How the gut microbiota and immune system maintain intestinal homeostasis in concert with the enteric nervous system (ENS) remains incompletely understood. To address this gap, we assessed small intestinal transit, enteric neuronal density, enteric neurogenesis, intestinal microbiota, immune cell populations and cytokines in wildtype and T-cell deficient germ-free mice colonized with specific pathogen-free (SPF) microbiota, conventionally raised SPF and segmented filamentous bacteria (SFB)-monocolonized mice. SPF microbiota increased small intestinal transit in a T cell-dependent manner. SPF microbiota increased neuronal density in the myenteric and submucosal plexuses of the ileum and colon, similar to conventionally raised SPF mice, independently of T cells. SFB increased neuronal density in the ileum in a T cell-dependent manner, but independently of T cells in the colon. SPF microbiota stimulated enteric neurogenesis (Sox2 expression in enteric neurons) in the ileum in a T cell-dependent manner, but in the colon this effect was T cell-independent. T cells regulated nestin expression in the ENS. SPF colonization increased Th17 cells, RORγT+ Treg cells, and IL-1β and IL-17A levels in the ileum and colon. By neutralizing IL-1β and IL-17A, we observed that they control microbiota-mediated enteric neurogenesis but were not involved in the regulation of motility. Together, these findings provide new insights into the microbiota-neuroimmune dialog that regulates intestinal physiology.

Few epidemiological evidence has focused on the impact of organophosphate esters (OPEs) and the risk of eczema, and underlying role of gut microbiota. Based on the Shanghai Maternal-Child Pairs Cohort, a nested case-control study including 332 eczema cases and 332 controls was conducted. Umbilical cord blood and stools were collected for OPEs detection and gut microbiota sequencing, separately. Eczema cases were identified using the International Study of Asthma and Allergies in Childhood core questionnaire and clinical diagnosis. The environmental risk score (ERS) for OPEs was developed to quantify OPEs burden. Conditional logistic regression models, multivariate analysis by linear models, negative-binomial hurdle regression, and mediation analysis were employed. Tris(2-butoxyethyl) phosphate (TBP), tris (2-butoxy ethyl) phosphate (TBEP), 2-ethylhexyl diphenyl phosphate (EHDPP), and tris(1,3-dichloro-2-propyl) phosphate (TDCPP) had detection rates > 50 %, with median concentrations ranged from 0.11 to 2.71 μg/L. TBP (OR = 1.12, 95 % CI: 1.01, 1.25), TDCPP (OR = 1.32, 95 % CI: 1.09, 1.59), and ERS (OR = 6.44, 95 % CI: 3.47, 11.94) were associated with elevated risk of eczema. OPEs exposure was correlated with increased alpha diversity and the abundance of several pathogenic bacteria, such as Klebsiella. Negative associations were observed between OPEs exposure and the abundances of Lachnospiraceae genera. Additionally, a positive correlation was identified between alpha diversity and the risk of eczema during childhood. Alpha diversity indices and Lachnospiraceae serve as significant mediators in this relationship. Results of this study indicate that prenatal exposure to OPEs is linked to an elevated risk of eczema and gut microbiota dysbiosis, potentially contributing to immunotoxicity of OPEs during early life.

In recent years, we have witnessed a rapidly growing interest in the intricate communications between intestinal microorganisms and the host immune system. Research on the human microbiome is evolving from merely descriptive and correlative studies to a deeper mechanistic understanding of the bidirectional interactions between gut microbiota and the mucosal immune system. Despite numerous challenges, it has become increasingly evident that an imbalance in gut microbiota composition, known as dysbiosis, is associated with the development and progression of various metabolic, immune, cancer, and neurodegenerative disorders. A growing body of evidence highlights the importance of small molecules produced by intestinal commensal bacteria, collectively referred to as gut microbial metabolites. These metabolites serve as crucial diffusible messengers, translating the microbial language to host cells. This review aims to explore the complex and not yet fully understood molecular mechanisms through which microbiota-derived metabolites influence the activity of the immune cells and shape immune reactions in the gut and other organs. Specifically, we will discuss recent research that reveals the close relationship between microbial indole-3-propionic acid (IPA) and mucosal immunity. Furthermore, we will emphasize the beneficial effects of IPA on intestinal inflammation and discuss its potential clinical implications.

Barrier organs such as the gastrointestinal tract, lungs, and skin are colonized by diverse microbial strains, including bacteria, viruses, and fungi. These microorganisms, collectively known as the commensal microbiota, play critical roles in maintaining health by defending against pathogens, metabolizing nutrients, and providing essential metabolites. In the gut, commensal-derived antigens are frequently sensed by the intestinal immune system. Maintaining tolerance toward these beneficial microbial species is crucial, as failure to do so can lead to chronic inflammatory conditions like inflammatory bowel disease (IBD) and can even affect systemic immune or metabolic health. The immune system carefully regulates responses to commensals through various mechanisms, including the induction of anti-inflammatory CD4⁺ T cell responses. Foxp3⁺ regulatory T cells (Foxp3+ Tregs) and Type 1 regulatory T cells (Tr1) play a major role in promoting tolerance, as both cell types can produce the anti-inflammatory cytokine IL-10. In addition to these regulatory T cells, effector T cell subsets, such as Th17 cells, also adopt anti-inflammatory functions within the intestine in response to the microbiota. This process of anti-inflammatory CD4+ T cell induction is heavily influenced by the microbiota and their metabolites. Microbial metabolites affect intestinal epithelial cells, promoting the secretion of anti-inflammatory mediators that create a tolerogenic environment. They also modulate intestinal dendritic cells (DCs) and macrophages, inducing a tolerogenic state, and can interact directly with T cells to drive anti-inflammatory CD4⁺ T cell functionality. The disrupted balance of these signals may result in chronic inflammation, with broader implications for systemic health. In this review, we highlight the intricate interplays between commensal microorganisms and the immune system in the gut. We discuss how the microbiota influences the differentiation of commensal-specific anti-inflammatory CD4⁺ T cells, such as Foxp3⁺ Tregs, Tr1 cells, and Th17 cells, and explore the mechanisms through which microbial metabolites modulate these processes. We further discuss the innate signals that prime and commit these cells to an anti-inflammatory fate.

Spondyloarthritis (SpA) is a group of chronic inflammatory disorders associated with the human leukocyte antigen (HLA) class I allele HLA-B27. Transgenic rats expressing HLA-B27 and human β2-microglobulin (B27 rats) develop clinical manifestations resembling SpA called rat SpA. IL-17 and TNF are key proinflammatory cytokines implicated in both human and rat SpA. We aimed to determine which T cell subset(s) produce IL-17 and TNF during rat SpA, characterize their tissue distribution and tested their pathogenicity in vivo.

