Gut-liver axis in diabetes: Mechanisms and therapeutic opportunities

Table 1 Key mediators of the gut-liver axis relevant to diabetes and insulin resistance

Mediator	Mechanism of action	Clinical relevance in T2D	Ref.
Pro-inflammatory cytokines (IL-6, TNF-α, IL-1β)	Impair insulin signaling via IRS-1 inhibition; Activate hepatic inflammation through NF-κB/JNK pathways	Elevated in T2D, targets for anti-inflammatory therapies	Lara-Guzmán et al[48]; Rodrigues et al[49]; Liu et al[50]; D'Alessandris et al[51]
Lipopolysaccharides (LPS) and TLR4-JNK-NF-κB pathway	Trigger hepatic inflammation and insulin resistance following microbial translocation	LPS-driven endotoxemia links dysbiosis to metabolic dysfunction	Li and Wu[58]; Li et al[59]; Li et al[60]; Tanti and Jager[61]; Li et al[62]
FXR and TGR5 receptors	Regulate bile acid metabolism, inhibit gluconeogenesis, promote GLP-1 secretion, and suppress inflammation	Dysregulated in T2D; Therapeutic targets (e.g., FXR agonists)	Grüner and Mattner[39]; Kumari et al[43]; Bertolini et al[64]; Evangelakos et al[65]
Loss of SCFA-producing bacteria (e.g., Faecalibacterium prausnitzii)	Reduces gut barrier integrity, lowers SCFA and GLP-1 production, enhances intestinal permeability	Restoration improves insulin sensitivity and gut-liver communication	Garcia-Gutierrez et al[66]; He et al[67]; Verhoog et al[68]; Moran-Ramos et al[69]
Expansion of pathobionts (e.g., Prevotella copri)	Elevates LPS and BCAA production; activates mTOR-S6K1 pathway impairing insulin signaling	Associated with metabolic endotoxemia, systemic inflammation, and worsened glucose control	Murugesan et al[8]; Leite et al[70]; Gong et al[72]
Microbial metabolites (imidazole propionate, IPA, H2S, succinate, EE, PAGln)	Modulate insulin signaling, oxidative stress, hepatic lipotoxicity, and inflammatory cascades	Emerging biomarkers and therapeutic targets for metabolic dysfunction	Zeng et al[80]; Koh et al[81]; Koh et al[82]; Cussotto et al[83]; Yang et al[84]; Munteanu et al[85]; Huang et al[86]; Xue et al[87]; Chen et al[88]; Drda and Smith[89]
Bacterial extracellular vesicles	Transfer microbial molecules (e.g., LPS, DNA) across intact barriers to hepatic immune cells, triggering inflammation	Represent a novel barrier-independent mechanism contributing to hepatic insulin resistance	Melo-Marques et al[90]; Butcko et al[91]
Innate lymphoid cells (ILC3-IL-22 signaling)	Maintain epithelial barrier integrity and mucosal immune balance; Regulate gut homeostasis	ILC dysregulation associated with intestinal permeability defects and systemic inflammation in T2D	Wang et al[122]; Yin et al[123]; Horn and Sonnenberg[127]
Endocannabinoid system (ECS)	Modulates intestinal permeability, immune activation, hepatic lipid metabolism, and inflammatory tone	Dysregulated ECS signaling contributes to obesity, insulin resistance, and steatohepatitis	Bazwinsky-Wutschke et al[133]; Liu et al[134]; Cuddihey et al[135]; Lipina et al[136]; Roser et al[137]; O'Sullivan et al[138]; Ellermann[139]

IL-1β: Interleukin-1 beta; IL-6: Interleukin-6; TNF-α: Tumor necrosis factor-α; TLR4: Toll-like receptor 4; JNK: C-Jun N-terminal kinase; NF-κB: Nuclear factor kappa B; LPS: Lipopolysaccharide; FXR: Farnesoid X receptor; TGR5: Takeda G protein-coupled receptor 5; SCFAs: Short-chain fatty acids; IPA: Indole-3-propionic acid; H₂S: Hydrogen sulfide; EE: Endogenous ethanol; PAGln: Phenylacetylglutamine; ILC3: Group 3 innate lymphoid cell; ECS: Endocannabinoid system; IRS-1: Insulin receptor substrate-1; GLP-1: Glucagon-like peptide-1; BCAA: Branched-chain amino acids; S6K1: Ribosomal protein S6 kinase 1; mTOR: Mechanistic target of rapamycin; T2D: Type 2 diabetes.

