Inflammatory Bowel Disease (IBD) is a spectrum of chronic inflammatory diseases of the intestine that includes subtypes of ulcerative colitis (UC) and Crohn's Disease (CD) and currently has no cure. While IBD results from a complex interplay between genetic, environmental, and immunological factors, sequencing advances over the last 10-15 years revealed signature changes in gut microbiota that contribute to the pathogenesis of IBD. These findings highlight IBD as a disease target for microbiome-based therapies, with the potential to treat the underlying microbial pathogenesis and provide adjuvant therapy to the emerging spectrum of advanced therapies for IBD. Building on the success of fecal microbiota transplantation (FMT) for Clostridioides difficile infection, therapies targeting gut microbiota have emerged as promising approaches for treating IBD; however, unique aspects of IBD pathogenesis highlight the need for more precision in the approach to microbiome therapeutics that leverage aspects of recipient and donor selection, diet and xenobiotics, and strain-specific interactions to enhance the efficacy and safety of IBD therapy. This review focuses on both pre-clinical and clinical studies that support the premise for microbial therapeutics for IBD and aims to provide a framework for the development of precision microbiome therapeutics to optimize clinical outcomes for patients with IBD.

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.

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.

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.

Total glucosides of paeony (TGP), an active ingredient extracted from the dried root of Paeonia lactiflora Pall., has been approved in China for the treatment of various autoimmune diseases. However, the role and mechanism of TGP in UC have yet to be fully elucidated. This study aims to investigate the regulatory effects and underlying mechanisms of TGP on intestinal homeostasis disruption and immune imbalance in a mouse model of dextran sulfate sodium (DSS)-induced colitis. The results showed that TGP alleviated DSS induced body weight loss, colonic shortening and histopathological changes in mice, and also enhanced the integrity of the intestinal barrier by up-regulating the expression of ZO-1, Occludin and tight junction protein in the colon. The results of 16S and antibiotic cocktail (ABX) experiments showed that TGP alleviated colitis by inhibiting Th17 cell differentiation by correcting intestinal microbial imbalance in UC mice. Mechanism studies showed that TGP inhibited the activation of JAK2/STAT3 signaling pathway in UC mice, and decreased the levels of inflammatory factors in colon supernatant and serum. Importantly, TGP regulates JAK2/STAT3 to inhibit Th17 cell differentiation depending on gut flora. In addition, TGP can also improve the metabolic imbalance in UC mice, especially purine metabolism. In conclusion, TGP promotes the normalization of purine metabolism and relies on gut microbiota to regulate JAK2/STAT3 pathway, inhibit Th17 cell differentiation, and alleviate colitis. Our findings highlight TGP as a promising treatment candidate for ulcerative colitis.

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.

Emerging evidence suggests that probiotics are beneficial for immunity and play a crucial role in regulating gut microbiota. However, the immune-enhancing effects of specific bacterial species remain uncertain. This study investigated the effects of two potential probiotic strains, Latilactobacillus curvatus WiKim0169 (Wilac L004, W4) and Pediococcus acidilactici WiKim0170 (Wilac L002, W2) isolated from fermented cabbage, on immune enhancement and gut microbiota changes in a cyclophosphamide-induced immunosuppression rat model. The results revealed that W4 and W2 improved natural killer cell activity, serum nitrite, and immunoglobulin levels. They also increased cytokine levels and activated the nuclear factor-κB pathway, substantiating the underlying mechanism of the immune-enhancing effects. Additionally, both strains altered gut microbiota composition by increasing bacteria that are being studied for their potential association with immune function. Taken together, both strains improved immune-related biomarkers and the gut microbiota. These findings suggest W4 and W2 as promising probiotics with immune-enhancing properties.

