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Asthma susceptibility is linked to dysbiosis in early-life gut microbiota, and the antibody secretory immunoglobulin (Ig)A (SIgA) is a key determinant of gut microbiota composition. SIgA is obtained through breast milk during the critical early-life window. We use a mouse model of SIgA deficiency and the house dust mite (HDM) model of asthma to elucidate the role of maternal SIgA in modulating the early-life gut microbiota and asthma protection. Mice that do not receive maternal SIgA display a transient bloom of segmented filamentous bacteria (SFB) in the small intestine during the early post-weaning period. Mice that do not receive maternal SIgA also display elevated T helper type 17 (Th17) cell activation in the intestine, which persists into adulthood and is associated with more severe inflammation in response to the HDM model of asthma. This study demonstrates a mechanism by which breast-milk-derived SIgA influences immune development and asthma susceptibility by modulating the early-life gut microbiota., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Induction of commensal-specific immunity contributes to tissue homeostasis, yet the mechanisms underlying induction of commensal-specific B cells remain poorly understood in part due to a lack of tools to identify these cells. Using phage display, we identified segmented filamentous bacteria (SFB) antigens targeted by serum and intestinal antibodies and generated B cell tetramers to track SFB-specific B cells in gut-associated lymphoid tissues. We revealed a compartmentalized response in SFB-specific B cell activation, with a gradient of immunoglobulin A (IgA), IgG1, and IgG2b isotype production along Peyer's patches contrasted by selective production of IgG2b within mesenteric lymph nodes. V(D)J sequencing and monoclonal antibody generation identified somatic hypermutation driven affinity maturation to SFB antigens under homeostatic conditions. Combining phage display and B cell tetramers will enable investigation of the ontogeny and function of commensal-specific B cell responses in tissue immunity, inflammation, and repair. [Display omitted] • Phage display screening identifies immunogenic commensal antigens • B cell antigen tetramers enable identification of SFB-specific B cells • SFB-specific B cells display anatomically compartmentalized effector functions • Affinity maturation of SFB-specific B cells occurs under homeostatic conditions Adaptive immunity to commensal microbes promotes tissue homeostasis, immunity, and repair, but approaches to identify commensal-specific B cell responses are lacking. Verma et al. utilize phage display screening and subsequent generation of B cell tetramers to identify anatomical compartmentalization of SFB-specific B cell responses in gut-associated lymphoid tissues. [ABSTRACT FROM AUTHOR]

Susceptibility to respiratory virus infections (RVIs) varies widely across individuals. Because the gut microbiome impacts immune function, we investigated the influence of intestinal microbiota composition on RVI and determined that segmented filamentous bacteria (SFB), naturally acquired or exogenously administered, protected mice against influenza virus (IAV) infection. Such protection, which also applied to respiratory syncytial virus and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was independent of interferon and adaptive immunity but required basally resident alveolar macrophages (AMs). In SFB-negative mice, AMs were quickly depleted as RVI progressed. In contrast, AMs from SFB-colonized mice were intrinsically altered to resist IAV-induced depletion and inflammatory signaling. Yet, AMs from SFB-colonized mice were not quiescent. Rather, they directly disabled IAV via enhanced complement production and phagocytosis. Accordingly, transfer of SFB-transformed AMs into SFB-free hosts recapitulated SFB-mediated protection against IAV. These findings uncover complex interactions that mechanistically link the intestinal microbiota with AM functionality and RVI severity. [Display omitted] • Gut microbiota composition influences severity of respiratory viral infection • Gut-restricted segmented filamentous bacteria reprograms lung macrophages • Expression levels of complement and Notch4 expression impact viral infection severity • Transplant of lung macrophages transfers proneness to respiratory viral infection Ngo, Lieber, and colleagues report that colonization of the intestine by segmented filamentous bacteria reprograms lung macrophages conferring them with enhanced ability to combat respiratory viruses, resulting in ameliorated disease. These findings demonstrate the potential of gut microbiome to influence the severity of respiratory viral infection via influencing lung macrophages. [ABSTRACT FROM AUTHOR]