Table 2 Key therapeutic strategies targeting gut-liver axis in diabetes

Strategy	Mechanism of action	Examples	Clinical tatus	Ref.
Probiotics	Modulate microbiota composition; Enhance SCFA production; Reinforce gut barrier integrity	Lactobacillus, Bifidobacterium strains	Approved adjuncts; Variable efficacy	Grylls et al[156]; Zhang et al[160]; Memon et al[162]; McLoughlin et al[163]
Prebiotics	Promote growth of beneficial microbes; Increase SCFA levels; Reduce gut permeability and inflammation	Inulin, resistant starch, fructooligosaccharides	Clinically validated for glycemic improvement	McLoughlin et al[163]; Luzzi et al[165]; Jayedi et al[171]
Synbiotics	Synergistic effect of probiotics and prebiotics; Improve glycemia and lipid profiles	Probiotic + fiber combinations	Emerging evidence; Under clinical study	McLoughlin et al[163]; Luzzi et al[165]; Jayedi et al[171]
Postbiotics	Deliver microbial metabolites (e.g., SCFAs) directly to host tissues to modulate metabolism and immunity	SCFA supplements (e.g., acetate, butyrate infusions)	Experimental	McLoughlin et al[163]; Fang et al[164]; Luzzi et al[165]
Fecal microbiota transplantation	Reconstitute healthy microbiome diversity; Restore SCFA and bile acid metabolism	Donor stool capsules or infusions	Experimental; Some success in T2D trials	Wu et al[167]; Yadegar et al[168]
Zonulin inhibitors	Prevent tight junction disassembly; Restore intestinal barrier integrity	Larazotide acetate (AT-1001)	Phase III for celiac; Early-stage for T2D	Choi et al[73]; Górecka et al[143]; Yonker et al[145]; Tajik et al[146]; Jayashree et al[178]; Yuan et al[179]
Dietary interventions	Enrich SCFA-producing bacteria; Upregulate tight junction proteins; Reduce systemic inflammation	High-fiber and polyphenol-rich diets (berries, teas)	Clinically recommended adjunct therapy	Verhoog et al[68]; Mazhar et al[147]; Han et al[169]
GLP-1 receptor agonists	Enhance insulin secretion; Reduce hepatic and gut inflammation; Improve barrier function	Liraglutide, semaglutide	Approved for T2D and obesity	Zhang et al[141]; Alharbi[149]
SGLT2 inhibitors	Improve glycemic control; Reduce systemic and hepatic inflammation	Empagliflozin, dapagliflozin	Approved for T2D and cardiovascular protection	Theofilis et al[150]; Zhang et al[151]
FXR agonists	Regulate bile acid metabolism; Restore barrier function; Suppress liver fibrosis and inflammation	Obeticholic acid	Approved for PBC; Under investigation for NASH	Zhang et al[152]
TLR4 antagonists	Block LPS signaling to prevent endotoxin-driven inflammation	Eritoran	Experimental	Liang et al[170]
Cytokine inhibitors	Suppress pro-inflammatory cytokines (e.g., IL-1β) to reduce hepatic and systemic inflammation	Canakinumab, anakinra	Under investigation	Everett et al[157]; Howard et al[158]
AhR agonists	Activate anti-inflammatory pathways; Stabilize tight junctions	Indole derivatives (e.g., FICZ, 5-HIAA)	Experimental; Preclinical promising	Cussotto et al[83]; Zheng et al[120]; Du et al[121]; Pernomian et al[159]
Gut-targeted biologics/probiotics	Modulate mucosal immunity; Reduce pro-inflammatory responses locally	Engineered probiotics, oral cytokine blockers	Preclinical and early-phase trials	Zhang et al[160]

This table summarizes current and emerging interventions aimed at modulating the gut microbiota, enhancing intestinal barrier integrity, reducing inflammation, and restoring gut-liver metabolic signaling. GLP-1: Glucagon-like peptide-1; SCFAs: Short-chain fatty acids; SGLT2: Sodium-glucose cotransporter-2; FXR: Farnesoid X receptor; TLR4: Toll-like receptor 4; AhR: Aryl hydrocarbon receptor; T2D: Type 2 diabetes; LPS: Lipopolysaccharide; PBC: Primary biliary cirrhosis; NASH: Non-alcoholic steatohepatitis; IL-1β: Interleukin-1 beta; FICZ: 6-formylindolo[3,2-b]carbazole; 5-HIAA: 5-hydroxyindole-3-acetic acid.