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The gastrointestinal tract harbors diverse microorganisms in the lumen. Epithelial cells segregate the luminal microorganisms from immune cells in the lamina propria by constructing chemical and physical barriers through the production of various factors to prevent excessive immune responses against microbes. Therefore, perturbations of epithelial integrity are linked to the development of gastrointestinal disorders. Several mesenchymal stromal cell populations, including fibroblasts, myofibroblasts, pericytes, and myocytes, contribute to the establishment and maintenance of epithelial homeostasis in the gut through regulation of the self-renewal, proliferation, and differentiation of intestinal stem cells. Recent studies have revealed alterations in the composition of intestinal mesenchymal stromal cells in patients with inflammatory bowel disease and colorectal cancer. A better understanding of the interplay between mesenchymal stromal cells and epithelial cells associated with intestinal health and diseases will facilitate identification of novel biomarkers and therapeutic targets for gastrointestinal disorders. This review summarizes the key findings obtained to date on the mechanisms by which functionally distinct mesenchymal stromal cells regulate epithelial integrity in intestinal health and diseases at different developmental stages., (© 2024. The Author(s).)

The liver is the main gateway from the gut, and the unidirectional sinusoidal flow from portal to central veins constitutes heterogenous zones, including the periportal vein (PV) and the pericentral vein zones 1-5 . However, functional differences in the immune system in each zone remain poorly understood. Here intravital imaging revealed that inflammatory responses are suppressed in PV zones. Zone-specific single-cell transcriptomics detected a subset of immunosuppressive macrophages enriched in PV zones that express high levels of interleukin-10 and Marco, a scavenger receptor that sequesters pro-inflammatory pathogen-associated molecular patterns and damage-associated molecular patterns, and consequently suppress immune responses. Induction of Marco + immunosuppressive macrophages depended on gut microbiota. In particular, a specific bacterial family, Odoribacteraceae, was identified to induce this macrophage subset through its postbiotic isoallolithocholic acid. Intestinal barrier leakage resulted in inflammation in PV zones, which was markedly augmented in Marco-deficient conditions. Chronic liver inflammatory diseases such as primary sclerosing cholangitis (PSC) and non-alcoholic steatohepatitis (NASH) showed decreased numbers of Marco + macrophages. Functional ablation of Marco + macrophages led to PSC-like inflammatory phenotypes related to colitis and exacerbated steatosis in NASH in animal experimental models. Collectively, commensal bacteria induce Marco + immunosuppressive macrophages, which consequently limit excessive inflammation at the gateway of the liver. Failure of this self-limiting system promotes hepatic inflammatory disorders such as PSC and NASH., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive dermatomyositis (DM) is characterized by amyopathic DM with interstitial lung disease (ILD). Patients with anti-MDA5 antibody-associated ILD frequently develop rapidly progression and present high mortality rate in the acute phase. Here, we established a murine model of ILD mediated by autoimmunity against MDA5. Mice immunized with recombinant murine MDA5 whole protein, accompanied with complete Freund's adjuvant once a week for four times, developed MDA5-reactive T cells and anti-MDA5 antibodies. After acute lung injury induced by intranasal administration of polyinosinic-polycytidylic acid [poly (I:C)] mimicking viral infection, the MDA5-immunized mice developed fibrotic ILD representing prolonged respiratory inflammation accompanied by fibrotic changes 2 wk after poly (I:C)-administration, while the control mice had quickly and completely recovered from the respiratory inflammation. Treatment with anti-CD4 depleting antibody, but not anti-CD8 depleting antibody, suppressed the severity of MDA5-induced fibrotic ILD. Upregulation of interleukin (IL)-6 mRNA, which was temporarily observed in poly (I:C)-treated mice, was prolonged in MDA5-immunized mice. Treatment with anti-IL-6 receptor antibody ameliorated the MDA5-induced fibrotic ILD. These results suggested that autoimmunity against MDA5 exacerbates toll-like receptor 3-mediated acute lung injury, and prolongs inflammation resulting in the development of fibrotic ILD. IL-6 may play a key role initiating ILD in this model., Competing Interests: Competing interests statement:The authors declare no competing interest.

