Secondary bile acids, lithocholic acid and deoxycholic acid (LCA and DCA), are dehydroxylated derivatives of primary bile acids. However, in addition to LCA and DCA the intestinal microbiota produced a variety of poorly characterized metabolites. Allo-LCA, a LCA metabolite, acts as a dual GPBAR1 agonist and RORγt inverse agonist and modulates intestinal immunity, although is not yet known whether allo-LCA exerts regulatory functions outside the intestine. In the present study we have therefore investigated whether administration of allo-LCA, 10 mg/kg/day, to mice administered a high fat/high fructose diet (HFD-F) and carbon tetrachloride (Ccl4), a model for metabolic dysfunction-associated steatohepatitis (MASH), protects from development of liver damage. In vitro allo-LCA functions as GPBAR1 agonist and RORγt inverse agonist and prevents macrophages M1 polarization and Th17 polarization of CD4 cells. In vivo studies, while exposure to a HFD-F/Ccl4 promoted insulin resistance and development of a pro-atherogenic lipid profile and liver steatosis and fibrosis, allo-LCA reversed this pattern by improving insulin sensitivity and liver lipid accumulation. The liver transcriptomic profile demonstrated that allo-LCA reversed the dysregulation of multiple pathways associated with immunological, inflammatory and metabolic signaling. Allo-LCA also restored bile acid homeostasis, reversing HFD/Ccl4-induced shifts in bile acid pool composition and restored adipose tissue histopathology and function by reducing the expression of leptin and resistin, two pro-inflammatory adipokines, and restored a healthier composition of the intestinal microbiota. In conclusion, present results expand on the characterization of entero-hepatic signaling and suggest that allo-LCA, a microbial metabolite, might have therapeutic potential in liver diseases.

We developed a two-tiered strategy aiming to identify gut bacteria functionally linked to the development of multiple sclerosis (MS). First, we compared gut microbial profiles in a cohort of 81 monozygotic twins discordant for MS. This approach allowed to minimize confounding effects by genetic and early environmental factors and identified over 50 differently abundant taxa with the majority of increased taxa within the Firmicutes. These included taxa previously described to be associated with MS (Anaerotruncus colihominis and Eisenbergiella tayi), along with newly identified taxa, such as Copromonas and Acutalibacter. Second, we interrogated the intestinal habitat and functional impact of individual taxa on the development of MS-like disease. In an exploratory approach, we enteroscopically sampled microbiota from different gut segments of selected twin pairs and compared their compositional profiles. To assess their functional potential, samples were orally transferred into germfree transgenic mice prone to develop spontaneous MS-like experimental autoimmune encephalomyelitis (EAE) upon bacterial colonization. We found that MS-derived ileal microbiota induced EAE at substantially higher rates than analogous material from healthy twin donors. Furthermore, female mice were more susceptible to disease development than males. The likely active organisms were identified as Eisenbergiella tayi and Lachnoclostridium, members of the Lachnospiraceae family. Our results identify potentially disease-facilitating bacteria sampled from the ileum of MS affected twins. The experimental strategy may pave the way to functionally understand the role of gut microbiota in initiation of MS.

Intestinal bacteria play a critical role in the regulation of the host immune system and an imbalance in the intestinal bacterial composition induces various host diseases. Therefore, maintaining a balance in the intestinal bacterial composition is crucial for health. Immunoglobulin A (IgA), produced through T cell-dependent and T cell-independent (TI) pathways, is essential for host defense against pathogen invasion and maintaining the balance of intestinal symbiotic bacteria. Interleukin (IL)-5 is constitutively produced by Group 2 innate lymphoid cells (ILC2s) and plays a critical role in the survival and proliferation of B cells and eosinophils. Here, we show the role of IL-5-producing ILC2s in intestinal TI IgA production at steady state using T cell receptor α deficient mice. In this mouse model, ILC2s increased fecal TI IgA levels in a non-inflammatory state in an IL-5-dependent manner. The administration of recombinant IL-33 (rIL-33) increased the amount of TI IgA production, accompanied by an increase in the number of IL-5-producing ILC2s in the large intestine. In addition, rIL-33 treatment increased IL-5-dependent IgA+ cells in isolated lymphoid follicles, the site of TI IgA production. Furthermore, eosinophils recruited by ILC2s were required for the maximal production of IgA in the TI pathway. Moreover, IL-5 increased the frequency of TI IgA-binding intestinal bacteria and was involved in the maintenance of intestinal bacterial composition. These findings indicate that IL-5-producing ILC2s together with eosinophils contribute to TI IgA production. In addition to their role in TI IgA production, IL-5-producing ILC2s may contribute to the homeostasis of intestinal commensal bacteria.

