (MESH:D005947), RO5527239 (MESH:C000591388), SCFAs (MESH:D005232), beta-glucans (MESH:D047071), acetate (MESH:D000085), sphingolipid (MESH:D013107), tryptophan (MESH:D014364), T3 (MESH:D014284), alcohol (MESH:D000438), IAA (MESH:C030737), LPS (MESH:D008070), lipid (MESH:D008055), OCA (MESH:C464660), isobutyrate (MESH:D058610), pioglitazone (MESH:D000077205), prebiotics (MESH:D056692), carboxymethylcellulose (MESH:D002266), UDCA (MESH:D014580), sodium butyrate (MESH:D020148), fructooligosaccharides (MESH:C116580), tricarboxylic acid (MESH:D014233), Choline (MESH:D002794), TMAO (MESH:C005855), TC (MESH:D013667), deoxycholic acid (MESH:D003840), ethanol (MESH:D000431), cholesterol (MESH:D002784), TMA (MESH:C023336), aldehydes (MESH:D000447), ceramide (MESH:D002518), branched-chain amino acid (MESH:D000597), alkaloid (MESH:D000470), inulin (MESH:D007444), free fatty acids (MESH:D005230), theabrownins (MESH:C569455), Metformin (MESH:D008687)
- **Species:** Bifidobacterium (genus) [taxon 1678], Homo sapiens (human, species) [taxon 9606], [Clostridium] leptum (species) [taxon 1535], Bacteria Latreille et al. 1825 (Bacteria stick insect, genus) [taxon 629395], Escherichia coli Nissle 1917 (strain) [taxon 316435], Bacteroides xylanisolvens (species) [taxon 371601], Lactobacillus gasseri (species) [taxon 1596], Akkermansia muciniphila (species) [taxon 239935], Beduinibacterium (genus) [taxon 1987009], gut metagenome (species) [taxon 749906], Limosilactobacillus reuteri (species) [taxon 1598], Aspergillus (genus) [taxon 5052], Christensenella (genus) [taxon 990721], Bacillota (clostridial firmicutes, phylum) [taxon 1239], Anaerotruncus (genus) [taxon 244127], Klebsiella pneumoniae (species) [taxon 573], Saccharomyces boulardii [taxon 252598], Saccharomyces cerevisiae (baker's yeast, species) [taxon 4932], Prevotella (genus) [taxon 838], Mus musculus (house mouse, species) [taxon 10090], Escherichia coli (E. coli, species) [taxon 562], Lachnoclostridium (genus) [taxon 1506553], Glycine max (soybean, species) [taxon 3847], Candida albicans (species) [taxon 5476], Nicotiana tabacum (American tobacco, species) [taxon 4097], [Clostridium] scindens (species) [taxon 29347], Enterobacterales (order) [taxon 91347], Fungi (kingdom) [taxon 4751], Enterococcus (genus) [taxon 1350], Aureobasidium pullulans (species) [taxon 5580], Agathobacter rectalis (species) [taxon 39491], Pseudomonadota (proteobacteria, phylum) [taxon 1224], Fusarium foetens (species) [taxon 246455], Desulfovibrio (genus) [taxon 872]
- **Mutations:** G/G, cysteine-aspartic acid, rs738409

## Full text

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## Figures

4 figures with captions in the complete paper: https://tomesphere.com/paper/PMC12942669/full.md

## References

194 references — full list in the complete paper: https://tomesphere.com/paper/PMC12942669/full.md

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Source: https://tomesphere.com/paper/PMC12942669