Ulcerative colitis (UC) is a chronic disorder of the large intestine with inflammation and ulceration. The incidence and prevalence of UC have been rapidly increasing worldwide, but its etiology remains unknown. In patients with UC, the accumulation of eosinophils in the large intestinal mucosa is associated with increased disease activity. However, the molecular mechanism underlying the promotion of intestinal eosinophilia in patients with UC remains poorly understood. Here, we show that uridine diphosphate (UDP)-glucose mediates the eosinophil-dependent promotion of colonic inflammation via the purinergic receptor P2Y14. The expression of P2RY14 mRNA was upregulated in the large intestinal mucosa of patients with UC. The P2Y14 receptor ligand UDP-glucose was increased in the large intestinal tissue of mice administered dextran sodium sulfate (DSS). In addition, P2ry14 deficiency and P2Y14 receptor blockade mitigated DSS-induced colitis. Among the large intestinal immune cells and epithelial cells, eosinophils highly expressed P2ry14 mRNA. P2ry14-/- mice transplanted with wild-type bone marrow eosinophils developed more severe DSS-induced colitis compared with P2ry14-/- mice that received P2ry14-deficient eosinophils. UDP-glucose prolonged the lifespan of eosinophils and promoted gene transcription in the cells through P2Y14 receptor-mediated activation of ERK1/2 signaling. Thus, the UDP-glucose/P2Y14 receptor axis aggravates large intestinal inflammation by accelerating the accumulation and activation of eosinophils., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Japanese Society for Immunology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Most animal species have a singular developmental pathway and adult ecology, but developmental plasticity is well-known in some such as honeybees where castes display profoundly different morphology and ecology. An intriguing case is the Atlantic deep-sea hydrothermal vent shrimp pair Rimicaris hybisae and R. chacei that share dominant COI haplotypes and could represent very recently diverging lineages or even morphs of the same species. Rimicaris hybisae is symbiont-reliant with a hypertrophied head chamber (in the Mid-Cayman Spreading Centre), while R. chacei is mixotrophic with a narrow head chamber (on the Mid-Atlantic Ridge). Here, we use X-ray micro-computed tomography and fluorescence in situ hybridization to show that key anatomical shifts in both occur during the juvenile-subadult transition, when R. hybisae has fully established symbiosis but not R. chacei. On the Mid-Atlantic Ridge, the diet of R. chacei has been hypothetically linked to competition with the obligatorily symbiotic congener R. exoculata, and we find anatomical evidence that R. exoculata is indeed better adapted for symbiosis. We speculate the possibility that the distinct development trajectories in R. hybisae and R. chacei may be determined by symbiont colonization at a "critical period" before subadulthood, though further genetic studies are warranted to test this hypothesis along with the true relationship between R. hybisae and R. chacei., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Society for the Study of Evolution (SSE).)

Tumor necrosis factor receptor-associated factor 6 (TRAF6) plays a pivotal role in the induction of inflammatory responses not only in innate immune cells but also in non-immune cells, leading to the activation of adaptive immunity. Signal transduction mediated by TRAF6, along with its upstream molecule MyD88 in intestinal epithelial cells (IECs) is crucial for the maintenance of mucosal homeostasis following inflammatory insult. The IEC-specific TRAF6-deficient (TRAF6ΔIEC) and MyD88-deficient (MyD88ΔIEC) mice exhibit increased susceptibility to DSS-induced colitis, emphasizing the critical role of this pathway. Moreover, MyD88 also plays a protective role in Citrobacter rodentium (C. rodentium) infection-induced colitis. However, its pathological role of TRAF6 in infectious colitis remains unclear. To investigate the site-specific roles of TRAF6 in response to enteric bacterial pathogens, we infected TRAF6ΔIEC and dendritic cell (DC)-specific TRAF6-deficient (TRAF6ΔDC) mice with C. rodentium and found that the pathology of infectious colitis was exacerbated with significantly decreased survival rates in TRAF6ΔDC mice, but not in TRAF6ΔIEC mice, compared to those in control mice. TRAF6ΔDC mice showed increased bacterial burdens, marked disruption of epithelial and mucosal structures with increased infiltration of neutrophils and macrophages, and elevated cytokine levels in the colon at the late stages of infection. The frequencies of IFN-γ producing Th1 cells and IL-17A producing Th17 cells in the colonic lamina propria were significantly reduced in TRAF6ΔDC mice. Finally, we demonstrated that TRAF6-deficient DCs failed to produce IL-12 and IL-23 in response to C. rodentium stimulation, and to induce both Th1 and Th17 cells in vitro. Thus, TRAF6 signaling in DCs, but not in IECs, protects against colitis induced by C. rodentium infection by producing IL-12 and IL-23 that induce Th1 and Th17 responses in the gut., Competing Interests: Declaration of competing interest The authors have no competing financial interest to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The intestinal tract harbors diverse microorganisms, host- and microbiota-derived metabolites, and potentially harmful dietary antigens. The epithelial barrier separates the mucosa, where diverse immune cells exist, from the lumen to avoid excessive immune reactions against microbes and dietary antigens. Inflammatory bowel disease (IBD), such as ulcerative colitis and Crohn's disease, is characterized by a chronic and relapsing disorder of the gastrointestinal tract. Although the precise etiology of IBD is still largely unknown, accumulating evidence suggests that IBD is multifactorial, involving host genetics and microbiota. Alterations in the metabolomic profiles and microbial community are features of IBD. Advances in mass spectrometry-based lipidomic technologies enable the identification of changes in the composition of intestinal lipid species in IBD. Because lipids have a wide range of functions, including signal transduction and cell membrane formation, the dysregulation of lipid metabolism drastically affects the physiology of the host and microorganisms. Therefore, a better understanding of the intimate interactions of intestinal lipids with host cells that are implicated in the pathogenesis of intestinal inflammation might aid in the identification of novel biomarkers and therapeutic targets for IBD. This review summarizes the current knowledge on the mechanisms by which host and microbial lipids control and maintain intestinal health and diseases., (© 2023 Wiley-VCH GmbH.)