Cytokine production by T cell subsets was evaluated in target tissues and lymphoid organs during rat SpA. Pathogenicity of purified IL-17+ cells was assessed in vivo by cell transfer. Blood samples were used to translate B27 rats findings to SpA patients.

Conventional CD4+ T cells (Foxp3-; Tconv) and γδ T cells were the main producers of both IL-17 and TNF in B27 rats. IL-17-producing Tconv and γδ T cells were expanded in the colon of premorbid 3-weeks-old B27 rats. C-C motif chemokine receptor 6 (CCR6) allowed the isolation of IL-17+ Tconv (Th17) in rat. Transfer of B27 rat IL-17-producing CCR6+ Tconv but not of γδ T cells into disease-free nude B27 rats induced arthritis, directly demonstrating for the first time the arthritogenic potential of Th17 cells in SpA. Finally, a CCR6+ IL-17+ Tconv expansion enriched for IL-17F production was evidenced in SpA patients.

Our study demonstrates that IL-17+TNF+CCR6+ Th17 cells and IL-17+ γδ T cells are expanded preceding SpA onset in B27 rats and that only IL-17+TNF+CCR6+ Th17 cells can trigger arthritis.

Fish are exposed to numerous stressors which negatively affect their immune response and increase infection susceptibility. The risk of bacterial infections results in the excessive and preventive use of antibiotics. Therefore, we aimed to study how antibiotic treatment and restraint stress will affect the stress response, microbiota composition, gut morphology, and inflammatory reaction in common carp. Both restraint stress and antibiotic treatment increased cortisol level. Moreover, antibiotics induced dysbiosis in fish gut, manifested by a decrease in the total abundance of bacteria, and a shift in bacteria diversity, including a reduced number of Aeromonas, Bacteroides, Barnesiellaceae, Cetobacterium and Shewanella and an increased abundance of Flavobacterium. To a lesser extent, stress modified gut microbiota, as it decreased bacteria number and slightly changed the microbiota composition by decreasing Cetobacterium abundance and increasing Vibrio abundance. Microbiota of the antibiotic-treated and stressed fish shifted from the beneficial bacterial genera - Cetobacterium and Bacteroides, to the increased presence of unfavorable bacteria such as Brevinema, Flavobacterium and Desulfovibrionaceae. Stress and antibiotic-induced changes in the gut microbiota were related to the changes in the gut morphology when the higher abundance of goblet and rodlet cells and increased secretion activity of goblet cells were observed. Moreover, up-regulation of the expression of genes encoding pro-inflammatory mediators and cytokines involved in the Th17 immune response was present in the gut of the antibiotic-treated and stressed fish. We conclude that in carp antibiotics and stress alter the abundance and composition of the microbiota and induce Th17-dependent inflammatory reaction in the gut. Moreover, our results strongly suggest the interplay of the stress axis and the brain-gut-microbiota axis.

Clostridioides difficile causes debilitating colitis via secreted toxins that disrupt the intestinal barrier, and toxemia is associated with severe disease. Thus, therapies that fortify the intestinal barrier will reduce the severity of infection. Innate lymphoid cells (ILCs) are critical in the defense against acute C. difficile infection and represent a promising therapeutic target to limit disease. Here, we report that oral administration of the Toll-like receptor (TLR) 7 agonist R848 limits intestinal damage and protects mice from lethal C. difficile infection without impacting pathogen burden or altering the intestinal microbiome. R848 induced interleukin (IL)-22 secretion by ILCs, leading to STAT3 phosphorylation in the intestinal epithelium and increased stem cell proliferation. Genetic ablation of ILCs, IL-22, or epithelial-specific STAT3 abrogated R848-mediated protection. R848 reduced intestinal permeability following infection and limited systemic toxin dissemination. Combined, these data identify an immunostimulatory molecule that activates IL-22 production in ILCs to enhance host tissue defenses following C. difficile infection.

Excess dietary salt and salt-sensitivity contribute to cardiovascular disease. Distinct T cell phenotypic responses to high salt and hypertension, as well as influences from environmental cues, are not well understood. The aryl hydrocarbon receptor (AhR) is activated by dietary ligands, promoting T cell and systemic homeostasis. We hypothesized that activating AhR supports CD4+ homeostatic functions, such as cytokine production and mobilization, in response to high salt intake while mitigating salt-sensitive hypertension. In the intestinal mucosa, we demonstrate that a high-salt diet (HSD) is a key driving factor, independent of hypertension, in diminishing interleukin 17A (IL-17A) production by CD4+ T (Th17) cells without disrupting circulating cytokines associated with Th17 function. Previous studies suggest that hypertensive patients and individuals on a HSD are deficient in AhR ligands or agonistic metabolites. We found that activating AhR augments Th17 cells during experimental salt-sensitive hypertension. Further, we demonstrate that activating AhR in vitro contributes to sustaining Th17 cells in the setting of excess salt. Using photoconvertible Kikume Green-Red mice, we also revealed that HSD drives CD4+ T cell mobilization. Next, we found that excess salt augments T cell mobilization markers, validating HSD-driven T cell migration. Also, we found that activating AhR mitigates HSD-induced T cell migration markers. Using telemetry in a model of experimental salt-sensitivity, we found that activating AhR prevents the development of salt-sensitive hypertension. Collectively, stimulating AhR through dietary ligands facilitates immunologic and systemic functions amid excess salt intake and restrains the development of salt-sensitive hypertension.

Diabetes is the third most common chronic disorder worldwide. Diabetic wounds are a severe complication that is costly and often results in non-traumatic lower limb amputation. Recent investigations have demonstrated that the gut microbiota as a "virtual organ" can regulate metabolic diseases like diabetes. Fecal microbiota transplantation (FMT) is an innovative therapeutic approach for promoting wound healing, but its function remains incompletely defined. A diabetes model was established by supplying mice with a high-fat diet and performing an intraperitoneal injection of streptozotocin. Diabetic wounds were then created, followed by bacterial transplantation. The relevant indexes of wound healing were evaluated to verify the promoting effect of FMT on the diabetic wounds. Human skin keratinocytes were also cultured, and cell scratch experiments were conducted to further investigate the underlying mechanism. The FMT regulated the levels of specific bacteria in the diabetic mice and helped restore the balance of intestinal microbes. This transplantation also enhanced wound healing in the diabetic mice by augmenting the closure rate, accelerating re-epithelialization, and boosting collagen deposition in skin wounds. Furthermore, FMT promoted the production of IL-17A, which significantly enhanced the growth and movement of human keratinocytes. Inhibiting molecules related to the IL-17A-mTOR-HIF1α signaling axis were shown to hinder wound re-epithelialization.This study clarifies the function of the IL-17A-mTOR-HIF1α signaling axis in the utilization of FMT in diabetic wound healing, providing a new therapeutic method and target for promoting the healing of diabetic wounds.