Commensal microbes induce cytokine-producing effector tissue-resident CD4+ T cells, but the function of these T cells in mucosal homeostasis is not well understood. Here, we report that commensal-specific intestinal Th17 cells possess an anti-inflammatory phenotype marked by expression of interleukin (IL)-10 and co-inhibitory receptors. The anti-inflammatory phenotype of gut-resident commensal-specific Th17 cells was driven by the transcription factor c-MAF. IL-10-producing commensal-specific Th17 cells were heterogeneous and derived from a TCF1+ gut-resident progenitor Th17 cell population. Th17 cells acquired IL-10 expression and anti-inflammatory phenotype in the small-intestinal lamina propria. IL-10 production by CD4+ T cells and IL-10 signaling in intestinal macrophages drove IL-10 expression by commensal-specific Th17 cells. Intestinal commensal-specific Th17 cells possessed immunoregulatory functions and curbed effector T cell activity in vitro and in vivo in an IL-10-dependent and c-MAF-dependent manner. Our results suggest that tissue-resident commensal-specific Th17 cells perform regulatory functions in mucosal homeostasis. [Display omitted] • SFB-specific Th17 cells have anti-inflammatory phenotype driven by c-MAF and IL-10 • Commensal-induced Th17 cells regulate T cell activity in an IL-10-dependent manner • TCF1+ progenitor Th17 cells generate IL-10+ SFB-induced Th17 cells locally in the gut • IL-10 signaling in gut macrophages drives anti-inflammatory Th17 cell phenotype The function of commensal-specific Th17 cells in host homeostasis is unclear. Brockmann et al. report that tissue-resident commensal-induced Th17 cells have an anti-inflammatory phenotype and can regulate effector T cell responses. Anti-inflammatory Th17 cells are sustained locally from a resident gut TCF1+ progenitor population and signals from intestinal macrophages. [ABSTRACT FROM AUTHOR]

Ten years ago, we discovered that microbiota composition controls intestinal T cell homeostasis and alters T cell responses of mice in different animal facilities. Here I discuss how these discoveries, reported in Cell Host & Microbe in 2008, came to be and contributed to our understanding of microbiota immune effects. [ABSTRACT FROM AUTHOR]

Dietary fiber strongly impacts the microbiota. Here, we show that a low-fiber diet changes the small intestinal (SI) microbiota and impairs SI Th17, TCRαβ + CD8αβ + and TCRαβ + CD8αα + intraepithelial T cell development. We restore T cell development with dietary fiber supplementation, but this defect becomes persistent over generations with constant low-fiber diets. Offspring of low-fiber diet-fed mice have reduced SI T cells even after receiving a fiber-rich diet due to loss of bacteria important for T cell development. In these mice, only a microbiota transplant from a fiber-rich diet-fed mouse and a fiber-rich diet can restore T cell development. Low-fiber diets reduce segmented filamentous bacteria (SFB) abundance, impairing its vertical transmission. SFB colonization and a fiber-rich diet partially restore T cell development. Finally, we observe that low-fiber diet-induced T cell defects render mice more susceptible to Citrobacter rodentium infection. Together, these results demonstrate the importance of fiber to microbiota vertical transmission and host immune system development., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