Systemic sclerosis (SSc), or scleroderma, is a complex autoimmune connective tissue disease characterized by autoimmunity, vasculopathy, and progressive organ fibrosis, leading to severe organ dysfunction. The disease begins with a vascular injury triggered by autoimmune responses and environmental factors against a backdrop of genetic predisposition. This injury impairs angiogenesis and vasculogenesis, resulting in capillary loss and arteriolar constriction, which promotes immune cell infiltration and sustained inflammation within affected tissues. These vascular anomalies cause severe complications, including pulmonary artery hypertension, scleroderma renal crisis, and skin ulcers. Chronic inflammation fosters persistent fibroblast activation, resulting in extensive fibrosis that defines SSc. This review synthesizes the latest research on pathogenesis of SSc, highlighting the shift from fundamental research to a precision therapeutic approach. It explores the potential of technologies like flow cytometry and single-cell RNA sequencing to investigate pathogenic cell subtypes. These platforms integrate transcriptomic, genomic, proteomic, and epigenomic data to uncover insights into the underlying mechanisms of SSc pathogenesis. This review advocates for a multidisciplinary, patient-centric approach that harnesses recent scientific advances, directing future SSc research toward personalized and precise interventions.

Rheumatoid arthritis (RA) is a complex chronic autoimmune disease that remains incurable for most patients. With advances in our understanding of the disease's natural history, the concept of pre-RA has emerged as a window of opportunity to intervene before irreversible joint damage occurs. Numerous studies have indicated that the key step driving autoimmunity in early pre-RA lies at an extra-articular site, which is closely related to the regulatory T (Treg) cell-established immune tolerance to the gut microbiota. The intricate immunometabolic crosstalk between Treg cells and the gut microbiota is beginning to be understood, with the re-recognition of Treg cells as metabolic sensors in recent years. In the future, deciphering their immunometabolic dialogue may help to elucidate the underlying mechanisms of pre-RA. Identifying novel biological pathways in the pre-RA stage will bring insights into restoring immune tolerance, thereby potentially curing or preventing the onset of RA.

The gastrointestinal tract is continuously exposed to foreign antigens in food and commensal microbes with potential to induce adaptive immune responses. Peripherally induced T regulatory (pTreg) cells are essential for mitigating inflammatory responses to these agents1-4. While RORγt+ antigen-presenting cells (RORγt-APCs) were shown to program gut microbiota-specific pTreg5-7, their definition remains incomplete, and the APC responsible for food tolerance has remained elusive. Here, we identify a distinct subset of RORγt-APCs, designated tolerogenic dendritic cells (tDC), required for differentiation of both food- and microbiota-specific pTreg cells and for establishment of oral tolerance. tDC development and function require expression of the transcription factors Prdm16 and RORγt, as well as a unique Rorc(t) cis-regulatory element. Gene expression, chromatin accessibility, and surface marker analysis establish tDC as myeloid in origin, distinct from ILC3, and sharing epigenetic profiles with classical DC. Upon genetic perturbation of tDC, we observe a substantial increase in food antigen-specific T helper 2 (Th2) cells in lieu of pTreg, leading to compromised tolerance in mouse models of asthma and food allergy. Single-cell analyses of freshly resected mesenteric lymph nodes from a human organ donor, as well as multiple specimens of human intestine and tonsil, reveal candidate tDC with co-expression of PRDM16 and RORC and an extensive transcriptome shared with mice, highlighting an evolutionarily conserved role across species. Our findings suggest that a better understanding of how tDC develop and how they regulate T cell responses to food and microbial antigens could offer new insights into developing therapeutic strategies for autoimmune and allergic diseases as well as organ transplant tolerance.