The Intestinal microbiota, as the organ with the largest number of microorganisms in the body, plays a crucial role in the physiological functions of the human body. Normal microbiota can be involved in various functions such as energy absorption, metabolism, and immunity of the body, and microbiota imbalance is related to many diseases such as obesity and diabetes. Diabetes, as one of the world's three major chronic diseases, is a significant health issue that troubles more than a billion people globally. Diabetic wounds are a problem that all diabetic patients must confront when undergoing surgery, and it is an important cause of non-traumatic amputations. Exploring the role of intestinal microorganisms in the wound-healing process of diabetic mice can offer the possibility of using microorganisms as a therapeutic means to intervene in clinically related diseases.

The gut has long been hypothesized to be the "motor" of critical illness, propagating inflammation and playing a key role in multiple organ dysfunction. However, the exact mechanisms through which impaired gut integrity potentially contribute to worsened clinical outcome remain to be elucidated. Critical elements of gut dysregulation including intestinal hyperpermeability and a perturbed microbiome are now recognized as potential therapeutic targets in critical care.

The gut is a finely tuned ecosystem comprising ~ 40 trillion microorganisms, a single cell layer intestinal epithelia that separates the host from the microbiome and its products, and the mucosal immune system that actively communicates in a bidirectional manner. Under basal conditions, these elements cooperate to maintain a finely balanced homeostasis benefitting both the host and its internal microbial community. Tight junctions between adjacent epithelial cells selectively transport essential molecules while preventing translocation of pathogens. However, critical illness disrupts gut barrier function leading to increased gut permeability, epithelial apoptosis, and immune activation. This disruption is further exacerbated by a shift in the microbiome toward a "pathobiome" dominated by pathogenic microbes with increased expression of virulence factors, which intensifies systemic inflammation and accelerates organ dysfunction. Research has highlighted several potential therapeutic targets to restore gut integrity in the host, including the regulation of epithelial cell function, modulation of tight junction proteins, and inhibition of epithelial apoptosis. Additionally, microbiome-targeted therapies, such as prebiotics, probiotics, fecal microbiota transplantation, and selective decontamination of the digestive tract have also been extensively investigated to promote restoration of gut homeostasis in critically ill patients. Future research is needed to validate the potential efficacy of these interventions in clinical settings and to determine if the gut can be targeted in an individualized fashion.

Increased gut permeability and a disrupted microbiome are common in critical illness, potentially driving dysregulated systemic inflammation and organ dysfunction. Therapeutic strategies to modulate gut permeability and restore the composition of microbiome hold promise as novel treatments for critically ill patients.

The development of the human immune system starts during the fetal period in a largely, but probably not completely, sterile environment. During and after birth, the immune system is exposed to an increasingly complex microbiota. The first microbiota encountered during passage through the birth canal colonize the infant gut and induce the tolerance of the immune system. Transplacentally derived maternal IgG as well as IgA from breast milk protect the infant from infections during the first 100 days, during which the immune system further develops and immunological memory is formed. The Weaning and introduction of solid food expose the immune system to novel (food) antigens and allow for other microbiota to colonize. The cells and molecules involved in the mutual and intricate interactions between microbiota and the developing immune system are now beginning to be recognized. These include bacterial components such as polysaccharide A from Bacteroides fragilis, as well as bacterial metabolites such as the short-chain fatty acid butyrate, indole-3-aldehyde, and indole-3-propionic acid. All these, and probably more, bacterial metabolites have specific immunoregulatory functions which shape the development of the human immune system during the first 1000 days of life.

Tissue-resident memory T (TRM) cells are a distinct subset of memory T cells that persist in non-lymphoid tissues, providing localized and rapid immune responses to infection and malignancy. Unlike circulating memory T cells, TRM cells have unique homing and functional characteristics that are shaped by the tissue microenvironment. In the gut, TRM cells play a pivotal role in maintaining mucosal immunity, exhibiting phenotypic and functional heterogeneity in different intestinal compartments and in response to aging and pathological conditions.

This review aims to systematically examine the definition, spatial heterogeneity and functional roles of intestinal TRM (iTRM) cells. It highlights their contributions to physiological immunity, their involvement in pathological processes such as inflammatory bowel disease (IBD) and colorectal cancer (CRC), and their age-related dynamics. The review also explores emerging therapeutic implications of modulating iTRM cells for intestinal health and disease management. KEY SCIENTIFIC CONCEPTS OF REVIEW: iTRM cells are defined by surface markers like CD69 and CD103, transcriptional regulators such as Hobit, Runx3, Blimp-1, as well as cytokine signals including TGF-β, IFN-β, IL-12. They exhibit spatial and functional heterogeneity across intestinal layers (epithelium versus lamina propria) and regions (small intestine versus colon). In IBD, iTRM cells play a dual role, contributing to both inflammation and tissue repair, whereas in CRC, specific subsets of iTRM cells (e.g., CD8+ CD103+ CD39+) are associated with enhanced antitumor immunity. Aging impacts iTRM functionality, with shifts in the CD4+/CD8+ ratio and reduced cytokine production in elderly individuals. Insights into the metabolic, transcriptional, and environmental regulation of iTRM cells provide avenues for targeted therapies in intestinal diseases, cancer immunotherapy, and interventions to delay intestinal aging.

The human placenta is a unique organ that forms under specific physiological conditions and plays a crucial role in nutrient and metabolite exchange between the mother and fetus. Research on the placenta is important for understanding maternal-fetal diseases. Traditionally, the placenta was considered "sterile," but advancements in detection techniques have revealed the presence of a low level of microorganisms. This discovery challenges the traditional notion that the uterine placenta is sterile. The revelation of this truth marks a significant breakthrough in medical research, prompting more researchers to focus on this vital organ, the placenta. Placental microbial communities may originate from the oral, vaginal, and intestinal microbiota of expectant mothers. These microorganisms may reach the maternal-fetal interface, collectively shaping the placental microbiota and contributing to the composition of normal placental microbial communities. Abnormal placental microbial communities may be associated with some pregnancy complications and fetal developmental issues such as preterm birth, gestational hypertension, fetal growth restriction, and gestational diabetes mellitus. Intervention strategies targeting microbial communities, which include modulation of placental microbiota composition or function, such as probiotics, may help prevent or treat complications related to abnormal placental microbiota during pregnancy.