Objectives: Prevotella copri is considered to be a contributing factor in rheumatoid arthritis (RA). However, in some non-Westernised countries, healthy individuals also harbour an abundance of P. copri in the intestine. This study investigated the pathogenicity of RA patient-derived P. copri ( P. copri RA ) compared with healthy control-derived P. copri ( P. copri HC )., Methods: We obtained 13 P . copri strains from the faeces of patients with RA and healthy controls. Following whole genome sequencing, the sequences of P. copri RA and P. copri HC were compared. To analyse the arthritis-inducing ability of P. copri , we examined two arthritis models (1) a collagen-induced arthritis model harbouring P. copri under specific-pathogen-free conditions and (2) an SKG mouse arthritis model under P. copri -monocolonised conditions. Finally, to evaluate the ability of P. copri to activate innate immune cells, we performed in vitro stimulation of bone marrow-derived dendritic cells (BMDCs) by P. copri RA and P. copri HC ., Results: Comparative genomic analysis revealed no apparent differences in the core gene contents between P. copri RA and P. copri HC , but pangenome analysis revealed the high genome plasticity of P. copri . We identified a P. copri RA -specific genomic region as a conjugative transposon. In both arthritis models, P. copri RA -induced more severe arthritis than P. copri HC . In vitro BMDC stimulation experiments revealed the upregulation of IL-17 and Th17-related cytokines (IL-6, IL-23) by P. copri RA ., Conclusion: Our findings reveal the genetic diversity of P. copri , and the genomic signatures associated with strong arthritis-inducing ability of P. copri RA . Our study contributes towards elucidation of the complex pathogenesis of RA., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Health anxiety has many damaging effects on patients with chronic illness. Physicians are often unable to alleviate concerns related to living with a disease that has an impact on daily life, and unregulated websites can overrepresent extreme anxiety-inducing outcomes. Educational clinician video interventions have shown some success as an acute anxiolytic in health settings. However, little research has evaluated if peer-based video interventions would be a feasible alternative or improvement., Objective: This pilot study assesses the efficacy of anxiety reduction for patients with Crohn disease (CD) and those with ulcerative colitis (UC) by showing patient testimonial videos during hospital visits. It investigates the degree to which patient testimonials can affect state anxiety, and whether patients are comfortable enough with the technology to share their stories., Methods: Patients with CD (n=51) and those with UC (n=49) were shown testimonial videos of patients with CD during their physician consultations at Kitasato University Kitasato Institute Hospital in Japan. The video testimonials were collected from Dipex Japan, the Japan branch of an international organization specializing in understanding patient experiences. Patients completed a Visual Analogue Scale for Anxiety before and after viewing the videos, a Hospital Anxiety and Depression Scale (HADS) survey before the videos, and satisfaction surveys. Patients receiving infusion therapy participated in the study while receiving treatment to minimize hospital workflow disruption., Results: Anxiety reduction, on the Visual Analog Scale for Anxiety, was significant in the entire cohort both when viewed as an ordinal variable (P=.003, t 98 =1086.5) and as a continuous variable (P=.01, t 94 =-2.54, 90% CI -3.47 to -0.72). Eighty percent (n=15) of patients with high HADS Anxiety (HADS-A) scores and 71% (n=24) of patients with high starting state anxiety experienced reduced anxiety after watching testimonials. Patients with high state anxiety but low HADS-A scores experienced anxiety reduction (69%, n=16). Forty-two percent (n=100) of patients responded that they would share their stories for future users. When patients with UC received testimonials from patients with CD, 71% (n=49) of patients reported that they were relevant despite differences in condition., Conclusions: Our pilot results suggest that patient testimonial videos can reduce illness-related state anxiety for patients with CD and those with UC, especially in those with higher baseline state anxiety. The success of this study in reducing anxiety and achieving patient involvement suggests that video interventions for reducing anxiety might be a low-cost intervention that could scale to any number of hospitals, suggesting that technology can help scale up efforts to record and share patient testimonials. Future work can establish whether patient testimonials can be helpful in other contexts, such as before major surgeries or when a family member receives a difficult diagnosis., (©Joel Shor, Yusuke Miyatani, Etsuko Arita, Pohung Chen, Yusuke Ito, Hiroki Kayama, Jacob Reiter, Kaho Kobayashi, Taku Kobayashi. Originally published in JMIR Formative Research (https://formative.jmir.org), 09.02.2023.)