This study aimed to explore the potential mechanism of Xiexin Tang in improving type 2 diabetes mellitus from the perspective of intestinal barrier function. The results indicated that Xiexin Tang could notably promote the expression of GPRs while suppressing the expression of HDACs in colon epithelial cells, then significantly elevate the levels of TGF-β1 and IL-18 to regulate the differentiation of T cells and further maintain the intestinal immune homeostasis. Meanwhile, it could markedly inhibit the inflammatory signaling pathway to improve intestinal barrier function, relieving type 2 diabetes mellitus.

Regulatory T (Treg) cells are a specialized CD4+ T cell lineage with essential anti-inflammatory functions. Analysis of Treg cell adaptations to non-lymphoid tissues that enable their specialized immunosuppressive and tissue-supportive functions raises questions about the underlying mechanisms of these adaptations and whether they represent stable differentiation or reversible activation states. Here, we characterize distinct colonic effector Treg cell transcriptional programs. Attenuated T cell receptor (TCR) signaling and acquisition of substantial TCR-independent functionality seems to facilitate the terminal differentiation of a population of colonic effector Treg cells that are distinguished by stable expression of the immunomodulatory cytokine IL-10. Functional studies show that this subset of effector Treg cells, but not their expression of IL-10, is indispensable for colonic health. These findings identify core features of the terminal differentiation of effector Treg cells in non-lymphoid tissues and their function.

Conventional dendritic cells (cDCs) are sentinels of the mammalian immune system that sense a wide range of danger and homeostatic signals to induce appropriately targeted T cell immune responses. Traditionally classified into two main subsets, cDC1 and cDC2, recent research shows that cDC2s exhibit significant heterogeneity and can be further subdivided. Studies in mice and humans show that, beyond their ontogeny, cDC2s acquire dynamic and tissue-specific characteristics that are influenced by local environmental signals, which impact on their functions during homeostasis, inflammation, and infection. The novel concept is proposed that tissue-derived signals and tissue plasticity can override preestablished developmental programming, thereby redefining developmental trajectories and cDC2 functionality. Ultimately, understanding cDC2 heterogeneity and plasticity has important implications for modulating T cell immunity in health and disease.

Dendritic cells (DCs) are crucial gatekeepers of the balance between immunity and tolerance. They exist in two functional states, immature or mature, that refer to an information-sensing versus an information-transmitting state, respectively. Historically, the term DC maturation was used to describe the acquisition of immunostimulatory capacity by DCs following their triggering by pathogens or tissue damage signals. As such, immature DCs were proposed to mediate tolerance, whereas mature DCs were associated with the induction of protective T cell immunity. Later studies have challenged this view and unequivocally demonstrated that two distinct modes of DC maturation exist, homeostatic and immunogenic DC maturation, each with a distinct functional outcome. Therefore, the mere expression of maturation markers cannot be used to predict immunogenicity. How DCs become activated in homeostatic conditions and maintain tolerance remains an area of intense debate. Several recent studies have shed light on the signals driving the homeostatic maturation programme, especially in the conventional type 1 DC (cDC1) compartment. Here, we highlight our growing understanding of homeostatic DC maturation and the relevance of this process for immune tolerance.

Given the role of Receptor for Activated C Kinase 1 (RACK1) in both immune cell activation and in the maintenance of the intestinal epithelial barrier integrity, we investigated whether it was involved in inflammatory bowel disease (IBD).

RACK1 expression was analyzed in intestinal mucosal samples of healthy and IBD patients, in mice with chemically induced colitis, and in diseased in vitro 2D and 3D coculture models by luciferase assay, reverse transcription-quantitative PCR, Western blotting, immunofluorescence, and immunohistochemistry. Based on our finding that glucocorticoid-induced leucine zipper (GILZ or tsc22d3) positively correlates with RACK1 expression in IBD patients, GILZ knockout mice and cell silencing experiments were performed.

RACK1 was significantly decreased in IBD, especially in ulcerative colitis. This was associated with an NF-κB/c-Rel-related mechanism, correlating with decreased GILZ protein expression. GILZ depletion confirmed a decrease in RACK1 expression, which favored SRC activation and led to a significant reduction in E-cadherin, resulting in impaired epithelial barrier integrity. Finally, our data highlighted that this novel mechanism could be considered to develop new therapies since dexamethasone, the first line of treatment in IBD, restored RACK1 expression through the glucocorticoid receptor in a c-Rel/GILZ-independent manner.

