---
title: "mTOR–glycolysis axis in ulcerative colitis: immunometabolic drivers of barrier dysfunction"
id: "frontiers-in-immunology-1-unraveling-the-pleiotropic-roles-of-the-mtor-glycolytic-axis-in-ulcerative"
canonical_url: "https://medichelpline.com/clinical-feed/frontiers-in-immunology-1-unraveling-the-pleiotropic-roles-of-the-mtor-glycolytic-axis-in-ulcerative"
content_type: "clinical_feed_article"
specialty: "Infectious Disease"
source_name: "Frontiers in Immunology"
source_url: "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1889686"
published_at: "2026-09-02T00:00:00.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# mTOR–glycolysis axis in ulcerative colitis: immunometabolic drivers of barrier dysfunction
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/frontiers-in-immunology-1-unraveling-the-pleiotropic-roles-of-the-mtor-glycolytic-axis-in-ulcerative
- **Specialty:** [Infectious Disease](https://medichelpline.com/clinical-feed/infectious-disease.md)
- **Primary Source:** Frontiers in Immunology
- **Source URL:** [Original Journal Publication](https://www.frontiersin.org/articles/10.3389/fimmu.2026.1889686)
- **Published At:** 2026-09-02T00:00:00.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
- Ulcerative colitis (UC) is a chronic relapsing inflammation of the colonic mucosa driven by interactions among epithelial barrier integrity, host immunity, and microbial metabolism. The mTOR signaling pathway sits at the center of this immunometabolic network. - The review frames the **mTOR–glycolysis axis** as a cell-type–specific regulator that integrates nutrient cues, microbial signals, and inflammatory inputs to reprogram glycolytic flux across immune and epithelial populations in UC. - mTOR functions in two complexes: **mTORC1** (sensing amino acids, energy, oxygen) and **mTORC2** (responding to growth factors and translational state); both converge to promote glycolytic reprogramming through HIF-1α, c-Myc, and AKT-driven pathways. - Key glycolytic control points in UC include GLUT1/3-mediated glucose uptake, mitochondrial-bound **HK2** catalyzing rate-limiting phosphorylation, and the oligomeric-state–dependent functions of **PKM2** that couple metabolism to transcription. - Aberrant mTOR–glycolysis activation in neutrophils, macrophages, ILC3s, and CD4+ effector T cells fuels inflammatory programs (oxidative burst, NETosis, M1 polarization, Th17 pathogenicity) while impairing Treg function and metabolic fitness. - In intestinal epithelial cells, mTOR-driven glycolytic rewiring undermines barrier integrity, disrupts epithelial regeneration, and establishes a metabolic–secretory crosstalk that sustains mucosal inflammation. - Clinical biomarkers tied to glycolytic metabolism in UC include serum or tissue PKM2, fecal lactate, tissue HIF-1α, PDK2, GLUT1, and HK2; these correlate with disease activity, inflammation markers, and mucosal damage. - Therapeutic implications emphasize cell-selective targeting of metabolic checkpoints within the mTOR–glycolysis axis rather than broad systemic inhibition, positioning precision metabolic modulation as a potential avenue to restore mucosal homeostasis. - The review synthesizes molecular mechanisms, regulatory nodes, and cell-specific consequences of mTOR–glycolysis dysregulation, but detailed interventional outcomes or clinical trial data were not reported in the source.