There is growing recognition that regionalization of bacterial colonization and immunity along the intestinal tract has an important role in health and disease. Yet, the mechanisms underlying intestinal regionalization and its dysregulation in disease are not well understood. This study found that regional epithelial expression of the transcription factor GATA4 controls bacterial colonization and inflammatory tissue immunity in the proximal small intestine by regulating retinol metabolism and luminal IgA. Furthermore, in mice without jejunal GATA4 expression, the commensal segmented filamentous bacteria promoted pathogenic inflammatory immune responses that disrupted barrier function and increased mortality upon Citrobacter rodentium infection. In celiac disease patients, low GATA4 expression was associated with metabolic alterations, mucosal Actinobacillus, and increased IL-17 immunity. Taken together, these results reveal broad impacts of GATA4-regulated intestinal regionalization on bacterial colonization and tissue immunity, highlighting an elaborate interdependence of intestinal metabolism, immunity, and microbiota in homeostasis and disease. [Display omitted] • GATA4 prevents small intestinal inflammation by restricting bacterial colonization • GATA4 regulates bacterial colonization in part by regulating IgA and retinol metabolism • GATA4 deficiency, SFB, and Citrobacter rodentium synergize to drive immunopathology • Th17 immunity is found in celiac patients with GATA4 deficiency and Actinobacillus Regulators of intestinal regionalization are vital, yet poorly understood. Here, Earley et al. demonstrate how the transcription factor GATA4 regulates metabolic pathways and luminal IgA to control adherent bacteria colonization. Proper gut regionalization and commensal colonization is critical in preventing dysregulated Th17 responses and immunopathology in humans and mice. [ABSTRACT FROM AUTHOR]

T helper 17 (Th17) cells regulate mucosal barrier defenses but also promote multiple autoinflammatory diseases. Although many molecular determinants of Th17 cell differentiation have been elucidated, the transcriptional programs that sustain Th17 cells in vivo remain obscure. The transcription factor RORγt is critical for Th17 cell differentiation; however, it is not clear whether the closely related RORα, which is co-expressed in Th17 cells, has a distinct role. Here, we demonstrated that although dispensable for Th17 cell differentiation, RORα was necessary for optimal Th17 responses in peripheral tissues. The absence of RORα in T cells led to reductions in both RORγt expression and effector function among Th17 cells. Cooperative binding of RORα and RORγt to a previously unidentified Rorc cis -regulatory element was essential for Th17 lineage maintenance in vivo. These data point to a non-redundant role of RORα in Th17 lineage maintenance via reinforcement of the RORγt transcriptional program. [Display omitted] • RORα is required for sustained Th17 responses in vivo • RORα shares genomic binding sites with RORγt • RORα binding depends on RORγt, whereas RORγt can bind ROREs in the absence of RORα • A Rorc (t) +11 kb cis -element is required for RORα-maintained RORγt expression in vivo The transcription factor RORα is recognized for contributing to Th17 cell differentiation and pathogenesis, but the underlying mechanisms are unclear. Hall, Pokrovskii, et al. find that RORα reinforces the RORγt transcriptional program by binding to a cis -regulatory element within the Rorc locus that maintains RORγt expression in vivo , thus potentiating inflammatory disease. [ABSTRACT FROM AUTHOR]

How intestinal microbes regulate metabolic syndrome is incompletely understood. We show that intestinal microbiota protects against development of obesity, metabolic syndrome, and pre-diabetic phenotypes by inducing commensal-specific Th17 cells. High-fat, high-sugar diet promoted metabolic disease by depleting Th17-inducing microbes, and recovery of commensal Th17 cells restored protection. Microbiota-induced Th17 cells afforded protection by regulating lipid absorption across intestinal epithelium in an IL-17-dependent manner. Diet-induced loss of protective Th17 cells was mediated by the presence of sugar. Eliminating sugar from high-fat diets protected mice from obesity and metabolic syndrome in a manner dependent on commensal-specific Th17 cells. Sugar and ILC3 promoted outgrowth of Faecalibaculum rodentium that displaced Th17-inducing microbiota. These results define dietary and microbiota factors posing risk for metabolic syndrome. They also define a microbiota-dependent mechanism for immuno-pathogenicity of dietary sugar and highlight an elaborate interaction between diet, microbiota, and intestinal immunity in regulation of metabolic disorders. [Display omitted] • Commensal-induced Th17 cells regulate epithelial lipid absorption • Sugar and ILC3 increase Faecalibaculum rodentium to displace Th17-inducing bacteria • Microbiota-induced Th17 cells protect from diet-induced obesity and metabolic disease • Sugar eliminates commensal Th17 cells to increase the risk for metabolic disease Sugar in mouse diets promotes metabolic disease by upsetting the gut microbial balance and driving loss of the Th17 cells that regulate lipid absorption by the intestinal epithelium. [ABSTRACT FROM AUTHOR]

