Gut-liver axis in diabetes: Mechanisms and therapeutic opportunities

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.