We provide the first evidence that an alteration of RACK1/SRC/E-cadherin regulatory mechanism, correlating with decreased GILZ protein expression, is involved in epithelial barrier disruption. The clinical relevance is based on the fact that this mechanism involving GILZ/c-Rel-related RACK1 expression could be considered to improve IBD therapies, particularly in patients with low or no response to glucocorticoid treatment.

We sought to investigate the impact of CpG oligodeoxynucleotides (CpG-ODN) administration on the lung and gut microbiota in asthmatic mice, specifically focusing on changes in composition, diversity, and abundance, and to elucidate the microbial mechanisms underlying the therapeutic effects of CpG-ODN and identify potential beneficial bacteria indicative of its efficacy.

HE staining were used to analyze inflammation in lung, colon and small intestine tissues. High-throughput sequencing technology targeting 16S rRNA was employed to analyze the composition, diversity, and correlation of microbiome in the lung, colon and small intestine of control, model and CpG-ODN administration groups.

(1) Histopathologically, both lung and intestinal tissue in asthmatic mice exhibited significant structural damage and inflammatory response, whereas the structure of both lung and intestinal tissue approached normal levels, accompanied by a notable improvement in the inflammatory response after CpG-ODN treatment. (2) In the specific microbiota composition analysis, bacterial dysbiosis observed in the asthmatic mice, accompanied by enrichment of Proteobacteria found to cause lung and intestinal epithelial damage and inflammatory reaction. After CpG-ODN administration, bacterial dysbiosis was improved, and a notable enrichment of beneficial bacteria, indicating a novel microecology. Meanwhile Oscillospira and Clostridium were identified as two biomarkers of the CpG-ODN treatment. (3) Heatmap analysis revealed significant correlations among lung, small intestine, and colon microbiota.

CpG-ODN treatment can ameliorate OVA-induced asthma in mice. One side, preserving the structural integrity of the lung and intestine, safeguarding the mucosal physical barrier, the other side, improving the dysbiosis of lung and gut microbiota in asthmatic mice. Beneficial bacteria and metabolites take up microecological advantages, regulate immune cells and participate in the mucosal immune response to protect the immune barrier. Meanwhile, Oscillospira and Clostridium as biomarkers for CpG-ODN treatment, has reference significance for exploring precise Fecal microbiota transplantation treatment for asthma.

The role of microbes and their metabolites in modulating tuft cell (TC) dynamics in the large intestine and the relevance of this pathway to infections is unknown. Here, we uncover that microbiome-driven colonic TC hyperplasia protects against Clostridioides difficile infection. Using selective antibiotics, we demonstrate increased type 2 cytokines and TC hyperplasia in the colon but not in the ileum. We demonstrate the causal role of the microbiome in modulating this phenotype using fecal matter transplantation and administration of consortia of succinate-producing bacteria. Administration of succinate production-deficient microbes shows a reduced response in a Pou2f3-dependent manner despite similar intestinal colonization. Finally, antibiotic-treated mice prophylactically administered with succinate-producing bacteria show increased protection against C. difficile-induced morbidity and mortality. This effect is nullified in Pou2f3-/- mice, confirming that the protection occurs via the TC pathway. We propose that activation of TCs by the microbiota in the colon is a mechanism evolved by the host to counterbalance microbiome-derived cues that facilitate invasion by pathogens.

Crohn's disease (CD) is a chronic, complex inflammatory disorder of the gastrointestinal tract that presents significant therapeutic challenges. Despite the availability of a wide range of treatments, many patients experience primary non-response, secondary loss of response, or adverse events, limiting the overall effectiveness of current therapies. Clinical trials often report response rates below 60%, partly due to stringent inclusion criteria. Emerging therapies that target novel pathways offer promise in overcoming these limitations. This review explores the latest investigational drugs in phases I, II, and III clinical trials for treating both luminal and perianal CD. We highlight promising therapies that target known mechanisms, including selective Janus kinase inhibitors, anti-adhesion molecules, tumor necrosis factor inhibitors, and IL-23 selective inhibitors. In addition, we delve into novel therapeutic strategies such as sphingosine-1-phosphate receptor modulators, miR-124 upregulators, anti-fractalkine (CX3CL1), anti-TL1A, peroxisome proliferator-activated receptor gamma agonists, TGFBRI/ALK5 inhibitors, anti-CCR9 agents, and other innovative small molecules, as well as combination therapies. These emerging approaches, by addressing new pathways and mechanisms of action, have the potential to surpass the limitations of existing treatments and significantly improve CD management. However, the path to developing new therapies for inflammatory bowel disease (IBD) is fraught with challenges, including complex trial designs, ethical concerns regarding placebo use, recruitment difficulties, and escalating costs. The landscape of IBD clinical trials is shifting toward greater inclusivity, improved patient diversity, and innovative trial designs, such as adaptive and Bayesian approaches, to address these challenges. By overcoming these obstacles, the drug development pipeline can advance more effective, accessible, and timely treatments for CD.