## Clinical Analysis & Structured Key Points
Frontiers | Unraveling the pleiotropic roles of the mTOR-glycolytic axis in ulcerative colitis: from immunometabolic dysregulation to mucosal barrier remodeling REVIEW article Front. Immunol. , 02 September 2026 Sec. Autoinflammatory Disorders Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1889686 Published in Frontiers in Immunology Autoinflammatory Disorders 7 impact factor 11.3 citescore Editor & Reviewers Edited by R M Ravi Misra Reviewed by M O Masoud Ojarudi H T Heikrujam Thoihen Meitei Outline Figures and Tables Figure 1 View in article Table 1 Clinical biomarkers related to glycolytic metabolism in UC. View in article Table 2 The role and mechanism of mTOR and glycolysis in regulating immune cells in the intestinal microenvironment of UC. View in article Table 3 The role and mechanism of mTOR and glycolysis in regulating intestinal epithelial cells in the intestinal microenvironment of UC. View in article Table 4 Clinically approved mTOR inhibitors. View in article REVIEW article Front. Immunol. , 02 September 2026 Sec. Autoinflammatory Disorders Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1889686 Unraveling the pleiotropic roles of the mTOR-glycolytic axis in ulcerative colitis: from immunometabolic dysregulation to mucosal barrier remodeling Y C Yanjie Chen 1,2 J X JinYin Xiao 1 L X Limin Xiao 2 A C Anni Chen 1,2 L H Lizhi He 1 Z W Zhenquan Wang 1 * 1. Department of Anorectal, the Second Affiliated Hospital of Hunan University of Traditional Chinese Medicine, Changsha, China 2. Graduate School of Hunan University of Chinese Medicine, Changsha, China Article metrics View details Abstract Ulcerative colitis (UC) is a chronic, relapsing inflammatory disorder of the colonic mucosa, whose pathogenesis is intricately linked to metabolic reprogramming within both immune and epithelial compartments. The mechanistic target of rapamycin (mTOR) signaling pathway serves as a central immunometabolic hub that integrates nutrient availability, microbial cues, and inflammatory signals to orchestrate glycolytic flux, thereby profoundly shaping the functional plasticity of diverse intestinal cell populations. This review systematically delineates, from a cell-type-specific perspective, the divergent regulatory roles of the mTOR-glycolysis axis in intestinal immunity and mucosal barrier homeostasis. We first outline the core molecular architecture of mTORC1/mTORC2-driven glycolytic reprogramming, highlighting key regulatory nodes including GLUT1/3-mediated glucose uptake, HK2-dependent rate-limiting phosphorylation, and PKM2-governed metabolic-transcriptional switching. Subsequently, we examine how aberrant mTOR-glycolysis axis activation in neutrophils, macrophages, type 3 innate lymphoid cells, and CD4+ T effector subsets propagates a feed-forward inflammatory loop—exacerbating oxidative burst, NETosis, M1 polarization, and Th17 pathogenicity—while simultaneously undermining the metabolic fitness and suppressive integrity of regulatory T cells. Moreover, we discuss the metabolic rewiring of intestinal epithelial cells via the mTOR-glycolysis axis, which compromises barrier integrity, disrupts epithelial regeneration, and initiates a “metabolic-secretory” crosstalk that perpetuates mucosal inflammation. Collectively, this review positions the mTOR-glycolysis axis as a rheostat governing the transition from homeostatic immunosurveillance to pathogenic inflammation in UC, and proposes that cell-selective metabolic checkpoint targeting—rather than broad systemic inhibition—represents a promising precision strategy for future therapeutic intervention. 1 Introduction Ulcerative colitis (UC) is a chronic, idiopathic inflammatory bowel disease (IBD) characterized by a relapsing-remitting course of colonic mucosal inflammation. Typically, the disease process originates in the rectum and propagates proximally in a continuous fashion, involving variable extents of the colon ( 1 ). Although the incidence of UC has historically predominated in Western nations, its global epidemiological landscape is undergoing a profound transition. While trends in high-income countries have begun to plateau, newly industrialized regions—including Asia, Latin America, and Africa—are witnessing a rapid and disproportionate surge in disease prevalence ( 2 ). The pathogenesis of UC is widely conceptualized as a multifactorial process wherein environmental triggers and dysregulated microbial metabolic signatures converge in genetically susceptible individuals to incite a chronic, aberrant immune response against the colonic mucosa, ultimately culminating in the collapse of epithelial barrier homeostasis ( 3 ). To date, the triad of intestinal epithelial barrier integrity, host immune reactivity, and gut microbial metabolic homeostasis remains pivotal in both the pathogenesis and therapeutic landscape of UC. The management paradigm has undergone a fundamental shift from reactive symptom control toward