The gut microbiota (GM) may play a crucial role in the development and progression of central nervous system (CNS) diseases. Microecologics and exercise can influence the composition and function of GM, thereby exerting positive effects on the CNS. Combined interventions of exercise and microecologics are expected to more comprehensively and effectively address CNS diseases through the microbiota-gut-brain axis (MGBA), potentially outperforming single interventions. However, there is currently a lack of relevant reviews on this topic. In this review, we examine the associations between changes in the microbiota and CNS diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and autism spectrum disorder (ASD). We also summarize studies on various types of microecologics (such as probiotics, prebiotics, synbiotics, and postbiotics) and exercise in improving CNS disease symptoms. Although current individual studies on microecologics and exercise have achieved certain results, the mechanisms underlying their synergistic effects remain unclear. This review aims to explore the theoretical basis, potential mechanisms, and clinical application prospects of combined interventions of microecologics and exercise in improving CNS diseases through the MGBA, providing a scientific basis for the development of more comprehensive and effective therapeutic interventions.

The REG/Reg gene locus encodes a conserved family of potent antimicrobial but also pancreatitis-associated proteins. Here we investigated whether REG/Reg family members differ in their baseline expression levels and abilities to be regulated in the pancreas and gut upon perturbations. We found, in humans and mice, the pancreas and gut differed in REG/Reg isoform levels and preferences, with the duodenum most resembling the pancreas. Pancreatic acinar cells and intestinal enterocytes were the dominant REG producers. Intestinal symbiotic microbes regulated the expression of the same, select Reg members in gut and pancreas. These Reg members had the most STAT3-binding sites close to the transcription start sites and were partially IL-22 dependent. We thus categorized them as "inducible" and others as "constitutive". Indeed, in pancreatic ductal adenocarcinoma and pancreatitis models, only inducible Reg members were upregulated in the pancreas. While intestinal Reg expression remained unchanged upon pancreatic perturbation, pancreatitis altered the microbial composition of the duodenum and feces shortly after disease onset. Our study reveals differential usage and regulation of REG/Reg isoforms as a mechanism for tissue-specific innate immunity, highlights the intimate connection of pancreas and duodenum, and implies a gut-to-pancreas communication axis resulting in a coordinated Reg response.

Inflammatory bowel disease (IBD), which includes Crohn's Disease (CD) and ulcerative colitis (UC), is characterized by chronic inflammation of the gastrointestinal tract. A key component of the inflammatory pathway in IBD is interleukin 23 (IL-23), which promotes the differentiation and maintenance of Th17 cells. These cells are major contributors to intestinal inflammation and the release of pro-inflammatory cytokines. A dysregulated IL-23/Th17 axis can lead to excessive gut inflammation. Notably, IL-23 affects Th17 cell responses differently in UC and CD, fostering IL-17 production in UC and interferon-gamma (IFN-γ) production in CD. Genetic studies have pinpointed specific variants of the IL-23 receptor (IL23R) gene that confer protection against IBD. The R381Q (rs11209026) variant has been linked to a reduced risk of developing both CD and UC. Additionally, other variants, such as G149R (rs76418789) and V362I (rs41313262), inhibit IL23R function by disrupting intracellular trafficking and protein stability. This disruption results in decreased phosphorylation of downstream signal transducers, such as STAT3 and STAT4, and reduced IL23R expression on the cell surface, ultimately dampening the activation of pro-inflammatory pathways. The protective effects of these genetic variants underscore the IL-23/IL23R pathway as a significant therapeutic target in IBD management. Therapies designed to modulate this pathway have the potential to reduce pro-inflammatory cytokine production and enhance anti-inflammatory mechanisms. Ongoing research into the IL23R gene and its variants continues to provide valuable insights, paving the way for more targeted and effective treatments for IBD patients.

The increasing global burden of allergic diseases and multimorbidity underscores the urgent need for innovative strategies to strengthen immune health. This review explores the complex relationships among nutrition, gut microbiota, immune regulation, allergic diseases, and multimorbidity. It highlights how targeted nutritional and microbial interventions may influence disease outcomes. Dietary components and microbial metabolites dynamically modulated immune function, highlighting the critical role of the gut-immune-metabolism axis in disease pathogenesis and management. Personalized nutrition, guided by advances in diagnostics such as component-resolved diagnostics, basophil activation tests, and epigenetic biomarkers, allows for precise dietary interventions tailored to individual allergy phenotypes and multimorbidity profiles. The Mediterranean diet, breastfeeding, and microbiota-targeted therapies have emerged as effective strategies to enhance immune resilience, reduce inflammation, and manage allergic reactions. Technological advancements, including artificial intelligence-driven dietary assessments, wearable devices, and mobile applications, have further revolutionized personalized dietary management, enabling real-time, precise nutritional monitoring and intervention. Despite these advances, challenges in implementing personalized nutrition persist, including variability in dietary patterns, cultural and socioeconomic factors, and accessibility concerns. Future research should focus on long-term interventional and longitudinal studies to validate precision nutrition strategies and enhance clinical applicability. This integrative approach, combining nutrition, microbiome science, technology, and personalized healthcare, holds substantial promises for sustainable disease prevention and enhanced immune resilience across diverse populations.

