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.