Bitter side of sweet: A stage-dependent immunometabolic model linking metabolic syndrome and inflammatory bowel disease

Table 1 Shared pathophysiological mechanisms linking metabolic syndrome and inflammatory bowel disease

	Shared feature	MetS	IBD
Epithelial barrier	Barrier dysfunction; increased intestinal permeability	LPS entry fuels systemic low-grade inflammation	Barrier loss enables microbial entry into the lamina propria, driving localized chronic mucosal inflammation
	TJ protein dysregulation	Dysregulated claudin-1, claudin-4, claudin-7 expression	Claudin-2 (increase); (decrease) claudin-4, claudin-5, claudin-8
	Mucus layer alterations (MUC2)	HFD and fructose impair Muc2 expression, secretion and mucus thickness	UC: MUC2 deficiency leads to spontaneous colitis and increased susceptibility to injury. CD: Mucus quality is impaired
	Paneth cell dysfunction and defensin loss	Protect against diet-induced metabolic dysfunction	Contributes to dysbiosis and barrier breakdown
Immune system	Macrophage polarization	M1 (increase): Promotes chronic adipose inflammation. M2 (decrease): Suppressed via IRS-2 inhibition by hyperinsulinemia	M1 (increase): Contributes to mucosal damage. M2 (decrease): Downregulated by inflammatory cytokine milieu
	Neutrophil involvement	Drives obesity-related complications	Hallmark of active mucosal inflammation
	ILC1s	Adipose-resident ILC1s produce IFN-γ promoting M1 macrophage activation and insulin resistance	ILC1 (increase) cells in the inflamed mucosa and produce IFN-γ
	ILC3s	ILC3 derived IL-22 improves barrier function	Dual role via IL-17A/IL-22 (pro-inflammatory or protective)
	Th1/Th2/Th17 imbalance	HFD promotes Th17 polarization and Treg suppression	CD: Th1/Th17; UC: Th2/Th17

MetS: Metabolic syndrome; IBD: Inflammatory bowel disease; TJ: Tight junction; MUC2: Mucin 2; ILC1s: Group 1 innate lymphoid cells; ILC3s: Group 3 innate lymphoid cells; Th1: T helper type 1 cells; Th2: T helper type 2 cells; Th17: T helper type 17 cells; HFD: High-fat diet; LPS: Lipopolysaccharide; IRS-2: Insulin receptor substrate 2; IL: Interleukin; IFN: Interferon; Treg: Regulatory T cells; UC: Ulcerative colitis; CD: Crohn’s disease.

Table 2 Hypothesized stage-specific immunometabolic biomarkers and therapeutic opportunities in metabolic syndrome-associated ulcerative colitis

Target/mechanism	Proposed biomarker or therapy	Early-stage MetS (stage I-III)	Terminal-stage MetS (stage IV)
Gal-3	Candidate biomarker of regulatory immune activity	Elevated in our MetS + UC cohort; associated with the proposed tolerogenic phenotype	Less prominent; therapeutic relevance remains uncertain
Gal-1	Candidate biomarker and investigational target	Preserved expression	Reduced expression associated with the proposed pro-inflammatory stage; depleted candidate therapy; caution due to links with insulin resistance and cancer
IL-10	Candidate marker of regulatory immune responses	Elevated levels observed in MetS + UC; associated with immune regulation	Reduced relative contribution to the inflammatory profil
IL-6/CXCL8	Biomarker; therapeutic target	Generally not dominant inflammatory pathways	Increased levels associated with advanced-stage inflammation; rationale for investigating IL-6-directed therapies
TNF-α	Inflammatory biomarker; established therapeutic pathway	Monitoring may be informative	May contribute to inflammatory amplification; anti-TNF therapies remain relevant
Composite ratios (Gal-1/IL-6, Gal-3/IL-17, IL-10/IL-6)	Candidate staging biomarkers	Potential indicators of regulatory immune predominance	Potential indicators of inflammatory predominance
IL-22 pathway	Barrier-restoring strategy	Potential relevance for maintenance of epithelial integrity	Potential relevance for restoration of impaired barrier function
Microbiota-targeted therapy	FMT, next-gen probiotics, prebiotics, postbiotics	Preserve SCFA producers; support Gal-3/IL-10 axis	May help counter dysbiosis and endotoxin-associated inflammation
GLP-1 receptor agonists	Metabolic and immunomodulatory therapy	May be particularly relevant due to effects on metabolic homeostasis, barrier integrity, and low-grade inflammation	Potential adjunctive metabolic therapy; stage-specific efficacy unknown
Metformin	Metabolic and barrier-supportive therapy	Potentially relevant due to effects on microbiota and barrier function	Potential adjunctive metabolic therapy
SGLT2 inhibitors	Metabolic and immunomodulatory therapy	Limited stage-specific rationale currently available	Mechanistically attractive due to effects on IL-6 signaling and macrophage polarization; requires validation
FXR agonists/INSR enhancers/uPA-uPAR modulation	Mucosal homeostasis restoration	Potential modulators of metabolic and mucosal homeostasis	Potential adjunctive approaches requiring further study; combined with immunomodulators

MetS: Metabolic syndrome; Gal-1: Galectin-1; Gal-3: Galectin-3; IL: Interleukin; CXCL8: C-X-C motif chemokine ligand 8; TNF: Tumor necrosis factor; GLP-1: Glucagon-like peptide-1; SGLT2: Sodium-glucose co-transporter 2; FXR: Farnesoid X receptor; INSR: Insulin receptor; uPA/uPAR: Urokinase-type plasminogen activator and its receptor; FMT: Fecal microbiota transplantation; UC: Ulcerative colitis; SCFA: Short-chain fatty acids.