The mammalian gut harbours trillions of commensal bacteria that interact with their hosts through various bioactive molecules1,2. However, the mutualistic strategies that hosts evolve to benefit from these symbiotic relationships are largely unexplored. Here we report that mouse enterocytes secrete apolipoprotein L9a and b (APOL9a/b) in the presence of microbiota. By integrating flow cytometry sorting of APOL9-binding bacterial taxa with 16S ribosomal RNA gene sequencing (APOL9-seq), we identify that APOL9a/b, as well as their human equivalent APOL2, coat gut bacteria belonging to the order of Bacteroidales with a high degree of specificity through commensal ceramide-1-phosphate (Cer1P) lipids. Genetic abolition of ceramide-1-phosphate synthesis pathways in gut-dominant symbiote Bacteroides thetaiotaomicron significantly decreases the binding of APOL9a/b to the bacterium. Instead of lysing the bacterial cells, coating of APOL9a/b induces the production of outer membrane vesicles (OMVs) from the target bacteria. Subsequently, the Bacteroides-elicited outer membrane vesicles enhance the host's interferon-γ signalling to promote major histocompatibility complex class II expression in the intestinal epithelial cells. In mice, the loss of Apol9a/b compromises the gut major histocompatibility complex class II-instructed immune barrier function, leading to early mortality from infection by intestinal pathogens. Our data show how a host-elicited factor benefits gut immunological homeostasis by selectively targeting commensal ceramide molecules.

Aging manifests a decline of immune function, induces microbiome dysbiosis, drives organ inflammation, and impedes the resolution of inflammation. However, the mechanisms underlying age-related intestinal inflammation remain poorly described. Here, we find that the resolution of T cell-initiated intestinal inflammation is impaired with aging. This impairment is mediated by disrupting the immune-microbiota interplay, controlled by intestinal eicosanoid metabolism. Pharmacologically inhibiting eicosanoid biosynthesis, blocking the prostaglandin E receptor subtype 4 (EP4), or genetically ablating EP4 diminishes age-related impairment of intestinal inflammation resolution. Mechanistically, mononuclear phagocyte-intrinsic eicosanoid-EP4 signaling impedes the resolution of intestinal inflammation through fostering gut microbial dysbiosis and, more importantly, interrupting segmented filamentous bacterial adhesion to the intestinal epithelium. Colonization with EP4-ablated mouse microbiota or segmented filamentous bacteria improves the resolution of intestinal inflammation. These findings reveal that eicosanoid-dependent immune-microbiota interactions impair inflammation resolution in the aged intestine, highlighting potential intervention strategies for improving age-related gut health.

Intestinal CD4+ T cells that are specific for self-, diet-, or commensal-derived antigens are critical for host tolerance but must also be tightly regulated to prevent aberrant activation and conditions like inflammatory bowel disease (IBD). However, it is unclear how the antigen source and location dictate the intestinal TCR repertoire. Here, we hierarchically classified self-, diet-, or microbiota-dependent TCRs using TCliβ TCRβ transgenic mice. This demonstrated that microbiota had a greater influence than diet on CD4+ T cell responses throughout the intestine at homeostasis. Complex bi-directional interactions between microbes and diet were also observed. In the context of murine colitis as a model of IBD, we showed that antigen-free diet substantially altered the microbiota and associated T cell responses, which ameliorated intestinal inflammation. Collectively, these findings suggest how deconvoluting the gut immune interactome may facilitate identifying primary microbial and dietary drivers of T cell responses during health and disease.