Throughout a 24-h period, the small intestine (SI) is exposed to diurnally varying food- and microbiome-derived antigenic burdens but maintains a strict immune homeostasis, which when perturbed in genetically susceptible individuals, may lead to Crohn disease. Herein, we demonstrate that dietary content and rhythmicity regulate the diurnally shifting SI epithelial cell (SIEC) transcriptional landscape through modulation of the SI microbiome. We exemplify this concept with SIEC major histocompatibility complex (MHC) class II, which is diurnally modulated by distinct mucosal-adherent SI commensals, while supporting downstream diurnal activity of intra-epithelial IL-10+ lymphocytes regulating the SI barrier function. Disruption of this diurnally regulated diet-microbiome-MHC class II-IL-10-epithelial barrier axis by circadian clock disarrangement, alterations in feeding time or content, or epithelial-specific MHC class II depletion leads to an extensive microbial product influx, driving Crohn-like enteritis. Collectively, we highlight nutritional features that modulate SI microbiome, immunity, and barrier function and identify dietary, epithelial, and immune checkpoints along this axis to be potentially exploitable in future Crohn disease interventions. • Small intestinal epithelial cell (SIEC) transcriptome features diurnal oscillations • Diurnal SIEC MHC class II expression is driven by dietary timing and content and the microbiome • SIEC MHC class II modulates diurnal SI IL-10 secretion and barrier function • Disruption of the diurnal diet-microbiome-host axis exacerbates Crohn-like enteritis The diurnal regulation of gut immunity depends upon the expression of MHCII induced by a population of commensal bacteria adherent to the small intestine in a diet-dependent manner. [ABSTRACT FROM AUTHOR]

Psychological stress has adverse effects on various human diseases, including those of the cardiovascular system. However, the mechanisms by which stress influences disease activity remain unclear. Here, using vaso-occlusive episodes (VOEs) of sickle cell disease as a vascular disease model, we show that stress promotes VOEs by eliciting a glucocorticoid hormonal response that augments gut permeability, leading to microbiota-dependent interleukin-17A (IL-17A) secretion from T helper 17 (Th17) cells of the lamina propria, followed by the expansion of the circulating pool of aged neutrophils that trigger VOEs. We identify segmented filamentous bacteria as the commensal essential for the stress-induced expansion of aged neutrophils that enhance VOEs in mice. Importantly, the inhibition of glucocorticoids synthesis, blockade of IL-17A, or depletion of the Th17 cell-inducing gut microbiota markedly reduces stress-induced VOEs. These results offer potential therapeutic targets to limit the impact of psychological stress on acute vascular occlusion. • Psychological stress triggers vaso-occlusive episodes (VOEs) in sickle cell disease • Stress-induced VOEs depend on the microbiota • The stress response is enabled by the hypothalamic-pituitary-adrenal axis • Stress-induced VOEs are mediated by aged neutrophil expansion via the IL-17/G-CSF pathway Psychological stress has adverse effects on various human diseases, but the mechanisms by which stress influences disease activity remain unclear. Xu et al. discover that the influence of psychological stress vaso-occlusion in sickle cell disease depends on the gut microbiota and IL-17/G-CSF pathway. [ABSTRACT FROM AUTHOR]

