The unique biology of the intestinal epithelial barrier is linked to a low baseline oxygen pressure (pO₂), characterised by a high rate of metabolites circulating through the intestinal blood and the presence of a steep oxygen gradient across the epithelial surface. These characteristics require tight regulation of oxygen homeostasis, achieved in part by hypoxia-inducible factor (HIF)-dependent signalling. Furthermore, intestinal epithelial cells (IEC) possess metabolic identities that are reflected in changes in mitochondrial function. In recent years, it has become widely accepted that oxygen metabolism is key to homeostasis at the mucosae. In addition, the gut has a vast and diverse microbial population, the microbiota. Microbiome–gut communication represents a dynamic exchange of mediators produced by bacterial and intestinal metabolism. The microbiome contributes to the maintenance of the hypoxic environment, which is critical for nutrient absorption, intestinal barrier function, and innate and/or adaptive immune responses in the gastrointestinal tract. In this review, we focus on oxygen homeostasis at the epithelial barrier site, how it is regulated by hypoxia and the microbiome, and how oxygen homeostasis at the epithelium is regulated in health and disease.

The metabolic capacity of many cells is tightly regulated and can adapt to changes in metabolic resources according to environmental changes. Tissue-resident memory (T _RM ) CD8 ⁺ T cells are one of the most abundant T cell populations and offer rapid protection against invading pathogens, especially at the epithelia. T _RM cells metabolically adapt to their tissue niche, such as the intestinal epithelial barrier. In the small intestine, the types of T _RM cells are intraepithelial lymphocytes (IELs), which contain high levels of cytotoxic molecules and express activation markers, suggesting a heightened state of activation. We hypothesize that the tissue environment may determine IEL activity. We show that IEL activation, in line with its semiactive status, is metabolically faster than circulating CD8 ⁺ T cells. IEL glycolysis and oxidative phosphorylation (OXPHOS) are interdependently regulated and are dependent on rapid access to metabolites from the environment. IELs are restrained by local availability of metabolites, but, especially, glucose levels determine their activity. Importantly, this enables functional control of intestinal T _RM cells by metabolic means within the fragile environment of the intestinal epithelial barrier.

In the past years, there have been significant advances in the understanding of how environmental conditions alone or in conjunction with pathogen invasion affect the metabolism of T cells, thereby influencing their activation, differentiation, and longevity. Detailed insights of the interlinked processes of activation and metabolism can contribute to major advances in immunotherapies. Naive and memory T cells circulate the body. In a quiescent state with low metabolic demands, they predominantly use oxidative phosphorylation for their energy needs. Recognition of cognate antigen combined with costimulatory signals results in a proliferative burst and effector molecule production, requiring rapid release of energy, achieved via dynamically reprogramming metabolic pathways. After activation, most T cells succumb to activation induced cell death, but few differentiate into memory T cells. Of note, some memory T cells permanently occupy tissues without circulating. These, tissue resident T cells are predominantly CD8 T cells, maintained in a metabolic state distinct from naïve and circulating memory CD8 T cells with elements similar to effector CD8 T cells but without undergoing proliferative burst or secreting immune mediators. They continually interact with tissue cells as part of an immune surveillance network, are well-adapted to the tissues they have made their home and where they may encounter different metabolic environments. In this review, we will discuss recent insights in metabolic characteristics of CD8 T cell biology, with emphasis on tissue resident CD8 T cells at the epithelial barriers.

Non-lymphoid organs, in mice and humans, contain CD8⁺ tissue-resident memory T (T_RM) cells. They play important roles in tissue homoeostasis as well as defence against infections and cancer. T_RM cells have common characteristics that enables their tissue residency and function. However, the wide variety of tissues, some with continually exposure to invading microbes, distinct organ structures and functions, impose tissue-specific differences on T_RM cells. Upon tissue-entry, they need to adapt to local circumstances by modifying their transcriptional machinery, enabling interactions with the - often specialised - surrounding cells and available metabolites. Heterogeneity amongst T_RM cells may have implications for their defence function, organ-specific autoimmunity and chronic immune disorders. Here we indicate shared and unique T_RM cell features within different tissues to provide a better understanding of their function and discuss possible future research directions.

The global rise in inflammatory bowel disease (IBD) and other non-communicable diseases (NCDs) over the past five decades has coincided with the widespread adoption of a Western diet and lifestyle. These conditions, characterised by chronic inflammation, are shaped by complex interactions between genetic, environmental, immunological, and microbial factors. The Western diet rich in, refined sugars, unhealthy fats, ultra-processed foods and excess salt, is increasingly recognised as a major contributor to immune dysfunction, microbial dysbiosis, and compromised intestinal barrier integrity, all hallmarks of IBD. Systems biology offers a powerful framework for untangling the complexity of IBD by integrating large-scale biological data from various sources, leveraging computational modelling, high-throughput analyses, and network-based approaches to identify key regulatory pathways and molecular interactions driving disease progression. Complementary to this, nutritional epidemiology provides critical insights into the role of diet in IBD pathogenesis. By combining systems biology with nutritional epidemiology, researchers can move toward personalised dietary interventions and new therapeutic strategies, offering new opportunities for prevention and addressing the growing burden of IBD in societies adopting Western lifestyles. This review synthesise current findings and proposes integrated approaches for future precision prevention and treatment of IBD.

Clitocybe nebularis lectin (CNL) is a GalNAcβ1‐4GlcNAc‐binding lectin that exhibits an antiproliferative effect exclusively on the Jurkat leukemic T cell line by provoking homotypic aggregation and dose‐dependent cell death. Cell death of Jurkat cells exhibited typical features of early apoptosis, but lacked the activation of initiating and executing caspases. None of the features of CNL‐induced cell death were effectively blocked with the pan‐caspase inhibitor or different cysteine peptidase inhibitors. Furthermore, CNL binding induced Jurkat cells to release the endogenous damage‐associated molecular pattern molecule high‐mobility group box 1 (HMGB1). A plant lectin with similar glycan‐binding specificity, Wisteria floribunda agglutinin (WFA) showed less selective toxicity and induced cell death in Jurkat, Tall‐104, and Hut‐87 cell lines. HMGB1 release was also detected when Jurkat cells were treated with WFA. We identified the CD45 and CD43 cell surface glycoproteins on Jurkat cells as the main targets for CNL binding. However, the blockade of CD45 phosphatase activity failed to block either CNL‐induced homotypic agglutination or cell death. Overall, our results indicate that CNL triggers atypical cell death selectively on Jurkat cells, suggesting the potential applicability of CNL in novel strategies for treating and/or detecting acute T cell leukemia.