Wilms' tumor 1 (WT1) is a promising tumor-associated antigen for cancer immunotherapy. We developed an oral protein vaccine platform composed of WT1-anchored, genetically engineered Bifidobacterium longum (B. longum) and conducted an in vivo study in mice to examine its anticancer activity. Mice were orally treated with phosphate-buffered saline, wild-type B. longum105-A, B. longum 2012 displaying only galacto-N-biose/lacto-N-biose I-binding protein (GLBP), and WT1 protein- and GLBP-expressing B. longum 420. Tumor size reduced significantly in the B. longum 420 group than in the B. longum 105-A and 2012 groups (P < 0.00 l each), indicating B. longum 420's antitumor activity via WT1-specific immune responses. CD8 + T cells played a major role in the antitumor activity of B. longum 420. The proportion of CD103 + CD11b + CD11c + dendritic cells (DCs) increased in the Peyer's patches (PPs) from mice in the B. longum 420 group, indicating the definite activation of DCs. In the PPs, the number and proportion of CD8 + T cells capable of producing interferon-gamma were significantly greater in the B. longum 420 group than in the B. longum 2012 group (P < 0.05 or < 0.01). The production of WT1-specific IgG antibody was significantly higher in the B. longum 420 group than in the 2012 group (P < 0.05). The B. longum 420 group showed the most intense intratumoral infiltration of CD4 + and CD8 + T cells primed by activated DCs in the PPs of mice in the B. longum 420 group. Our findings provide insights into a novel, intestinal bacterium-based, cancer immunotherapy through intestinal immunity., (© 2022. The Author(s).)

Western high-fat diets (HFD) are regarded as a major risk factor for prostate cancer (PCa). Using prostate-specific Pten-knockout mice as a PCa model, we previously reported that HFD promoted inflammatory PCa growth. The composition of the gut microbiota changes under the influence of diet exert various effects on the host through immunological mechanisms. Herein, we investigated the etiology of HFD-induced inflammatory cancer growth and the involvement of the gut microbiome. The expression of Hdc, the gene responsible for histamine biosynthesis, and histamine levels were upregulated in large prostate tumors of HFD-fed mice, and the number of mast cells increased around the tumor foci. Administration of fexofenadine, a histamine H1 receptor antagonist, suppressed tumor growth in HFD-fed mice by reducing the number of myeloid-derived suppressor cells and suppressing IL6/STAT3 signaling. HFD intake induced gut dysbiosis, resulting in the elevation of serum lipopolysaccharide (LPS) levels. Intraperitoneal injection of LPS increased Hdc expression in PCa. Inhibition of LPS/Toll-like receptor 4 signaling suppressed HFD-induced tumor growth. The number of mast cells increased around the cancer foci in total prostatectomy specimens of severely obese patients. In conclusion, HFD promotes PCa growth through histamine signaling via mast cells. Dietary high-fat induced gut dysbiosis might be involved in the inflammatory cancer growth., (© 2022 UICC.)

