T cells differentiate into highly diverse subsets and display plasticity depending on the environment. Although lymphocytes are key mediators of inflammation, functional specialization of T cells in inflammatory bowel disease (IBD) has not been effectively described. Here, we performed deep profiling of T cells in the intestinal mucosa of IBD and identified a CD4 ⁺ tissue-resident memory T cell (Trm) subset that is increased in Crohn’s disease (CD) showing unique inflammatory properties. Functionally and transcriptionally distinct CD4 ⁺ Trm subsets are observed in the inflamed gut mucosa, among which a CD-specific CD4 ⁺ Trm subset, expressing CD161 and CCR5 along with CD103, displays previously unrecognized pleiotropic signatures of innate and effector activities. These inflammatory features are further enhanced by their spatial proximity to gut epithelial cells. Furthermore, the CD-specific CD4 ⁺ Trm subset is the most predominant producer of type 1 inflammatory cytokines upon various stimulations among all CD4 ⁺ T cells, suggesting that the accumulation of this T cell subset is a pathological hallmark of CD. Our results provide comprehensive insights into the pathogenesis of IBD, paving the way for decoding of the molecular mechanisms underlying this disease.

Advances in high-throughput sequencing technologies in the past decade has led to a tremendous growth in knowledge about the role played by microorganisms on our body health. Trillions of microbes live in close symbiosis with their host, and have impacts on various aspects of host physiology as well as predisposition to disease. This is a consequence of the direct interaction between host cells and microbes or their signaling molecules, such as metabolites, which can reach and exert their effects in distal tissues. Among the essential factors modulating the human body's ecosystem of symbionts, the circadian clock might be one of the key regulators. The endogenous clock is a highly conserved timekeeper able to align organismal physiology to the daily cycle, thus maximizing survival and fitness. Circadian rhythms coordinate whole-body biological processes synchronizing cellular biochemical reactions, tissue function and finally controlling systemic homeostasis. Intriguingly, growing body of evidence has demonstrated that the host circadian cycle governs the structure of the gut microbiota community and its diurnal rhythmicity, whereas the microbes contribute to maintenance of clock function. In this review, we will give an overview of the multisystem aspects of microbiome-host interactions in the context of circadian rhythmicity. In particular, the effect of the interaction clock-microbial communities on immune system function and metabolic homeostasis will be discussed. Finally, the possible implication of daily rhythm on the gut-microbiome-brain axis will be analyzed, focusing on the reciprocal effects of clock disruption and microbiota alterations on brain function and behavior.

The consumption of a high-fat, low-carbohydrate diet (ketogenic diet) has diverse effects on health and is expected to have therapeutic value in neurological disorders, metabolic syndrome, and cancer. Recent studies have shown that a ketogenic diet not only pronouncedly shifts the cellular metabolism to pseudo-starvation, but also exerts a variety of physiological functions on various organs through metabolites that act as energy substrates, signaling molecules, and epigenetic modifiers. In this review, we highlight the latest findings on the molecular mechanisms of a ketogenic diet and speculate on the significance of these functions in the context of the epigenome and microbiome. Unraveling the molecular basis of the bioactive effects of a ketogenic diet should provide solid evidence for its clinical application in a variety of diseases including cancer.

The intestinal lumen is rich in gut microbial metabolites that serve as signaling molecules for gut immune cells. G-protein-coupled receptors (GPCRs) sense metabolites and can act as key mediators that translate gut luminal signals into host immune responses. However, the impacts of gut microbe–GPCR interactions on human physiology have not been fully elucidated. Here, we show that GPR31, which is activated by the gut bacterial metabolite pyruvate, is specifically expressed on type 1 conventional dendritic cells (cDC1s) in the lamina propria of the human intestine. Using human induced pluripotent stem cell-derived cDC1s and a monolayer human gut organoid coculture system, we show that cDC1s extend their dendrites toward pyruvate on the luminal side, forming transepithelial dendrites (TED). Accordingly, GPR31 activation via pyruvate enhances the fundamental function of cDC1 by allowing efficient uptake of gut luminal antigens, such as dietary compounds and bacterial particles through TED formation. Our results highlight the role of GPCRs in tuning the human gut immune system according to local metabolic cues.

Ulcerative colitis (UC) develops through a complicated interaction between the host and microbiota. Intestinal fibroblasts are believed to play crucial roles in the pathogenesis of UC, but the influence of the host-microbiota interaction on the pathophysiology of intestinal fibroblasts remains poorly understood. Here, we demonstrate that OTU deubiquitinase 3 (OTUD3) suppresses pathologic activation of fibroblasts exposed to microbial cyclic GMP-AMP (3′3’-cGAMP) in the colon by deubiquitinating stimulator of interferon genes (STING). Mice harboring a UC risk missense variant in the Otud3 gene showed pathological features of UC in the colon after transplantation of a fecal microbiota with the potential to produce excessive cGAMP from patients with UC. Collectively, these results highlight a mechanism of the interaction between OTUD3 in host fibroblasts and STING-activating microbiota in UC development.

Tissue-resident memory T cells (T_RM) serve as the frontline of host defense, playing a critical role in protection against invading pathogens. This emphasizes their role in providing rapid on-site immune responses across various organs. The physiological significance of T_RM is not just confined to infection control; accumulating evidence has revealed that T_RM also determine the pathology of diseases such as autoimmune disorders, inflammatory bowel disease, and cancer. Intensive studies on the origin, mechanisms of formation and maintenance, and physiological significance of T_RM have elucidated the transcriptional and functional diversity of these cells, which are often affected by local cues associated with their presence. These were further confirmed by the recent remarkable advancements of next-generation sequencing and single-cell technologies, which allow the transcriptional and phenotypic characterization of each T_RM subset induced in different microenvironments. This review first overviews the current knowledge of the cell fate, molecular features, transcriptional and metabolic regulation, and biological importance of T_RM in health and disease. Finally, this article presents a variety of recent studies on disease-associated T_RM, particularly focusing and elaborating on the T_RM in the gut, which constitute the largest and most intricate immune network in the body, and their pathological relevance to gut inflammation in humans.