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.