Prenatal viral infections can lead to neurodevelopmental disorders in offspring. However, how viral-induced maternal perturbations impact fetal brain macrophages remains insufficiently clear. Here, we demonstrated that inflammatory decidual natural killer (NK) cells, triggered by viral infection-induced maternal immune activation, drove macrophage activation, neurodevelopmental disorders, and behavioral deficits in offspring. Extracellular granzyme B (GzmB), predominantly released by the maternal CD49a+ tissue-resident NK subset under type I interferon stimulation, crossed the maternal-fetal barrier and promoted interferon-stimulated gene (ISG)-expressing fetal macrophage accumulation and microglial activation. Targeting extracellular GzmB through the systemic administration of the serine protease inhibitor Serpina3n or genetic ablation of Gzmb in maternal NK cells mitigated neuroimmune disorders in the fetal brain. These findings suggest that exposure to a perturbed maternal milieu reprograms decidual NK cell immunity, disrupting fetal neuroimmune homeostasis and increasing offspring susceptibility to neurodevelopmental disorders later in life.

Crosstalk between the immune system and the microbiome is critical for maintaining immune homeostasis. Here, we examined this communication and the impact of immune-suppressive IL-10 signaling on pulmonary homeostasis. We found that IL-10 sensing by interstitial macrophages (IMs) is required to prevent spontaneous lung inflammation. Loss of IL-10 signaling in IMs initiated an inflammatory cascade through the activation of classical monocytes and CD4+ T cell subsets, leading to chronic lung inflammation with age. Analyses of antibiotic-treated and germ-free mice established that lung inflammation in the animals lacking IL-10 signaling was triggered by commensal bacteria. 16S rRNA sequencing revealed Delftia acidovorans and Rhodococcus erythropolis as potential drivers of lung inflammation. Intranasal administration of these bacteria or transplantation of human fecal microbiota elicited lung inflammation in gnotobiotic Il10-deficient mice. These findings highlight that IL-10 sensing by IMs contributes to pulmonary homeostasis by preventing lung inflammation caused by commensal dysbiosis.

Recently, the gut microbiota has been found to be associated with multiple organs and systems in the human body, playing a key role in the occurrence and development of various diseases, such as the gut-brain axis and the gut-liver axis. However, its interaction with miscarriages remains poorly understood. This article reviews the characteristics of gut microbiota and its metabolites in patients with recurrent spontaneous abortion (RSA), the mechanism of gut microbiota inducing RSA, and potential therapeutic strategies. Therefore, it provides a new perspective on the gut microbiota in the pathogenesis and treatment of recurrent abortion, and the prospect of the future research direction of gut microbiota and recurrent abortion is proposed based on existing studies.

Tumor is one of the leading causes of death worldwide. The occurrence and development of tumors are related to multiple systems and factors such as the immune system, gut microbiota, and nervous system. The immune system plays a critical role in tumor development. Studies have also found that the gut microbiota can directly or indirectly affect tumorigenesis and tumor development. With increasing attention on the tumor microenvironment in recent years, the nervous system has emerged as a novel regulator of tumor development. Some tumor therapies based on the nervous system have also been tested in clinical trials. However, the nervous system can not only directly interact with tumor cells but also indirectly affect tumor development through the gut microbiota. The nervous system-mediated gut microbiota can regulate tumorigenesis, growth, invasion, and metastasis through the immune system. Here, we mainly explore the potential effects of the nervous system-gut microbiota-immune system axis on tumorigenesis and tumor development. The effects of the nervous system-gut microbiota-immune system axis on tumors involve the nervous system regulating immune cells through the gut microbiota, which can prevent tumor development. Meanwhile, the direct effects of the gut microbiota on tumors and the regulation of the immune system by the nervous system, which can affect tumor development, are also reviewed.