Host-microbiota cooperation is critical for successful intestinal homeostasis. The commensal segmented filamentous bacteria (SFB) are crucial for orchestrating the post-natal maturation of the host gut immune system and establishing a healthy state of physiological inflammation, which largely depends on their intimate attachment to the ileal mucosa. However, the signaling pathways used by SFB to induce gut immune responses and how such responses ultimately control SFB colonization remain controversial. Using gnotobiotic approaches, we showed that SFB load is controlled by complex interactions involving the gut microbiota and the host immune system. Therefore, to clearly determine the role of host immune responses induced by SFB in directly controlling their growth, immunodeficient mice monocolonized with SFB were used. Here, we show that in the absence of a complex microbiota, the humoral immune response is dispensable to control SFB growth in the jejunum and ileum, shortly and later after colonization. In contrast, MyD88 signaling in myeloid cells is critical for licensing interleukin (IL)-22 production by type 3 innate lymphoid cells (ILC3) and CD4+ T cells, which ultimately limits SFB expansion. Thus, by revisiting the hierarchy of immune mechanisms that directly control SFB growth, our results emphasize the necessary and sufficient role of a hematopoietic MyD88/IL-22 axis.

The retinoic acid-related orphan receptor gamma (RORγt) acts as the major transcriptional activator in Th17 cell development and function to mediate adaptive immune defenses against pathogenic infection. RORγt engages accessible DNA response elements in the genome and interplays with coactivator proteins and accessory transcription factors to drive gene expression. However, how the chromatin environment mediates RORγt structure, dynamics, and function remains unclear. Here, we profile how the nucleosome promotes or restricts access to the main RORγt DNA response elements found in native enhancers and promoters, revealing preferential binding in regions of free DNA and nucleosomal entry/exit sites, with single base-pair resolution. Solution phase measurements using hydrogen deuterium exchange coupled to mass spectrometry identify novel allosteric effects that influence RORγt binding and mediate chromatin dynamics. A high-resolution structure of RORγt bound to the nucleosome reveals how structured elements assemble to confer binding specificity and avidity to chromatin substrates. The observations suggest an activation model where RORγt binding to chromatinized DNA promotes coregulator recruitment and chromatin decompaction.

The gastrointestinal tract is inhabited by trillions of micro-organisms that form the gut microbiome, which serves various functions that can influence neurological pathways. It can release metabolites that could affect the nervous system. The bidirectional communication between the intestine and the central nervous system is known as the gut-brain axis. This communication can be impacted by the microbiota in various direct and indirect ways. There has been a suggested connection between the microbiome and many neurological disorders, including epilepsy, Alzheimer's disease, Parkinson's disease and multiple sclerosis. This has been explored in human and animal studies. While no microbial biomarkers have been identified yet, alterations in several taxa have been suggested to be associated with disease states. The potential of the microbiome to modulate neurological function has sparked multiple clinical trials using gut-altering treatments, some with positive preliminary results.

Hydrogen sulfide is a gaseous, reactive molecule specifically enriched in the gastrointestinal tract. Here, we uncover a non-redundant role for sulfide in the control of both microbial and immune homeostasis of the gut. Notably, depletion of sulfide via both pharmaceutical and dietary interventions led to a profound collapse of CD4 T cells in the ileum of the small intestine lamina propria and significant impact on microbial ecology. As a result, mice with reduced sulfide within the gut were deficient in their ability to mount T cell dependent antibody responses to oral vaccine. Mechanistically, our results support the idea that sulfide could act directly on CD4 T cells via enhanced AP-1 activation, leading to heightened proliferation and cytokine production. This study uncovers sulfides as keystone components in gut ecology and provides mechanistic insight between diet, gut sulfide production and mucosal immunity.

Cardiovascular disease is one of the leading causes of death worldwide. Even while receiving adequate pharmacological treatment for their hypertension, people are nonetheless at greater risk for cardiovascular disease. There is growing evidence that the gut microbiota may have major positive and negative effects on blood pressure and illnesses related with it as more study into this topic is conducted. Trimethylamine n-oxide (TMAO) and short-chain fatty acids (SCFA) are two major by-products of the gut microbiota. TMAO is involved in the formation of other coronary artery diseases, including atherosclerosis and hypertension, while SCFAs play an important role in controlling blood pressure. Numerous investigations have confirmed the established link between dietary salt intake and hypertension. Reducing sodium in the diet is linked to lower rates of cardiovascular disease morbidity and mortality as well as lower rates of blood pressure and hypertension. In both human and animal research, high salt diets increase local and systemic tissue inflammation and compromise gut architecture. Given that the gut microbiota constantly interacts with the immune system and is required for the correct maturation of immune cells, it is scientifically conceivable that it mediates the inflammatory response. This review highlights the therapeutic possibilities for focusing on intestinal microbiomes as well as the potential functions of the gut microbiota and its metabolites in the development of hypertension.

The human gut microbiota is a vast and complex microbial community. According to statistics, the number of bacteria residing in the human intestinal tract is approximately ten times that of total human cells, with over 1000 different species. The interaction between the gut microbiota and various organ tissues plays a crucial role in the pathogenesis of local and systemic diseases, exerting a significant influence on disease progression. The relationship between the gut microbiota and intestinal diseases, along with its connection to the pulmonary immune environment and the development of lung diseases, is commonly referred to as the "gut-lung axis." The incidence of bronchial asthma is rising globally. With ongoing research on gut microbiota, it is widely believed that intestinal microorganisms and their metabolic products directly or indirectly participate in the occurrence and development of asthma. Based on the gut-lung axis, this review examines recent research suggesting that the intestinal microbiota can influence the occurrence and progression of allergic asthma through the modulation of cytokine immune balance and mucosal integrity. Though the precise immune pathways or microbial species influencing asthma through the gut-lung axis are still under exploration, summarizing the immune modulation through the gut-lung axis in allergic asthma may provide insights for the clinical management of the condition.

TNFα has long stood as a hallmark feature of both inflammatory bowel disease and arthritis with its therapeutic potential demonstrated in neutralizing monoclonal antibody treatments such as Infliximab. Due to the high global burden of latent Mycobacterium tuberculosis (TB) infections, prior to receiving anti-TNF therapy, patients testing positive for latent TB are given prophylactic treatment with anti-tuberculoid medications including the first described TB-selective antibiotic, Isoniazid. While this is common clinical practice to prevent the emergence of TB, little is known about whether Isoniazid modifies intestinal inflammation alone. The aim of this study, therefore, was to determine whether Isoniazid presents a novel TB-independent therapeutic option for the treatment of Crohn's disease (CD)-like ileitis and uncover new mechanisms predisposing the host to intestinal inflammation.