proactive, target-driven strategies centered on “mucosal healing”. Nevertheless, conventional pharmacological interventions—including aminosalicylates, corticosteroids, immunomodulators, and biologics—encounter a formidable “therapeutic ceiling,” with a significant subset of patients exhibiting primary non-response or secondary loss of response to existing biologics and small-molecule inhibitors ( 4 ). Therefore, elucidating UC pathogenesis from novel mechanistic perspectives and identifying innovative therapeutic targets are of paramount importance for overcoming the limitations inherent in current clinical interventions. mTOR is a highly conserved serine/threonine kinase that acts as a pivotal immunometabolic hub. It integrates extrinsic signals, including nutrient availability and immune challenges, to coordinate essential cellular processes such as growth, autophagy, and immune cell lineage specification ( 5 ). Emerging evidence indicates that the mTOR signaling pathway integrates luminal nutrient cues with host immune inputs to modulate the reciprocal balance between pro-inflammatory T helper 17 (Th17) and regulatory T (Treg) cells. Dysregulation of this signaling axis precipitates the breakdown of intestinal immune tolerance and exacerbates the chronic inflammatory milieu characteristic of UC ( 6 ). By positioning the mTOR pathway at the nexus of luminal metabolic equilibrium and systemic immune reactivity, fine-tuning this signaling axis offers a dual therapeutic potential: not only to dampen refractory inflammation but also to reinstate metabolic homeostasis within the intestinal epithelial cells of UC patients ( 7 , 8 ). Beyond its canonical role in bioenergetic replenishment, glycolysis serves as a critical metabolic nexus that shunts glucose-derived carbon intermediates into divergent biosynthetic branches. This redirection fulfills the heightened anabolic demands of cells and fuels the inflammatory effector functions of activated immune subsets ( 9 ). Evidence suggests that this metabolic transition toward accelerated glycolysis—commonly termed metabolic reprogramming—functions as a fundamental bioenergetic engine. It governs the pro-inflammatory polarization of mucosal macrophages and the differentiation of Th17 cells, thereby precipitating a cytokine storm and exacerbating the breakdown of intestinal immune tolerance ( 10 ). Consequently, the aberrant upregulation of glycolysis within the intestinal microenvironment represents a pivotal pathophysiological driver that transcends mere bioenergetic provision. During UC pathogenesis, the mTOR signaling pathway functions as a central immunometabolic hub, orchestrating glycolytic reprogramming across diverse intestinal cell populations and profoundly impacting both mucosal barrier integrity and intestinal immunity ( 11 ). Accordingly, this review adopts a cell-type-specific framework to systematically delineate the divergent regulation of the mTOR-glycolysis axis in intestinal immunity and barrier integrity, aiming to provide novel strategic perspectives and therapeutic avenues for the management of UC. 2 Overview of the core molecular mechanisms governing the mTOR-glycolysis axis 2.1 Molecular mechanisms of synergistic metabolic reprogramming driven by mTORC1 and mTORC2 complexes mTOR functions through two distinct complexes: mTORC1 and mTORC2. As a central metabolic sensor, mTORC1 integrates diverse cues—including amino acids, growth factors, energy status (ATP/AMP), and oxygen levels—via its precise lysosomal localization. In contrast, mTORC2 primarily responds to growth factor signaling and associates with functional ribosomes to integrate the cellular translational state ( 12 , 13 ). Mechanistically, mTORC1 synergizes with the core transcriptional networks of HIF-1α and c-Myc to remodel the glycolytic landscape ( 14 ). The mTORC1-eIF4E axis not only stimulates the translation of HIF-1α mRNA but also counteracts its VHL-mediated degradation under normoxia through robust protein synthesis. This culminates in the pathological stabilization of HIF-1α protein, thereby driving the transcription of GLUT1, HK2, PFKFB3, and LDHA ( 15 ). Simultaneously, mTORC1 enhances both the translation and protein stability of c-Myc by inhibiting its ubiquitination-mediated degradation. In turn, c-Myc directly drives the transcription of virtually all glycolytic enzymes and PDK1, compelling the cells into a lactate-producing mode ( 16 ). Through this HIF-1α/c-Myc transcriptional axis, mTORC1 establishes a positive feedback loop that sustains high glycolytic flux, thereby meeting the biosynthetic demands of rapidly proliferating cells ( 17 , 18 ). mTORC2 modulates glycolytic metabolism through various downstream effector pathways, with the AKT signaling axis serving as the primary regulator. Upon growth factor stimulation, mTORC2 phosphorylates AKT at Ser473; subsequently, activated AKT drives the glycolytic program at both transcriptional and post-translational levels ( 12 ). At the transcriptional