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with limited treatment options and poor prognosis. The gut microbiota, a diverse community of microorganisms in the gastrointestinal tract, plays a crucial role in regulating immune responses through the gut-immune axis. Recent studies have highlighted its significant impact on TNBC progression and the efficacy of immunotherapies. This review examines the interactions between gut microbiota and the immune system in TNBC, focusing on key immune cells and pathways involved in tumor immunity. It also explores microbiota modulation strategies, including probiotics, prebiotics, dietary interventions, and fecal microbiota transplantation, as potential methods to enhance immunotherapeutic outcomes. Understanding these mechanisms offers promising avenues for improving treatment efficacy and patient prognosis in TNBC.

The multidimensional regulatory mechanism of the gut-brain-immune axis in the context of inflammatory bowel disease (IBD) has garnered significant attention, particularly regarding how intestinal microbiota finely regulates immune responses through immune cells and sensory neurons.

Metabolites produced by intestinal microbiota influence the phenotype switching of immune cells via complex signalling pathways, thereby modulating their anti-inflammatory and pro-inflammatory functions during intestinal inflammation. Furthermore, sensory neurons exhibit heightened sensitivity to microbial-derived signals, which is essential for preserving intestinal balance and controlling pathological inflammation by integrating peripheral environmental signals with local immune responses. The dynamic equilibrium between immune cells and the neuroimmunoregulation mediated by sensory neurons collectively sustains immune homeostasis within the intestine. However, this coordination mechanism is markedly disrupted under the pathological conditions associated with IBD.

An in-depth exploration of the interactions among immune cells, gut microbiota and sensory neurons may yield significant insights into the pathological mechanisms underlying IBD and guide the creation of new treatment approaches.

The gut microbiota regulates the gut-brain-immune axis, modulating neuroimmune interactions in IBD. Microbiota-derived metabolites influence immune cells, thereby affecting neurons. Neurons secrete mediators, enabling bidirectional neuroimmune communication essential for intestinal homeostasis. Disruptions contribute to IBD, offering therapeutic targets.

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.

Dysbiosis of gut microbiome is one of the most important factors leading to inflammatory bowel disease (IBD). Intake of phytochemicals from fruits and vegetables is an effective way to improve IBD, but how these bioactivators regulate gut microbiota to exert healthy effects remains unclear. Here, we found that pretreatment with CiLi juice, particularly its polyphenol component, alleviated dextran sulfate sodium (DSS)-induced colitis while preserving intestinal barrier integrity. CiLi polyphenols (CL_PP) reduced inflammation and oxidative stress in colon tissue and enriched fecal short-chain fatty acids. Importantly, CL_PP significantly regulated the gut microbiome diversity, increasing beneficial bacteria (e.g., Clostridia_UCG-014, f_Muribaculaceae and Ileibacterium_valens) while decreasing harmful bacteria (Escherichia-Shigella and Romboutsia). Multiomics analysis revealed that CL_PP upregulated bioactive lipid metabolites, particularly those derived from polyunsaturated fatty acids (e.g., resolvin D2, prostaglandin A1, and glycerophosphocholine) related gene expressions (Pltp, Alox15 and Pld4). Additionally, CL-PP downregulated the oxidative stress markers (oxidized glutathione and glutathione peroxidase 3), and immune cell markers (CD8 and CD68). Fecal microbiota transplantation confirmed that the fecal microbiota from CL_PP-treated mice exhibited anti-colitis effects. These effects were diminished in antibiotic-treated mice, underscoring the importance of the gut microbiota in mediating the CL_PP's anti-inflammatory benefits. This study suggests that CL_PP is a potential modulator of gut microbiome dysbiosis for the prevention and treatment of colitis.

Much remains unknown regarding T follicular helper 17 (TFH17) cells commonly found in autoimmune patients. We previously showed that (and here ask why) egress of gut segmented filamentous bacteria (SFB)-induced TFH cells from Peyer's patches (PP) to systemic sites promotes arthritis. We found splenic TFH17 cells are gut derived. Functional analyses using fate-mapping mice revealed a c-Maf-dependent and SFB-induced TH17-to-TFH cell reprogramming that dominantly occurs in PPs. Unlike conventional TFH cells, TH17-derived TFH cells are highly migratory and atypically concentrated in the dark zone of germinal centers (GCs). Compared to conventional TFH cells, TH17-derived TFH cells express higher levels of TFH-associated functional molecules and more robustly conjugate with B cells. Gain- and loss-of-function studies demonstrated their dominance in promoting GC B cells and arthritis. Notably, murine gut TH17-derived TFH signatures exist in rheumatoid arthritis patients. Thus, gut T cell plasticity generates atypical, potent TFH cells promoting systemic autoimmunity.