The transgenic TNFΔARE mouse model of Crohn's-like terminal ileitis was used. The impact of Isoniazid administration (10 mg/kg/day dose in drinking water) on disease development was monitored between 8 and 12 weeks of age using a variety of behavioral and serological assays. Behavioral and motor functions were assessed using the LABORAS automated monitoring system while systemic and local tissue inflammation were determined at experimental termination using multiplex cytokine analysis. Whole-mount tissue immunofluorescence and fluorescent in situ hybridization were used to qualify changes within the host as well as the microbial compartment of the ileum and associated mesentery. Proposed cellular mechanisms of altered cytokine decay were performed on isolated primary splenocytes in vitro using selective pharmacological agents.

Compared to age-matched wild-type littermates, TNFΔARE mice display prominent progressive sickness behaviors from 8 through 12 weeks of age indicated by reduced movement, climbing, and rearing. Prophylactic administration of Isoniazid (10 mg/kg/day) is effectively able to protect TNFΔARE mice from this loss of function during the same period. Analysis revealed that Isoniazid was able to significantly reduce both systemic and intestinal inflammation compared to untreated vehicle controls impacting the epithelial colonization of known pathobiont segmented filamentous bacteria (SFB). Reduction in terminal ileal inflammation was also associated to the diminished formation of precursor-tertiary lymphoid organs within the associated ileal mesentery which were found to be associated with endospores derived SFB itself. Finally, we reveal that due to their genetic manipulation, TNFΔARE mice display accelerated posttranscriptional decay of IL-22 mRNA resulting in diminished IL-22 protein production and associated downstream antimicrobial peptide production.

Isoniazid protects against the development of intestinal and systemic inflammation in the TNFΔARE model of terminal ileitis by limiting the expansion of mucosal SFB and progression of the associated microbial-driven inflammation. This work highlights a possible mycobacterial-independent function of Isoniazid in limiting CD pathophysiology through limiting the mucosal establishment of pathobionts such as SFB and the association of such microbe-derived endospores linked to the formation of ectopic tertiary lymphoid organs seen commonly in patients.

The intestinal epithelium represents a critical interface between the host and external environment, serving as the second largest surface area in the human body after the lungs. This dynamic barrier is sustained by specialized epithelial cell types and their complex interactions with the gut microbiota. This review comprehensively examines the recent advances in understanding the bidirectional communication between intestinal epithelial cells and the microbiome. We briefly highlight the role of various intestinal epithelial cell types, such as Paneth cells, goblet cells, and enteroendocrine cells, in maintaining intestinal homeostasis and barrier function. Gut microbiota-derived metabolites, particularly short-chain fatty acids and bile acids, influence epithelial cell function and intestinal barrier integrity. Additionally, we highlight emerging evidence of the sophisticated cooperation between different epithelial cell types, with special emphasis on the interaction between tuft cells and Paneth cells in maintaining microbial balance. Understanding these complex interactions has important implications for developing targeted therapeutic strategies for various gastrointestinal disorders, including inflammatory bowel disease, metabolic disorders, and colorectal cancer.

Post-stroke depression (PSD) is one of the most common and devastating neuropsychiatric complications in stroke patients, affecting more than one-third of survivors of ischemic stroke (IS). Despite its high incidence, PSD is often overlooked or undertreated in clinical practice, and effective preventive measures and therapeutic interventions remain limited. Although the exact mechanisms of PSD are not fully understood, emerging evidence suggests that the gut microbiota plays a key role in regulating gut-brain communication. This has sparked great interest in the relationship between the microbiota-gut-brain axis (MGBA) and PSD, especially in the context of cerebral ischemia. In addition to the gut microbiota, another important factor is the gut barrier, which acts as a frontline sensor distinguishing between beneficial and harmful microbes, regulating inflammatory responses and immunomodulation. Based on this, this paper proposes a new approach, the microbiota-immune-barrier axis, which is not only closely related to the pathophysiology of IS but may also play a critical role in the occurrence and progression of PSD. This review aims to systematically analyze how the gut microbiota affects the integrity and function of the barrier after IS through inflammatory responses and immunomodulation, leading to the production or exacerbation of depressive symptoms in the context of cerebral ischemia. In addition, we will explore existing technologies that can assess the MGBA and potential therapeutic strategies for PSD, with the hope of providing new insights for future research and clinical interventions.

The relationship between the gut microbiome and ocular health has garnered increasing attention within the scientific community. Recent research has focused on the gut-eye axis, examining whether imbalances within the gut microbiome can influence the development, progression and severity of ocular diseases, including dry eye disease, uveitis, and glaucoma. Dysbiosis within the gut microbiome is linked to immune dysregulation, chronic inflammation, and epithelial barrier dysfunction, all of which contribute to ocular pathology. This review synthesises current evidence on these associations, exploring how gut microbiome alterations drive disease mechanisms. Furthermore, it examines the therapeutic potential of microbiome-targeted interventions, including antibiotics, prebiotics, probiotics, and faecal microbiota transplantation, all of which aim to restore microbial balance and modulate immune responses. As the prevalence of these conditions continues to rise, a deeper understanding of the gut-eye axis may facilitate the development of novel, targeted therapies to address unmet needs in the management of ocular diseases.

This study investigates how microbiome colonization influences the development of intestinal type 3 immunity in neonates. The results showed that reduced oxygen levels in the small intestine of neonatal rats induced by Saccharomyces boulardii accelerated microbiome colonization and type 3 immunity development, which protected against Salmonella enterica serovar Typhimurium infection. Microbiome maturation increased the abundance of microbiome-encoded bile salt hydrolase (BSH) genes and hyocholic acid (HCA) levels. Furthermore, reducing oxygen levels in the intestine increased the abundance of Limosilactobacillus reuteri, a bacterium encoding BSH, and promoted intestinal type 3 immunity. However, inhibition of BSH blocked the L. reuteri-induced development of intestinal type 3 immunity. Mechanistically, HCA promoted the development of gamma-delta T cells and type 3 innate lymphoid cells by stabilizing the mRNA expression of RAR-related orphan receptor C via the farnesoid X receptor-WT1-associated protein-N6-methyl-adenosine axis. These results reveal that gut microbiota-derived HCA plays a crucial role in promoting the development of intestinal type 3 immunity in neonates. This discovery introduces potential therapeutic avenues for strengthening intestinal immunity in early life or treating bacterial infections by targeting microbial metabolites.

