Dysregulated immunometabolism in gut inflammation

Abstract

Gut inflammatory diseases, including inflammatory bowel disease (IBD), infectious enteritis, and other inflammatory conditions, are among the most common non-neoplastic intestinal disorders. Their pathogenesis is often driven by an imbalance between pro-inflammatory and anti-inflammatory signals, with immune cells playing pivotal roles in maintaining this equilibrium. Immune cells in the gut exhibit complex, multifaceted functions: they eliminate pathogens, promote tissue repair, and counteract tumors, but excessive immune activation can exacerbate tissue damage and disease progression. Notably, metabolic reprogramming in inflammatory contexts serves as a key regulator of immune cell function and phenotypic switching. This includes alterations in cellular energy metabolism (e.g., macrophage polarization via disrupted glycolysis or fatty acid oxidation) and the modulation of immune responses by microenvironmental metabolites (e.g., bile acid-mediated Th17/Treg balance). While alterations in immune cell function and composition within the inflammatory milieu are well-established, the significance of disease-associated metabolic reprogramming—specifically how metabolism regulates immune cell function—has garnered increasing attention. This review explores how cellular metabolic reprogramming, changes in the metabolic microenvironment, and gut dysbiosis collectively influence the differentiation, proliferation, and function of immune cells in various intestinal inflammatory diseases, as well as their impact on disease progression.

1. Introduction

Intestinal homeostasis is crucial for human health, enabling efficient nutrient absorption, protecting against pathogen invasion, and maintaining immune balance. Disruption of this equilibrium leads to various inflammatory disorders of the gut, including inflammatory bowel disease (IBD), a chronic, non-specific inflammatory condition encompassing ulcerative colitis (UC) and Crohn’s disease (CD), and infectious enteritis caused by pathogenic bacteria, fungi, viruses, or parasites, as well as other inflammatory diseases, such as necrotizing enterocolitis (NEC). If left unchecked, these conditions cause progressive tissue damage, increase the risk of systemic infection, and, in severe cases, lead to sepsis, multi-organ failure, or malignant transformation [1].

The immune system is central to maintaining intestinal homeostasis, providing crucial protection under normal conditions. However, when immune responses become dysregulated, either through excessive activation or loss of tolerance, they can drive intestinal inflammation. In IBD, aberrant immune responses, such as inappropriate activation of macrophages, dysregulated T helper (Th) cells, and impaired regulatory T cells (Tregs), along with compromised epithelial barrier integrity, lead to the uncontrolled secretion of pro-inflammatory cytokines and sustained mucosal injury [1]. In infectious enteritis, the immune system’s ability to promptly recognize pathogens via pattern recognition receptors is critical. Effective innate immune responses, including neutrophil recruitment and antimicrobial peptide release, along with the activation of pathogen-specific adaptive immunity, are essential for pathogen clearance [2]. Failure in these mechanisms leads to persistent infections, extensive tissue damage, and potential systemic dissemination. In other inflammatory diseases, such as NEC and Celiac disease, immune cells also act as primary responders to tissue injury, as their activation triggers inflammatory cascades that influence both disease severity and recovery [3,4]. Ultimately, the delicate balance between protective immunity and pathological immune responses determines the susceptibility, clinical manifestations, and disease course of gut inflammation.

Metabolism in immune cells is not merely a source of energy but a dynamic and integral regulator of immune activation, function, and fate, particularly in the context of gut inflammation [5,6]. This concept, known as metabolic reprogramming, plays a critical role in both the pathogenesis and resolution of gut inflammation. In the inflamed intestinal microenvironment, characterized by hypoxia, fluctuating nutrient availability, and microbial stimuli, immune cells undergo profound metabolic shifts to meet increased functional demands [7]. For example, glycolysis is upregulated to support effector functions, such as neutrophil antimicrobial activity and macrophage-driven pro-inflammatory cytokine production [8]. Oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO) are preferentially utilized by long-lived memory cells and Tregs, supporting their survival and suppressive capacity [9]. Crucially, these metabolic transitions actively shape immune cell behavior. Metabolic intermediates and cofactors, such as succinate, play pivotal roles in modulating immune responses.