Rheumatoid arthritis is a chronic autoimmune disorder characterized by destructive, symmetric joint inflammation and synovitis, resulting in substantial disability that profoundly compromises patients' quality of life. Its pathogenesis encompasses complex interactions between genetic and environmental factors. Recent advances in bacterial DNA sequencing technologies have uncovered a significant correlation between the human gut microbiota composition and rheumatoid arthritis progression. Growing clinical and experimental evidence establishes the gut-joint axis as a crucial mediator in rheumatoid arthritis pathogenesis. Comprehensive investigation of gut microbial communities and their metabolites' influence on rheumatoid arthritis mechanisms, coupled with the elucidation of microbiome's bidirectional regulatory effects in disease development, not only deepens our understanding of pathological processes but also establishes a theoretical framework for developing novel diagnostic biomarkers and personalized therapeutic interventions to enhance patient outcomes.

To investigate the therapeutic and gut microbiota-modulating effects of Qingreliangxuefang (QRLXF) on psoriasis.

We used network pharmacology, a computational approach, to identify key bioactive compounds and biological targets, and explored the molecular mechanisms of QRLXF. The effects of QRLXF on keratinocyte proliferation and inflammation were evaluated using a mouse model of psoriasis. Changes in the gut microbiota were analyzed via 16SrDNA sequencing, and T cell subsets were assessed using flow cytometry.

Network pharmacology analysis suggested that QRLXF ameliorated psoriasis by modulating Th17 cell differentiation. Further experiments confirmed the anti-inflammatory effects and relief of psoriatic lesions in IMQ-induced mice. 16SrDNA sequencing revealed significant shifts in the gut microbiota, notably increases in Ligilactobacillus and Lactobacillus genera and decreases in Anaerotruncus, Negativibacillus, Bilophila, and Mucispirillum, suggesting a potential relationship between specific microbiota changes and Th17 cell differentiation.

QRLXF alleviated psoriatic dermatitis by regulating Th17 cell responses and modifying gut microbiota profiles, highlighting its therapeutic potential for psoriasis treatment.

Anti-viral immunity can vary tremendously from individual to individual but mechanistic understanding is still scarce. Here, we show that a defined, low complex bacterial community (OMM12) but not the general absence of microbes in germ-free mice leads to a more potent immune response compared to the microbiome of specific-pathogen-free (SPF) mice after a systemic viral infection with LCMV Clone-13. Consequently, gnotobiotic mice colonized with OMM12 have more severe LCMV-induced disease pathology but also enhance viral clearance in the intestinal tract. Mechanistically, single-cell RNA sequencing analysis of adoptively transferred virus-specific T helper cells and endogenous T helper cells in the intestinal tract reveal a stronger pro-inflammatory Th1 profile and a more vigorous expansion in OMM12 than SPF mice. Altogether, our work highlights the causative function of the intestinal microbiome for shaping adaptive anti-viral immunity with implications for vaccination strategies and anti-cancer treatment regimens.

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.

Multiple sclerosis (MS) is a well-known, chronic autoimmune disorder of the central nervous system (CNS) involving demyelination and neurodegeneration. Research previously conducted in the area of the gut microbiome has highlighted it as a critical contributor to MS pathogenesis. Changes in the commensal microbiota, or dysbiosis, have been shown to affect immune homeostasis, leading to elevated levels of pro-inflammatory cytokines and disruption of the gut-brain axis. In this review, we provide a comprehensive overview of interactions between the gut microbiota and MS, especially focusing on the immunomodulatory actions of microbiota, such as influencing T-cell balance and control of metabolites, e.g., short-chain fatty acids. Various microbial taxa (e.g., Prevotella and Faecalibacterium) were suggested to lay protective roles, whereas Akkermansia muciniphila was associated with disease aggravation. Interventions focusing on microbiota, including probiotics, prebiotics, fecal microbiota transplantation (FMT), and dietary therapies to normalize gut microbial homeostasis, suppress inflammation and are proven to improve clinical benefits in MS patients. Alterations in gut microbiota represent opportunities for identifying biomarkers for early diagnosis, disease progression and treatment response monitoring. Further studies need to be conducted to potentially address the interplay between genetic predispositions, environmental cues, and microbiota composition to get the precise mechanisms of the gut-brain axis in MS. In conclusion, the gut microbiota plays a central role in MS pathogenesis and offers potential for novel therapeutic approaches, providing a promising avenue for improving clinical outcomes in MS management.