In early-life, the gut microbiota is highly modifiable, being modulated by external factors such as maternal microbiota, mode of delivery, and feeding strategies. The composition of the child's gut microbiota will deeply impact the development and maturation of its immune system, with consequences for future health. As one of the main sources of microorganisms to the child, the mother represents a crucial factor in the establishment of early-life microbiota, impacting the infant's wellbeing. Recent studies have proposed that dysbiotic maternal gut microbiota could be transmitted to the offspring, influencing the development of its immunity, and leading to the development of diseases such as obesity. This paper aims to review recent findings in gut microbiota and immune system interaction in early-life, highlighting the benefits of a balanced gut microbiota in the regulation of the immune system.

The intestinal microbiota has major influence on human physiology and modulates health and disease. Complex host-microbe interactions regulate various homeostatic processes, including metabolism and immune function, while disturbances in microbiota composition (dysbiosis) are associated with a plethora of human diseases and are believed to modulate disease initiation, progression and therapy response. The vast complexity of the human microbiota and its metabolic output represents a great challenge in unraveling the molecular basis of host-microbe interactions in specific physiological contexts. To increase our understanding of these interactions, functional microbiota research using animal models in a reductionistic setting are essential. In the dynamic landscape of gut microbiota research, the use of germ-free and gnotobiotic mouse technology, in which causal disease-driving mechanisms can be dissected, represents a pivotal investigative tool for functional microbiota research in health and disease, in which causal disease-driving mechanisms can be dissected. A better understanding of the health-modulating functions of the microbiota opens perspectives for improved therapies in many diseases. In this review, we discuss practical considerations for the design and execution of germ-free and gnotobiotic experiments, including considerations around germ-free rederivation and housing conditions, route and timing of microbial administration, and dosing protocols. This comprehensive overview aims to provide researchers with valuable insights for improved experimental design in the field of functional microbiota research.

The intestinal immune compartment is increasingly recognized as an important player in central nervous system (CNS) autoimmunity. We have recently reported that oral administration of the free fatty acid receptor 2 (FFAR2) agonist Cpd1 in the inductive phase of experimental autoimmune encephalomyelitis (EAE) in rats ameliorates the disease by stimulating the regulatory immune response in the intestine.

Here, the effects of Cpd1 on the gut microbiota and short-chain fatty acid (SCFA) composition were investigated in the same experimental system.

Increased levels of the phylum Proteobacteria, the class Gammaproteobacteria, the orders Burkholderiales and Erysipelotrichales, the families Sutterellaceae and Erysipelotrichaceae, and the genera Parasutterella and Faecalibaculum were observed in agonist-treated rats. The genera Allobaculum and Ileibacterium were only detected in the agonist-treated group. The treatment led to changes in the functional profile of the gut microbiota both in the KEGG orthologous pathways and in the clusters of orthologous genes. In addition, an altered profile of intestinal SCFA content was observed in the agonist-treated group.

The effects of Cpd1 on the gut microbiota and SCFA composition are relevant to the observed treatment benefit of FFAR2 agonism in the EAE model during the inductive phase of the disease.

Promoting resistance to enteric pathogen infection is a core function of the gut microbiota; however, many of the specific host-commensal interactions that mediate this protection remain uncharacterised. To address this knowledge gap, we monocolonised germ-free mice with mouse-derived commensal microbes to screen for microbiota-induced resistance to Salmonella Typhimurium infection.

We identified Enterocloster clostridioformis as a protective species against S. Typhimurium infection. E. clostridioformis selectively upregulates resistin-like molecule β and cell cycle pathway expression at the level of caecal epithelial cells and increases T-regulatory cells in the underlying mucosal immune system, potentially contributing to reduced infection-induced pathology.

We highlight novel mechanisms of host-microbe interactions that can mediate microbiota-induced resistance to acute salmonellosis. In the backdrop of increasing antibiotic resistance, this study identifies novel potential avenues for further research into protective host responses against enteric infections and could lead to new therapeutic approaches. Video Abstract.

Gastrointestinal (GI) colonization by methicillin-resistant Staphylococcus aureus (MRSA) is associated with a high risk of transmission and invasive disease in vulnerable populations. The immune and microbial factors that permit GI colonization remain unknown. Male sex is correlated with enhanced Staphylococcus aureus nasal carriage, skin and soft tissue infections, and bacterial sepsis. Here, we established a mouse model of sexual dimorphism during GI colonization by MRSA. Our results show that in contrast to male mice that were susceptible to persistent colonization, female mice rapidly cleared MRSA from the GI tract following oral inoculation in a manner dependent on the gut microbiota. This colonization resistance displayed by female mice was mediated by an increase in IL-17A+ CD4+ T cells (Th17) and dependent on neutrophils. Ovariectomy of female mice increased MRSA burden, but gonadal female mice that have the Y chromosome retained enhanced Th17 responses and colonization resistance. Our study reveals a novel intersection between sex and gut microbiota underlying colonization resistance against a major widespread pathogen.

The HECT E3 ubiquitin ligase Nedd4 has been shown to positively regulate T cell responses, but its role in T helper (Th) cell differentiation and autoimmunity is unknown. Th17 cells are believed to play a pivotal role in the development and pathogenesis of autoimmune diseases. Nevertheless, the regulation of RORγt activation during Th17 cell differentiation by TCR signaling is yet to be elucidated. These uncharted aspects inspire us to explore the potential role of Nedd4 in Th17-mediated autoimmunity.

We evaluated the impact of Nedd4 deficiency on mouse T cell development and differentiation using flow cytometry and siRNA transfection, and subsequently validated these findings in T cells from patients with multiple sclerosis (MS). Furthermore, we investigated the influence of Nedd4 deficiency on Th17-mediated autoimmunity through experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. Subsequently, we elucidated the molecular mechanism underlying the interaction between Nedd4 and RORgt through immunoprecipitation, mass spectrometry analysis, and lentiviral transduction. Additionally, we identified Nedd4 as an E3 ubiquitin ligase for RORγt. Moreover, we characterized the tyrosine residue sites and polyubiquitination patterns involved in RORγt ubiquitination.

In this study, we report that loss of Nedd4 in T cells specifically impairs pathogenic and non-pathogenic Th17 responses, and Th17-mediated EAE development. At the molecular level, Nedd4 binds to the PPLY motif within the ligand binding domain of RORγt, and targets RORγt at K112 for K27-linked polyubiquitination, thus augmenting its activity.

Nedd4 is a crucial E3 ubiquitin ligase for RORγt in the regulating Th17 cell development and offers potential therapeutic benefits for treating Th17-mediated autoimmune diseases.