In this paper, active polysaccharides were extracted from Brassica rapa L. polysaccharide (BRP), and structural characterization was preliminarily investigated. Its immunomodulatory activity and molecular biological mechanisms in cyclophosphamide-induced immunosuppressed mice were also explored, as well as its effects on intestinal microbiota. Results indicate that BRP is an acidic heteropolysaccharide with the main components of Ara, GalA, and GlcA and has α- and β-glycosidic linkages with pyranose bonds. The results of the study showed that BRP could effectively improve the thymus and spleen indices and repair Cy-induced immune tissue damage in immunosuppressed mice. Meanwhile, BRP increased the immune cell activity and antioxidant levels in mice. In addition, BRP increased the secretion of cytokines (IL-1β, IL-6, IL-10, and TNF-α) and immunoglobulins (IgA, IgG) in mouse serum. It also regulates the relative expression of genes related to the TLR4/NF-κB signaling pathways as well as regulates the diversity and composition of mouse intestinal microbiota. In conclusion, BRP was able to regulated the immune function in immunosuppressed mice, providing a theoretical basis for the development of immunomodulators.

The intestinal immune system is the largest immune organ in the human body. Excessive immune response to intestinal cavity induced by harmful stimuli including pathogens, foreign substances and food antigens is an important cause of inflammatory diseases such as celiac disease and inflammatory bowel disease (IBD). Although great progress has been made in the treatment of IBD by some immune-related biotherapeutic products, yet a considerable proportion of IBD patients remain unresponsive or immune tolerant to immunotherapeutic strategy. Therefore, it is necessary to further understand the mechanism of immune cell populations involved in enteritis, including dendritic cells, macrophages and natural lymphocytes, in the steady-state immune tolerance of IBD, in order to find effective IBD therapy. In this review, we discussed the important role of innate and adaptive immunity in the development of IBD. And the relationship between intestinal immune system disorders and microflora crosstalk were also presented. We also focus on the new findings in the field of T cell immunity, which might identify novel cytokines, chemokines or anti-cytokine antibodies as new approaches for the treatment of IBD.

Milk allergy commonly occurs in children, mainly caused by bovine-derived casein (CAS) protein. Neutrophil-activating protein (NAP) of Helicobacter pylori plays an immunomodulatory role with potential to suppress Th2-type immune responses. Bacillus subtilis (B. subtilis) spores are commonly used as oral vectors for drug delivery.

To investigate whether recombinantly expressed NAP on B. subtilis spores could be an effective treatment for CAS allergy in mouse.

After CAS sensitization, mice were orally administered B. subtilis spores expressing recombinant NAP for 6 weeks. Allergic symptoms and parameters were evaluated after CAS challenge oral gavage, including allergic inflammation, splenic cytokines, and serum-specific antibodies. Protein levels of Toll-like receptor 2 (TLR2) and c-JUN in the jejunum tissue were measured by western blot. Bone marrow-derived macrophages (BMDMs) were stimulated with inactivated NAP spores to measure the influence on cytokine profiles in vitro.

NAP recombinant spore treatment significantly reduced allergic symptoms and intestinal inflammation. Interleukin-12 and interferon-gamma levels increased, whereas serum CAS-specific IgG1 and IgE levels decreased. TLR2 and c-JUN expression levels were elevated in the jejunal tissue. Inactivated NAP spores polarized BMDMs to the M1 phenotype and enhanced cytokine expression, which were inhibited by a TLR2 neutralizing antibody.

NAP offers a new strategy in the treatment of CAS allergy by inhibiting the Th2 response, while eliciting macrophages to promote Th1 immune responses.