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.

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.

Antigen-specific recognition of microbiota by T cells enforces tolerance at homeostasis. Conversely, dysbiosis leads to imbalanced T-cell responses, triggering inflammatory and autoimmune diseases. Despite their significance, the identities of immunogenic microbial antigens remain largely enigmatic. Here, we leveraged a sensitive, unbiased, genome-wide screening platform to identify peptides from Akkermansia muciniphila (AKK) and Bacteroides thetaiotaomicron (BT) recognized by CD4+ T cells. The platform is based on screening peptide libraries using an NFAT-fluorescence reporter cell line transduced with a retrovirus encoding an MHC-TCR (MCR) hybrid molecule. We discovered several novel epitopes from AKK and BT. T-cell hybridomas reactive to AKK and BT bacteria demonstrated polyreactivity to microbiota-derived peptides in co-cultures with MCR reporter cells. Steady-state T cells recognized these epitopes in an MHC-restricted fashion. Intriguingly, most of the identified epitopes are broadly conserved within the given phylum and originate from membrane and intracellular proteins. Ex vivo stimulation of CD4+ T cells from mice vaccinated with the identified peptides revealed mono-specific IFN-γ and IL-17 responses. Our work showcases the potential of the MCR system for identifying immunogenic microbial epitopes, providing a valuable resource. Our study facilitates decoding antigen specificity in immune system-bacterial interactions, with applications in understanding microbiome and pathogenic bacterial immunity.

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.

The immune system encounters a diverse array of antigens, both self and foreign, necessitating mechanisms to maintain tolerance and prevent harmful inflammatory responses. CD4＋ T cells, crucial in orchestrating immune responses, play a critical role in mediating tolerance to both self and foreign antigens. While the mechanisms of CD4＋ T cell-mediated tolerance to self-antigens are well-documented, the understanding of tolerance to foreign antigens, including those from commensal microbes and food, remains incomplete. This review discusses recent progress in the mechanisms underlying immune tolerance to foreign antigens, with a focus on the role of CD4＋ T cells. We explore how inflammatory and tolerogenic CD4＋ T cell subsets are developed and maintained. Moreover, we delve into the complexities of immune responses to commensal microbes and food antigens by reviewing recent findings, highlighting the immunological contexts that shape immune tolerance. Understanding these mechanisms enhances our comprehension of how immune tolerance is established and sustained, providing insights into potential therapeutic approaches for managing chronic inflammatory diseases resulting from a loss of immune tolerance to foreign antigens. [BMB Reports 2025; 58(4): 158-168].

Interstitial lung disease (ILD) is a heterogeneous chronic form of lung disease. The pathogenesis of ILD is poorly understood and a common form of ILD, idiopathic pulmonary fibrosis (IPF) is associated with poor prognosis. There is evidence for substantial dysregulated immune responses in ILD. The microbiome is a key regulator of the immune response, and the lung microbiome correlates with alveolar immunity and clinical outcomes in ILD. Most observational lung microbiome studies have been conducted in patients with IPF. A consistent observation in these studies is that the bacterial burden of the lung is elevated in patients with IPF and predicts mortality. However, our understanding of the mechanism is incomplete and our understanding of the role of the lung microbiome in other forms of ILD is limited. The microbiomes of the oropharynx and gut may have implications for the lung microbiome and pulmonary immunity in ILD but require substantial further research. Here, we discuss the studies supporting a role for the lung microbiome in the pathogenesis of IPF, and briefly describe the putative role of the oral-lung axis and the gut-lung axis in ILD.