Autophagy, a cytoprotective mechanism in intestinal epithelial cells, plays a crucial role in maintaining intestinal homeostasis. Beyond its cell-autonomous effects, the significance of autophagy in these cells is increasingly acknowledged in the dynamic interplay between the microbiota and the immune response. In the context of colon cancer, intestinal epithelium disruption of autophagy has been identified as a critical factor influencing tumor development. This disruption modulates the composition of the gut microbiota, eliciting an anti-tumoral immune response. Here, we report that Atg7 deficiency in intestinal epithelial cells shapes the intestinal microbiota leading to an associated limitation of colitis induced by Citrobacter rodentium infection. Mice with an inducible, intestinal epithelial-cell-specific deletion of the autophagy gene, Atg7, exhibited enhanced clearance of C. rodentium, mitigated hyperplasia, and reduced pathogen-induced goblet cell loss. This protective effect is linked to a higher proportion of neutrophils and phagocytic cells in the early phase of infection. At later stages, it is associated with the downregulation of pro-inflammatory pathways and an increase in Th17 and Treg responses-immune responses known for their protective roles against C. rodentium infection, modulated by specific gut microbiota. Fecal microbiota transplantation and antibiotic treatment approaches revealed that the Atg7-deficiency-shapped microbiota, especially Gram-positive bacteria, playing a central role in driving resistance to C. rodentium infection. In summary, our findings highlight that inhibiting autophagy in intestinal epithelial cells contributes to maintaining homeostasis and preventing detrimental intestinal inflammation through microbiota-mediated colonization resistance against C. rodentium. This underscores the central role played by autophagy in shaping the microbiota in promoting immune-mediated resistance against enteropathogens.

The maternal microbiome is emerging as an important factor that influences the neurological health of mothers and their children. Recent studies highlight how microbial communities in the maternal gut can shape early-life development in ways that inform long-term health trajectories. Research on the neurodevelopmental effects of maternal microbiomes is expanding our understanding of the microbiome-gut-brain axis to include signaling across the maternal-offspring unit during the perinatal period. In this Review, we synthesize existing literature on how the maternal microbiome modulates brain function and behavior in both mothers and their developing offspring. We present evidence from human and animal studies showing that the maternal microbiome interacts with environmental factors to impact risk for neurodevelopmental abnormalities. We further discuss molecular and cellular mechanisms that facilitate maternal-offspring crosstalk for neuromodulation. Finally, we consider how advancing understanding of these complex interactions could lead to microbiome-based interventions for promoting maternal and offspring health.

The gut microbiota critically influences many aspects of host biology, from nutrient acquisition to immunological function, and is integral to metazoan life. While most microbiome research has focused on bacteria, the intestinal microbiota encompasses a diverse constellation of microorganisms, including viruses, fungi, archaea, and protists. Among these microbes, commensal protists have been particularly neglected, to the point that their status as true members of the microbiota remained contentious. However, findings over the past decade revealed that commensal protists, particularly those in the Parabasalia phylum (parabasalids), perform keystone roles within the intestinal ecosystem. Emerging evidence highlights how parabasalids dramatically impact host immunity, gut microbiome ecology, and host susceptibility to both infectious and inflammatory diseases. In this review, we discuss the recent discoveries of the varied and powerful roles of commensal parabasalids in the intestinal microbiota and outline the challenges and opportunities in this burgeoning new area of the microbiome field.

Trichinella spiralis has evolved complex immunomodulatory mechanisms mediated by excretory-secretory products (ESL1) that enable its survival in the host. Consequently, ESL1 antigens display excellent potential for treating autoimmune diseases such as multiple sclerosis (MS). However, whether timely controlled delivery of ESL1 antigens in vivo, as in natural infections, could enhance its therapeutic potential for MS is still unknown.

To test this, we encapsulated ESL1 antigens into biodegradable poly (lactide-co-glycolic) acid (PLGA) nanofibers by emulsion electrospinning as a delivery system and assessed their release dynamics in vitro, and in an animal MS model, experimental autoimmune encephalomyelitis (EAE), induced 7 days after PLGA/ESL1 subcutaneous implantation. PLGA/ESL1 effects on EAE symptoms were monitored along with multiple immune cell subsets in target organs at the peak and recovery of EAE. Gut barrier function and microbiota composition were analyzed using qPCR, 16S rRNA sequencing, and metabolomic analyses.

ESL1 antigens, released from PLGA and drained via myeloid antigen-presenting cells through lymph nodes, protected the animals from developing EAE symptoms. These effects correlated with reduced activation of myeloid cells, increased IL-10 expression, and reduced accumulation of proinflammatory natural killer (NK) cells, T helper (Th)1 and Th17 cells in the spleen and central nervous system (CNS). Additionally, CD4+CD25hiFoxP3+ regulatory T cells and IL-10-producing B cells were expanded in PLGA/ESL1-treated animals, compared to control animals. The migration of ESL1 to the guts correlated with locally reduced inflammation and gut barrier damage. Additionally, PLGA/ESL1-treated animals displayed an unaltered microbiota characterized only by a more pronounced protective mevalonate pathway and expanded short-chain fatty acid-producing bacteria, which are known to suppress inflammation.

The delivery of T. spiralis ESL1 antigens via biodegradable electrospun PLGA nanofiber implants efficiently protected the animals from developing EAE by inducing a beneficial immune response in the spleen, gut, and CNS. This platform provides excellent grounds for further development of novel MS therapies.

The gut microbiota plays a crucial role in safeguarding host health and driving the progression of intestinal diseases. Despite recent advances in the remarkable correlation between dysbiosis and extraintestinal cancers, the underlying mechanisms are yet to be fully elucidated. Pathogenic microbiota, along with their metabolites, can undermine the integrity of the gut barrier through inflammatory or metabolic pathways, leading to increased permeability and the translocation of pathogens. The dissemination of pathogens through the circulation may contribute to the establishment of an immune-suppressive environment that promotes carcinogenesis in extraintestinal organs either directly or indirectly. The oncogenic cascade always engages in the disruption of hormonal regulation and inflammatory responses, the induction of genomic instability and mutations, and the dysregulation of adult stem cell proliferation. This review aims to comprehensively summarize the existing evidence that points to the potential role of dysbiosis in the malignant transformation of extraintestinal organs such as the liver, breast, lung, and pancreas. Additionally, we delve into the limitations inherent in current methodologies, particularly the challenges associated with differentiating low loads gut-derived microbiome within tumors from potential sample contamination or symbiotic microorganisms. Although still controversial, an understanding of the contribution of translocated intestinal microbiota and their metabolites to the pathological continuum from chronic inflammation to tumors could offer a novel foundation for the development of targeted therapeutics.