The mammalian intestine is colonized by trillions of microorganisms that are collectively referred to as the gut microbiota. The majority of symbionts have co-evolved with their host in a mutualistic relationship that benefits both. Under certain conditions, such as in Crohn's disease, a subtype of inflammatory bowel disease, some symbionts bloom to cause disease in genetically susceptible hosts. Although the identity and function of disease-causing microorganisms or pathobionts in Crohn's disease remain largely unknown, mounting evidence from animal models suggests that pathobionts triggering Crohn's disease-like colitis inhabit certain niches and penetrate the intestinal tissue to trigger inflammation. In this Review, we discuss the distinct niches occupied by intestinal symbionts and the evidence that pathobionts triggering Crohn's disease live in the mucus layer or near the intestinal epithelium. We also discuss how Crohn's disease-associated mutations in the host disrupt intestinal homeostasis by promoting the penetration and accumulation of pathobionts in the intestinal tissue. Finally, we discuss the potential role of microbiome-based interventions in precision therapeutic strategies for the treatment of Crohn's disease.

Inflammatory bowel diseases (IBD), including Crohn's disease and ulcerative colitis, are chronic disorders characterized by dysregulated immune response and persistent inflammation. Recent studies suggest that bile acid receptors, particularly GPBAR1, and the transcription factor RORγt play critical roles in modulating intestinal inflammation. This study evaluates the therapeutic potential of PBT002, a dual GPBAR1 agonist and RORγt inverse agonist, in IBD models. The effects of PBT002 were assessed through in vitro and in vivo experiments. Macrophages and T lymphocytes obtained from the buffy coat were exposed to PBT002 to evaluate its immunomodulatory activity. The beneficial effects in vivo were evaluated in mouse models of colitis induced by TNBS, DSS or DSS + IL-23 using also a Gpbar1 knock-out male mice. PBT002 exhibited an EC50 of 1.2 µM for GPBAR1 and an IC50 of 2.8 µM for RORγt. In in vitro, PBT002 modulated macrophage polarization towards an anti-inflammatory M2 phenotype and reduced Th17 cell markers while increasing Treg markers. In the TNBS-induced colitis model, PBT002 reduced weight loss, CDAI, and colon damage, while it modulated cytokine gene expression towards an anti-inflammatory profile. In GPBAR1-/-, the anti-inflammatory effects of PBT002 were attenuated, indicating partial GPBAR1 dependence. RNA sequencing revealed significant modulation of inflammatory pathways by PBT002. In DSS+IL-23 induced colitis, PBT002 mitigated disease exacerbation, reducing pro-inflammatory cytokine levels and immune cell infiltration. In conclusion, PBT002, a GPBAR1 agonist and RORγt inverse agonist, modulates both the innate and adaptive immune responses to reduce inflammation and disease severity in models of IBD.

Food allergy (FA) is a common disorder in children and affects the health of children worldwide. The gut microbiota is closely related to the occurrence and development of FA. Fecal microbiota transplantation (FMT) is a way to treat diseases by reconstituting the microbiota; however, the role and mechanisms of FA have not been validated.

In this study, we established an ovalbumin (OVA)-induced juvenile mouse model and used 16S RNA sequencing, pathological histological staining, molecular biology, and flow-through techniques to evaluate the protective effects of FMT treatment on FA and to explore the mechanisms.

OVA-induced dysregulation of the gut microbiota led to impaired intestinal function and immune dysregulation in FA mice. FMT treatment improved the structure, diversity, and composition of the gut microbiota and restored it to a near-donor state. FMT treatment reduced levels of Th2-associated inflammatory factors, decreased intestinal tissue inflammation, and reduced IgE production. In addition, FMT reduced the number of mast cells and eosinophils and suppressed OVA-specific antibodies. Further mechanistic studies revealed that FMT treatment induced immune tolerance by inducing the expression of CD103+DCs and programmed cell death ligand 1 (PD-L1) in mesenteric lymph nodes and promoting the production of Treg through the programmed cell death protein 1 (PD-1)/PD-L1 pathway. Meanwhile, Th2 cytokines, OVA-specific antibodies, and PD-1/PD-L1 showed a significant correlation with the gut microbiota.

FMT could regulate the gut microbiota and Th1/Th2 immune balance and might inhibit FA through the PD-1/PD-L1 pathway, which would provide a new idea for the treatment of FA.