Targeting glycolysis has been considered therapeutically intractable owing to its essential housekeeping role. However, the context-dependent requirement for individual glycolytic steps has not been fully explored. We show that CRISPR-mediated targeting of glycolysis in T cells in mice results in global loss of Th17 cells, whereas deficiency of the glycolytic enzyme glucose phosphate isomerase (Gpi1) selectively eliminates inflammatory encephalitogenic and colitogenic Th17 cells, without substantially affecting homeostatic microbiota-specific Th17 cells. In homeostatic Th17 cells, partial blockade of glycolysis upon Gpi1 inactivation was compensated by pentose phosphate pathway flux and increased mitochondrial respiration. In contrast, inflammatory Th17 cells experience a hypoxic microenvironment known to limit mitochondrial respiration, which is incompatible with loss of Gpi1. Our study suggests that inhibiting glycolysis by targeting Gpi1 could be an effective therapeutic strategy with minimum toxicity for Th17-mediated autoimmune diseases, and, more generally, that metabolic redundancies can be exploited for selective targeting of disease processes. • PPP and OXPHOS compensate for Gpi1 loss in Th17 cells in normoxic environment • Gpi1 is essential in hypoxic inflamed tissue due to reduced OXPHOS compensation • Metabolic redundancy can vary according to the microenvironment • Targeting Gpi1 could be a tolerable approach for therapeutic glycolysis inhibition Metabolic redundancy differs according to microenvironments, making the glycolysis gene Gpi1 dispensable for homeostatic Th17 cells in normal tissue but essential for pathogenic Th17 cells in hypoxic inflamed tissue. [ABSTRACT FROM AUTHOR]

Lymphoid cells that produce interleukin (IL)-17 cytokines protect barrier tissues from pathogenic microbes but are also prominent effectors of inflammation and autoimmune disease. T helper 17 (Th17) cells, defined by RORγt-dependent production of IL-17A and IL-17F, exert homeostatic functions in the gut upon microbiota-directed differentiation from naive CD4+ T cells. In the non-pathogenic setting, their cytokine production is regulated by serum amyloid A proteins (SAA1 and SAA2) secreted by adjacent intestinal epithelial cells. However, Th17 cell behaviors vary markedly according to their environment. Here, we show that SAAs additionally direct a pathogenic pro-inflammatory Th17 cell differentiation program, acting directly on T cells in collaboration with STAT3-activating cytokines. Using loss- and gain-of-function mouse models, we show that SAA1, SAA2, and SAA3 have distinct systemic and local functions in promoting Th17-mediated inflammatory diseases. These studies suggest that T cell signaling pathways modulated by the SAAs may be attractive targets for anti-inflammatory therapies. • SAAs direct a distinct Th17 cell differentiation program independently of TGF-β • Expression of SAAs is associated with inflamed colon of IBD patients • Systemic SAAs in serum promote differentiation of pathogenic Th17 cells • Local SAA expression fuels pathogenicity of activated Th17 cells Serum amyloid A proteins dictate the balance between homeostatic and inflammatory Th17 cells. [ABSTRACT FROM AUTHOR]

Rotavirus (RV) encounters intestinal epithelial cells amidst diverse microbiota, opening possibilities of microbes influencing RV infection. Although RV clearance typically requires adaptive immunity, we unintentionally generated RV-resistant immunodeficient mice, which, we hypothesized, reflected select microbes protecting against RV. Accordingly, such RV resistance was transferred by co-housing and fecal transplant. RV-protecting microbiota were interrogated by heat, filtration, and antimicrobial agents, followed by limiting dilution transplant to germ-free mice and microbiome analysis. This approach revealed that segmented filamentous bacteria (SFB) were sufficient to protect mice against RV infection and associated diarrhea. Such protection was independent of previously defined RV-impeding factors, including interferon, IL-17, and IL-22. Colonization of the ileum by SFB induced changes in host gene expression and accelerated epithelial cell turnover. Incubation of RV with SFB-containing feces reduced infectivity in vitro , suggesting direct neutralization of RV. Thus, independent of immune cells, SFB confer protection against certain enteric viral infections and associated diarrheal disease. • Some mouse colonies developed spontaneous resistance to rotavirus (RV) infection • Fecal microbial transplantation transfers RV resistance • Protection against RV was mediated by segmented filamentous bacteria (SFB) • SFB impeded RV by increasing epithelial cell turnover A bacterium can protect against rotavirus infection in mice independent of the immune system. [ABSTRACT FROM AUTHOR]