level, AKT promotes the nuclear translocation of SREBP1c and upregulates glucokinase (GCK) expression, thereby facilitating glucose phosphorylation and channeling glucose-derived carbons into the glycolytic pathway. Post-translationally, mTORC2-activated AKT modulates the activity of GSK3β, whose inactivation relieves the inhibition of multiple downstream metabolic targets ( 19 ). In the liver, the mTORC2-AKT-glucokinase-SREBP1c axis orchestrates the coordination of glucose uptake and glycolytic pathways with de novo lipogenesis, thereby coupling carbohydrate catabolism to systemic metabolic homeostasis ( 20 ). In the context of cancer, the mTORC2-AKT signaling pathway interacts with PFKFB2, a rate-limiting regulator of glycolysis. PFKFB2 functions by promoting the production of fructose-2,6-bisphosphate, thereby sustaining high glycolytic rates in proliferating cells ( 21 , 22 ). 2.2 Key regulatory nodes of glycolysis Intestinal metabolic reprogramming relies on the exquisite modulation of multiple key nodes within the glycolytic pathway ( Table 1 ). Specifically, glucose uptake, HK2-catalyzed rate-limiting phosphorylation, and the dual metabolic and transcriptional roles of PKM2 constitute the core regulatory framework of glycolysis. Table 1 Biomarker Detection of source The role in glycolysis metabolism Correlation with UC clinical manifestations References PKM2 Peripheral serum PKM2 is the rate-limiting enzyme for glycolysis. Under inflammatory conditions, PKM2 transforms from a tetramer to a dimer, thereby inducing the release of pro-inflammatory factors. It is positively correlated with the Mayo score and CDAI score of UC, as well as the endoscopic activity. It is also significantly correlated with CRP and ESR. ( 23 ) lactic acid faeces Lactic acid is the final product of glycolysis. Accumulation of lactic acid indicates a shift in metabolism towards aerobic glycolysis, leading to acidosis in tissues. The fecal lactate levels in patients with active ulcerative colitis are significantly elevated. Excessive accumulation of lactate can lead to a decrease in intestinal pH, exacerbate mucosal damage, and indicate a lower clinical remission rate. ( 24 ) HIF-1α Intestinal mucosa Biopsy The upstream regulators and downstream targets of PKM2. It drives the transcription of glycolytic genes such as GLUT1 and LDHA. Epithelial cells express HIF-1α, which promotes repair, while immune cells express HIF-1α, which mediates damage. This is the core for evaluating the “spatiotemporal metabolic landscape”. ( 25 ) PDK2 Intestinal mucosa Biopsy The increase in PDK2 indicates a complete shift of the metabolic flow from the mitochondrial cycle to glycolysis, and it is a driver of tissue inflammation and oxidative stress. PDK2 is significantly upregulated in patients with active ulcerative colitis. High expression indicates severe mitochondrial dysfunction and a lower rate of clinical remission. ( 26 ) GLUT1 Intestinal mucosa Biopsy GLUT1 is the core transporter for cells to take in glucose. Its high expression directly drives a large influx of glucose, providing sufficient substrates for the subsequent glycolysis process. The expression intensity and spatial distribution of GLUT1 reflect the metabolic requirements of the tissue. In UC, it is a clear biomarker of high metabolic activity of cells. ( 27 ) HK2 Intestinal mucosa Biopsy HK2 efficiently utilizes ATP to phosphorylate glucose into 6-phosphoglucose by binding to the outer mitochondrial membrane, thereby irreversibly initiating and maintaining a high glucose glycolysis flux. The expression of HK2 at the top indicates that the epithelial cells are undergoing severe metabolic remodeling, suggesting that the mucosal barrier is about to develop ulcers or erosions. It can be used as an early biochemical warning indicator before endoscopic examination. ( 28 ) Clinical biomarkers related to glycolytic metabolism in UC. 2.2.1 Glucose uptake: GLUT1/3-mediated regulation of the metabolic gateway The initiation of glycolysis is predicated on transmembrane glucose transport as a rate-limiting prerequisite, which is primarily mediated by the transporters GLUT1 and GLUT3. Research indicates that while GLUT1 is ubiquitously overexpressed across various malignancies to sustain basal glucose requirements, GLUT3—possessing a five-fold higher substrate affinity and superior transport velocity—affords cancer cells a competitive advantage in glucose acquisition within low-glucose microenvironments ( 29 ). Accordingly, dysregulated GLUT1 and GLUT3 expression is considered a major contributor to the malignant evolution of tumors ( 30 ). Acting as a “metabolic switch”, the upregulation of GLUT1/3 facilitates accelerated glycolytic flux in UC mucosa, echoing its established role in cancer biology ( 31 ). Mechanistically, the transcriptional landscape is dominated by HIF-1α and c-Myc; stabilized HIF-1α under hypoxic conditions directly activates the transcription of these transporters, whereas c-Myc potently augments their levels via synergistic recruitment to the promoter elements ( 32 ). Furthermore, the PI3K/Akt signaling pathway orchestrates multi-layered glycolytic reprogramming by facilitating the membrane translocation and activation of GLUT1, while simultaneously phosphorylating a series of downstream metabolic enzymes, including HK2, PFKFB3/4, and PKM2 ( 33 ). 