The mucosal immune system is a critical first line of defense to infectious diseases, as many pathogens enter the body through mucosal surfaces, disrupting the balanced interactions between mucosal cells, secretory molecules, and microbiota in this challenging microenvironment. The mucosal immune system comprises of a complex and integrated network that includes the gut-associated lymphoid tissues (GALT). One of its primary responses to microbes is the secretion of IgA, whose role in the mucosa is vital for preventing pathogen colonization, invasion and spread. The mechanisms involved in these key responses include neutralization of pathogens, immune exclusion, immune modulation, and cross-protection. The generation and maintenance of high affinity IgA responses require a delicate balance of multiple components, including B and T cell interactions, innate cells, the cytokine milieu (e.g., IL-21, IL-10, TGF-β), and other factors essential for intestinal homeostasis, including the gut microbiota. In this review, we will discuss the main cellular components (e.g., T cells, innate lymphoid cells, dendritic cells) in the gut microenvironment as mediators of important effector responses and as critical players in supporting B cells in eliciting and maintaining IgA production, particularly in the context of enteric infections and vaccination in humans. Understanding the mechanisms of humoral and cellular components in protection could guide and accelerate the development of more effective mucosal vaccines and therapeutic interventions to efficiently combat mucosal infections.

Inflammatory Bowel Disease (IBD) is a chronic condition whose incidence has been rising globally. Synbiotic (SYN) is an effective means of preventing IBD. This study investigated the preventive effects and potential biological mechanisms of SYN (Bifidobacterium longum, Lactobacillus acidophilus, and sea buckthorn polysaccharides) on DSS-induced colitis in mice. The results indicated that dietary supplementation with SYN has a significant improvement effect on DSS mice. SYN ameliorated disease activity index (DAI), colon length, and intestinal barrier permeability in mice. In addition, RT-qPCR results indicated that after SYN intervention, the expression levels of pro-inflammatory factors (IL-6, IL-1β, TNF-α, and IL-17F) and transcription factor RORγt secreted by Th17 cells were significantly reduced, and the expression levels of anti-inflammatory factors (IL-10 and TGF-β) and transcription factor Foxp3 secreted by Treg cells were robustly increased. 16S rDNA sequencing analysis revealed that key intestinal microbiota related to Th17/Treg balance (Ligilactobacillus, Lactobacillus, Bacteroides, and Akkermansia) was significantly enriched. At the same time, a significant increase in microbial metabolites SCFAs and BAs was observed. We speculate that SYN may regulate the Th17/Treg balance by restructuring the structure and composition of the intestinal microbiota, thereby mitigating DSS-induced colitis.

The early development of the neonatal immune system is profoundly influenced by exposure to dietary and microbial antigens, which shapes mucosal tolerance. Successful oral tolerance induction is crucially dependent on microbially imprinted immune cells, most notably the RORγt+ regulatory T (Treg) and antigen presenting cells and is essential for preventing food allergy (FA). The development of FA can be envisioned to result from disruptions at key checkpoints (CKPTs) that govern oral tolerance induction. These include gut epithelial sensory and effector circuits that when dysregulated promote pro-allergic gut dysbiosis. They also include microbially imprinted immune regulatory circuits that are disrupted by dysbiosis and pro-allergic immune responses unleashed by the dysregulation of the aforementioned cascades. Understanding these checkpoints is essential for developing therapeutic strategies to restore immune homeostasis in FA.

Inflammatory bowel disease (IBD) has high prevalence in Western counties. The high fat content in Western diets is one of the leading causes for this prevalence; however, the underlying mechanisms have not been fully defined. Here, we find that high-fat diet (HFD) induces ferroptosis of intestinal regulatory T (Treg) cells, which might be the key initiating step for the disruption of immunotolerance and the development of colitis. Compared with effector T cells, Treg cells favor lipid metabolism and prefer polyunsaturated fatty acids (PUFAs) for the synthesis of membrane phospholipids. Therefore, consumption of HFD, which has high content of PUFAs such as arachidonic acid, cultivates vulnerable Tregs that are fragile to lipid peroxidation and ferroptosis. Treg-cell-specific deficiency of GPX4, the key enzyme in maintaining cellular redox homeostasis and preventing ferroptosis, dramatically aggravates the pathogenesis of HFD-induced IBD. Taken together, these studies expand our understanding of IBD etiology.