The interplay between human health and the microbiome has gained extensive attention, with probiotics emerging as pivotal therapeutic agents due to their vast potential in treating various health issues. As significant modulators of the gut microbiota, probiotics are crucial in maintaining intestinal homeostasis and enhancing the synthesis of short-chain fatty acids. Despite extensive research over the past decades, there remains an urgent need for a comprehensive and detailed review that encapsulates probiotics' latest insights and applications. This review focusses on the multifaceted roles of probiotics in promoting health and preventing disease, highlighting the complex mechanisms through which these beneficial bacteria influence both gut flora and the human body at large. This paper also explores probiotics' neurological and gastrointestinal applications, focussing on their significant impact on the gut-brain axis and their therapeutic potential in a broad spectrum of pathological conditions. Current innovations in probiotic formulations, mainly focusing on integrating genomics and biotechnological advancements, have also been comprehensively discussed herein. This paper also critically examines the regulatory landscape that governs probiotic use, ensuring safety and efficacy in clinical and dietary settings. By presenting a comprehensive overview of recent studies and emerging trends, this review aims to illuminate probiotics' extensive therapeutic capabilities, leading to future research and clinical applications. However, besides extensive research, further advanced explorations into probiotic interactions and mechanisms will be essential for developing more targeted and effective therapeutic strategies, potentially revolutionizing health care practices for consumers.

Periodontitis is an immuno-inflammatory disease of the soft tissues surrounding the teeth. Periodontitis is linked to many communicable and non-communicable diseases such as diabetes, cardiovascular disease, rheumatoid arthritis, and cancers. The oral-systemic link between periodontal disease and systemic diseases is attributed to the spread of inflammation, microbial products and microbes to distant organ systems. Oral bacteria reach the gut via swallowed saliva, whereby they induce gut dysbiosis and gastrointestinal dysfunctions. Some periodontal pathogens like Porphyromonas. gingivalis, Klebsiella, Helicobacter. Pylori, Streptococcus, Veillonella, Parvimonas micra, Fusobacterium nucleatum, Peptostreptococcus, Haemophilus, Aggregatibacter actinomycetomcommitans and Streptococcus mutans can withstand the unfavorable acidic, survive in the gut and result in gut dysbiosis. Gut dysbiosis increases gut inflammation, and induce dysplastic changes that lead to gut dysfunction. Various studies have linked oral bacteria, and oral-gut axis to various GIT disorders like inflammatory bowel disease, liver diseases, hepatocellular and pancreatic ductal carcinoma, ulcerative colitis, and Crohn's disease. Although the correlation between periodontitis and GIT disorders is well established, the intricate molecular mechanisms by which oral microflora induce these changes have not been discussed extensively. This review comprehensively discusses the intricate and unique molecular and immunological mechanisms by which periodontal pathogens can induce gut dysbiosis and dysfunction.

In complex organisms, functional units must interact cohesively to maintain homeostasis, especially within mucosal barriers that house diverse, specialized cell exposed to constant environmental challenges. Understanding how homeostasis at mucosal barriers is maintained and how its disruption can lead to autoimmune diseases or cancer, requires a holistic view. Although omics approaches and systems immunology have become powerful tools, they are not without limitations; interpretations may reflect researchers' assumptions, even if other explanations exist. In this perspective, I propose that applying game theory concepts to mucosal immunology could help interpret complex data, offering fresh perspectives and supporting the exploration of alternative scenarios. By framing the mucosal immune system as a network of strategic interactions with multiple possible outcomes, game theory, which analyzes strategic interactions and decision-making processes, could illuminate novel cell types and functions, cell interactions, and responses to pathogens and commensals, leading to a more comprehensive understanding of immune homeostasis and diseases. In addition, game theory might encourage researchers to consider a broader range of possibilities, reduce the risk of myopic thinking, and ultimately enable a more refined and comprehensive understanding of the complexity of the immune system at mucosal barriers. This perspective aims to introduce game theory as a complementary framework for mucosal immunologists, encouraging them to incorporate these concepts into data interpretation and system modeling.

The nervous and immune systems have complementary roles in the adaptation of organisms to environmental changes. However, the mechanisms that mediate cross-talk between the nervous and immune systems, called neuroimmune interactions, are poorly understood. In this Review, we summarize advances in the understanding of neuroimmune communication, with a principal focus on the central nervous system (CNS): its response to immune signals and the immunological consequences of CNS activity. We highlight these themes primarily as they relate to neurological diseases, the control of immunity, and the regulation of complex behaviours. We also consider the importance and challenges linked to the study of the neuroimmune connectome, which is defined as the totality of neuroimmune interactions in the body, because this provides a conceptual framework to identify mechanisms of disease pathogenesis and therapeutic approaches. Finally, we discuss how the latest techniques can advance our understanding of the neuroimmune connectome, and highlight the outstanding questions in the field.

The transplantation of allogeneic hematopoietic stem cells is a potentially curative treatment for hematological malignancies, inherited blood disorders and immune deficiencies. Unfortunately, 30-50% of patients receiving allogeneic hematopoietic stem cells will develop a potentially life-threatening inflammatory disease called acute graft-versus-host disease (aGVHD). In patients with aGVHD, graft-associated T cells, which typically target the skin, intestinal tract and liver, can also damage the lungs and lymphoid tissue. Damage to lymphoid tissue creates prolonged immunodeficiency that markedly increases the risk of infections and bleeding, resulting in considerable morbidity and mortality. Although mouse models of aGVHD have been instrumental to our understanding of this condition's pathogenesis, translation of preclinical data into new and more effective treatments for human disease has been limited for reasons that remain to be fully understood. However, evidence suggests that factors associated with mouse models of aGVHD likely contribute to these unsatisfactory results. In this Review, we identify and discuss the specific factors inherent to mouse models of aGVHD that may limit the translation of preclinical data to patient treatment, and suggest how to improve the translatability of these models.

The ubiquitous skin colonist Staphylococcus epidermidis elicits a CD8+ T cell response pre-emptively, in the absence of an infection1. However, the scope and purpose of this anticommensal immune programme are not well defined, limiting our ability to harness it therapeutically. Here, we show that this colonist also induces a potent, durable and specific antibody response that is conserved in humans and non-human primates. A series of S. epidermidis cell-wall mutants revealed that the cell surface protein Aap is a predominant target. By colonizing mice with a strain of S. epidermidis in which the parallel β-helix domain of Aap is replaced by tetanus toxin fragment C, we elicit a potent neutralizing antibody response that protects mice against a lethal challenge. A similar strain of S. epidermidis expressing an Aap-SpyCatcher chimera can be conjugated with recombinant immunogens; the resulting labelled commensal elicits high antibody titres under conditions of physiologic colonization, including a robust IgA response in the nasal and pulmonary mucosa. Thus, immunity to a common skin colonist involves a coordinated T and B cell response, the latter of which can be redirected against pathogens as a new form of topical vaccination.