Variations in offspring production according to feeding strategies or food supply have been recognized in many animals from various ecosystems. Despite an unusual trophic structure based on non-photosynthetic primary production, these relationships remain largely under-studied in chemosynthetic ecosystems. Here, we use Rimicaris shrimps as a study case to explore relationships between reproduction, diets, and food supply in these environments. For that, we compared reproductive outputs of three congeneric shrimps differing by their diets. They inhabit vents located under oligotrophic waters of tropical gyres with opposed latitudes, allowing us to also examine the prevalence of phylogenetic vs environmental drivers in their reproductive rhythms. For this, we used both our original data and a compilation of published observations on the presence of ovigerous females covering various seasons over the past 35 years. We report distinct egg production trends between Rimicaris species relying solely on chemosymbiosis- R. exoculata and R. kairei -and one relying on mixotrophy, R. chacei . Besides, our data suggest a reproductive periodicity that does not correspond to seasonal variations in surface production, with substantial proportions of brooding females during the same months of the year, despite those months corresponding to either boreal winter or austral summer depending on the hemisphere. These observations contrast with the long-standing paradigm in deep-sea species for which periodic reproductive patterns have always been attributed to seasonal variations of photosynthetic production sinking from the surface. Our results suggest the presence of an intrinsic basis for biological rhythms in the deep sea, and bring to light the importance of having year-round observations in order to understand the life history of vent animals., Competing Interests: The authors declare they have no conflict of interests., (© 2022 The Authors. Ecology and Evolution published by John Wiley & Sons Ltd.)

CX3CR1high myeloid cells in the small intestine mediate the induction of oral tolerance by driving regulatory T (Treg) cells. Bacterial metabolites, e.g. pyruvate and lactate, induce a dendrite extension of CX3CR1high myeloid cells into the intestinal lumen via GPR31. However, it remains unclear whether the pyruvate-GPR31 axis is involved in the induction of oral tolerance. Here, we show that pyruvate enhances oral tolerance in a GPR31-dependent manner. In ovalbumin (OVA)-fed Gpr31-deficient mice, an OVA-induced delayed-type hypersensitivity response was substantially induced, demonstrating the defective induction of oral tolerance in Gpr31-deficient mice. The percentage of RORγt+ Treg cells in the small intestine was reduced in Gpr31-deficient mice. In pyruvate-treated wild-type mice, a low dose of OVA efficiently induced oral tolerance. IL-10 production from intestinal CX3CR1high myeloid cells was increased by OVA ingestion in wild-type mice, but not in Gpr31-deficient mice. CX3CR1high myeloid cell-specific IL-10-deficient mice showed a defective induction of oral tolerance to OVA and a decreased accumulation of OVA-specific Treg cells in the small intestine. These findings demonstrate that pyruvate enhances oral tolerance through a GPR31-dependent effect on intestinal CX3CR1high myeloid cells., (© Crown copyright 2022.)

Microbiota alteration and IFN-γ-producing CD4+ T cell overactivation are implicated in Crohn's disease (CD) pathogenesis. However, it remains unclear how dysbiosis enhances Th1 responses, leading to intestinal inflammation. Here, we identified key metabolites derived from dysbiotic microbiota that induce enhanced Th1 responses and exaggerate colitis in mouse models. Patients with CD showed elevated lysophosphatidylserine (LysoPS) concentration in their feces, accompanied by a higher relative abundance of microbiota possessing a gene encoding the phospholipid-hydrolyzing enzyme phospholipase A. LysoPS induced metabolic reprogramming, thereby eliciting aberrant effector responses in both human and mouse IFN-γ-producing CD4+ T cells. Administration of LysoPS into two mouse colitis models promoted large intestinal inflammation. LysoPS-induced aggravation of colitis was impaired in mice lacking P2ry10 and P2ry10b, and their CD4+ T cells were hyporesponsive to LysoPS. Thus, our findings elaborate on the mechanism by which metabolites elevated in patients with CD harboring dysbiotic microbiota promote Th1-mediated intestinal pathology., (© 2022 Otake-Kasamoto et al.)

MicroRNAs are a class of non-coding short-chained RNAs that control cellular functions by downregulating their target genes. Recent research indicates that microRNAs play a role in the maintenance of gut homeostasis. miR-215 was found to be highly expressed in epithelial cells of the small intestine; however, the involvement of miR-215 in gut immunity remains unknown. Here, we show that miR-215 negatively regulates inflammation in the small intestine by inhibiting CXCL12 production. Mice lacking miR-215 showed high susceptibility to inflammation induced by indomethacin, accompanied by an increased number of Th17 cells in the lamina propria of the small intestine. Our findings provide a rationale for targeting miR-215 as a therapeutic intervention for inflammatory conditions in the small intestine., (© 2022 Molecular Biology Society of Japan and John Wiley & Sons Australia, Ltd.)