2.2.2 HK2: a mitochondrial-bound regulatory node governing rate-limiting phosphorylation Upon cellular entry, glucose is phosphorylated into glucose-6-phosphate (G6P) by hexokinase 2 (HK2), a reaction that constitutes the first irreversible and rate-limiting step of glycolysis ( 34 ). Distinct from other hexokinase isoforms, HK2 is markedly upregulated in tumor cells and possesses an exclusive mitochondrial-tethering capacity. This localization is orchestrated by its N-terminal hydrophobic domain, which mediates the interaction with the voltage-dependent anion channel (VDAC), thereby anchoring HK2 securely to the outer mitochondrial membrane ( 35 ). This subcellular compartmentalization endows HK2 with a dual functional edge: it facilitates the privileged access to mitochondrially exported ATP for glucose phosphorylation, thereby markedly accelerating glycolytic flux and fueling anabolism with abundant biosynthetic precursors. Concurrently, by safeguarding the permeability barrier of the outer mitochondrial membrane, HK2 suppresses cytochrome c release, directly antagonizing the intrinsic apoptotic signaling pathway ( 36 ). The transcriptional landscape of HK2 is orchestrated by a network of oncogenic cascades, including the PI3K/Akt ( 37 ), MAPK ( 38 ), and NF-κB ( 39 ) pathways. Beyond its canonical enzymatic hallmarks, emerging evidence identifies HK2 as a signaling transducer that modulates mTORC1 activity and drives the remodeling of the immune microenvironment ( 40 ). The mitochondrial dissociation of hexokinase 2 (HK2) represents a pivotal event in the immune cell response to acute stress. Under steady-state conditions or in the presence of pro-survival signaling, Akt suppresses GSK3β activity to maintain the mitochondrial localization of HK2 ( 41 ). Conversely, under inflammatory stress, activated GSK3β directly phosphorylates HK2 at residues Thr473 and Ser465, triggering its detachment from the mitochondria. This translocation not only impairs efficient energy coupling but also serves as a critical molecular switch orchestrating neutrophil apoptosis and the oxidative burst ( 42 ). 2.2.3 PKM2: a dual-function metabolic and transcriptional hub governed by oligomeric state switching The terminal regulatory gatekeeper of glycolysis is presided over by Pyruvate Kinase M2 (PKM2), which is distinguished by its ability to execute dual metabolic and transcriptional programs through reversible oligomeric switching. In its highly active tetrameric state, PKM2 catalyzes the irreversible conversion of phosphoenolpyruvate (PEP) to pyruvate, propelling glycolytic carbon flux toward its terminal stage for efficient ATP production. Conversely, when PKM2 dissociates into low-activity dimers, upstream glycolytic intermediates accumulate and are shunted into the pentose phosphate pathway and serine synthesis pathway. This metabolic rewiring provides essential biosynthetic building blocks—including nucleotides, amino acids, and lipids—to sustain the biomass demands of rapidly proliferating tumor cells ( 43 ). More pivotally, the dimeric form of PKM2 undergoes nuclear translocation, where it assumes non-canonical roles as both a transcriptional coactivator and a protein kinase ( 44 ). In the UC intestinal mucosal inflammatory microenvironment, the equilibrium between PKM2 tetramers and dimers is exquisitely regulated by a diverse repertoire of post-translational modifications (PTMs), FGFR1-mediated Tyr105 phosphorylation ( 45 ), Lys305 acetylation ( 46 ), and ROS-induced Cys358 oxidation collectively inhibit PKM2 activity ( 47 ), thereby diverting metabolic flux toward biosynthetic pathways. Concurrently, pro-inflammatory signaling triggers LDHA phosphorylation at the Tyr10 residue. This modification enhances the binding affinity of LDHA for its substrate NADH, accelerating the conversion of pyruvate to lactate to sustain the rapid energetic demands of immune cells under stress ( 48 ). Beyond rapid regulatory mechanisms such as phosphorylation and oxidation, the control of protein stability for key metabolic enzymes is a cornerstone of immune cell metabolic reprogramming. PFKFB3, a master regulator of glycolysis, is highly expressed during immune cell activation to drive ATP production. However, its intracellular abundance is stringently governed by the ubiquitin ligase complex APC/C-Cdh1, which mediates PFKFB3 ubiquitination and subsequent proteasomal degradation, effectively constraining glycolytic flux ( 49 ). In the intestinal inflammatory microenvironment, dysregulation of this degradation mechanism can lead to persistent metaboli
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