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

doi:10.3748/wjg.123426

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World Journal of Gastroenterology

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1007-9327

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Baishideng Publishing Group Inc, 7041 Koll Center Parkway, Suite 160, Pleasanton, CA 94566, USA

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Copyright: ©Author(s) 2027. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution-NonCommercial (CC BY-NC 4.0) license. No commercial re-use. See permissions. Published by Baishideng Publishing Group Inc.

World J Gastroenterol. Jan 7, 2027; 33(1): 123426
Published online Jan 7, 2027. doi: 10.3748/wjg.123426

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

Marina M Jovanovic, Bojana J Simovic Markovic, Nevena M Gajovic, Milan M Jovanovic, Miodrag V Jocic, Bojan S Stojanovic, Irfan F Corovic, Nevena Todorovic, Ivan P Jovanovic, Amedeo Amedei

Marina M Jovanovic, Department of Internal Medicine, Faculty of Medical Sciences, University of Kragujevac, Kragujevac 34000, Serbia

Bojana J Simovic Markovic, Nevena M Gajovic, Bojan S Stojanovic, Irfan F Corovic, Ivan P Jovanovic, Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Kragujevac 34000, Serbia

Nevena M Gajovic, Ivan P Jovanovic, Faculty of Medicine, University of East Sarajevo, Foca 73300, Srpska, Republika, Bosnia and Herzegovina

Milan M Jovanovic, Miodrag V Jocic, Medical Faculty of Military Medical Academy, University of Defense Belgrade, Belgrade 11000, Serbia

Irfan F Corovic, Department of Internal Medicine, General Hospital of Novi Pazar, Novi Pazar 36300, Serbia

Nevena Todorovic, Amedeo Amedei, Department of Experimental and Clinical Medicine, University of Florence, Florence 50134, Tuscany, Italy

Nevena Todorovic, Clinic for Infectious and Tropical Diseases, University Clinical Centre of Serbia, Belgrade 11000, Serbia

Ivan P Jovanovic, Institute of Public Health, Kragujevac 34000, Serbia

Amedeo Amedei, Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Florence 50139, Tuscany, Italy

Author contributions: Jovanovic MM conceived the review, performed the literature search, synthesized the evidence, developed the stage-dependent immunometabolic framework, and drafted the manuscript; Simovic Markovic BJ, Gajovic NM, Jocic MV, Stojanovic BS, Corovic IF, Todorovic N, and Jovanovic IP contributed to the scientific design of the review, interpretation of the literature, critical discussion of immunological and clinical evidence, and preparation of the manuscript; Stojanovic BS developed the graphical illustration of the proposed immunometabolic model; Jovanovic IP supervised the overall development of the manuscript, coordinated the revision process, and served as the corresponding author; Amedei A supervised the study, provided critical intellectual input, and contributed to the revision and refinement of the manuscript; Jovanovic MM, Simovic Markovic BJ, Gajovic NM, Jovanovic MM, Jocic MV, Stojanovic BS, Corovic IF, Todorovic N, Jovanovic IP, Amedei A reviewed, approved, and agreed to be accountable for the final version of the manuscript.

AI contribution statement: Portions of this manuscript were edited using AI tools (ChatGPT, OpenAI, version 5.0) solely for language refinement. The authors carefully reviewed and verified all AI-assisted outputs and take full responsibility for the scientific content of the manuscript.

Conflict-of-interest statement: The authors declare that they have no conflict of interest.

Corresponding author: Ivan P Jovanovic, MD, Professor, Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Svetozara Markovica 69, Kragujevac 34000, Serbia. ivanjovanovic77@gmail.com

Received: May 18, 2026
Revised: June 23, 2026
Accepted: August 31, 2026
Published online: January 7, 2027
Processing time: 175 Days and 10.6 Hours

Abstract

The increasing prevalence of metabolic syndrome (MetS) among patients with inflammatory bowel disease (IBD) has prompted renewed interest in their poorly defined bidirectional relationship, underpinned by shared mechanisms such as epithelial barrier disruption, chronic low-grade inflammation, and microbial dysbiosis. In this review, we comprehensively synthesize current evidence on the relationship between MetS and IBD, highlighting their shared pathophysiological mechanisms. We further propose a biphasic model of the MetS-IBD interaction, supported by original immunological data obtained from patients with ulcerative colitis (UC) and concomitant MetS. Early-stage MetS appears to promote a regulatory immune phenotype characterized by increased interleukin-10 and galectin-3-related pathways, which is associated with attenuated UC, whereas advanced MetS appears to be associated with a pro-inflammatory phenotype, increased interleukin-6 and C-X-C motif chemokine ligand 8 signaling, cytotoxic immune-cell infiltration, mucosal damage, and more severe UC. This paradigm should be regarded as hypothesis-generating and requires validation in independent longitudinal cohorts. Nevertheless, it provides a translational framework for future biomarker development, metabolic stratification, and stage-adapted therapeutic research in patients with IBD and metabolic comorbidity.

Keywords: Inflammatory bowel disease; Ulcerative colitis; Crohn’s disease; Metabolic syndrome; Immune dysregulation; Gut microbiota

Core Tip: This review explores the interplay between metabolic syndrome and inflammatory bowel disease through shared pathways and stage-specific immune alterations, presenting a conceptual model of their relationship, highlighting clinical and therapeutic implications, and outlining potentially new directions for future research.