The gastrointestinal (GI) tract redox environment, influenced by commensal microbiota and bacterial-derived metabolites, is crucial in shaping T-cell responses. Specifically, metabolites from gut microbiota (GM) exhibit robust anti-inflammatory effects, fostering the differentiation and regulation of CD8+ tissue-resident memory (TRM) cells, mucosal-associated invariant T (MAIT) cells, and stabilizing gut-resident Treg cells. Nitric oxide (NO), a pivotal redox mediator, emerges as a central regulator of T-cell functions and gut inflammation. NO impacts the composition of the gut microbiome, driving the differentiation of pro-inflammatory Th17 cells and exacerbating intestinal inflammation, and supports Treg expansion, showcasing its dual role in immune homeostasis. This review delves into the complex interplay between GI redox balance and GM metabolites, elucidating their profound impact on T-cell regulation. Additionally, it comprehensively emphasizes the critical role of GI redox, particularly reactive oxygen species (ROS) and NO, in shaping T-cell phenotype and functions. These insights offer valuable perspectives on disease mechanisms and potential therapeutic strategies for conditions associated with oxidative stress. Understanding the complex cross-talk between GI redox, GM metabolites, and T-cell responses provides valuable insights into potential therapeutic avenues for immune-mediated diseases, underscoring the significance of maintaining GI redox balance for optimal immune health.

Crohn disease (CD) is an inflammatory bowel disease whose pathogenesis involves inappropriate immune responses toward gut microbiota on genetically predisposed backgrounds. Notably, CD is associated with single-nucleotide polymorphisms affecting several genes involved in macroautophagy/autophagy, the catabolic process that ensures the degradation and recycling of cytosolic components and microorganisms. In a clinical translation perspective, monitoring the autophagic activity of CD patients will require some knowledge on the intrinsic functional status of autophagy. Here, we focused on monocyte-derived dendritic cells (DCs) to characterize the intrinsic quantitative features of the autophagy flux. Starting with DCs from healthy donors, we documented a reprogramming of the steady state flux during the transition from the immature to mature status: both the autophagosome pool size and the flux were diminished at the mature stage while the autophagosome turnover remained stable. At the cohort level, DCs from CD patients were comparable to control in term of autophagy flux reprogramming capacity. However, the homozygous presence of ATG16L1 rs2241880 A>G (T300A) and ULK1 rs12303764 (G/T) polymorphisms abolished the capacity of CD patient DCs to reprogram their autophagy flux during maturation. This effect was not seen in the case of CD patients heterozygous for these polymorphisms, revealing a gene dose dependency effect. In contrast, the NOD2 rs2066844 c.2104C>T (R702W) polymorphism did not alter the flux reprogramming capacity of DCs. The data, opening new clinical translation perspectives, indicate that polymorphisms affecting autophagy-related genes can differentially influence the capacity of DCs to reprogram their steady state autophagy flux when exposed to proinflammatory challenges.Abbreviation: BAFA1: bafilomycin A1, CD: Crohn disease; DC: dendritic cells; HD: healthy donor; iDCs: immature DCs; IL: interleukin; J: autophagosome flux; LPS: lipopolysaccharide; MHC: major histocompatibility complex; nA: autophagosome pool size; SNPs: single-nucleotide polymorphisms; PCA: principal component analysis; TLR: toll like receptor; τ: transition time; TNF: tumor necrosis factor.

With advances in next-generation sequencing technology, there is growing evidence that the gut microbiome plays a key role in the host's innate and adaptive immune system. Gut microbes and their metabolites directly or indirectly regulate host immune cells. Crucially, dysregulation of the gut microbiota is often associated with many immune system diseases. In turn, microbes modulate disease immunotherapy. Data from preclinical to clinical studies suggest that the gut microbiota may influence the effectiveness of tumor immunotherapy, particularly immune checkpoint inhibitors (ICIs). In addition, the most critical issue now is a COVID-19 vaccine that generates strong and durable immunity. A growing number of clinical studies confirm the potential of gut microbes to enhance the efficacy of COVID-19 vaccines. However, it is still unclear how gut bacteria interact with immune cells and what treatments are based on gut microbes. Here, we outline recent advances in the effects and mechanisms of the gut microbiota and its metabolites (tryptophan metabolites, bile acids, short-chain fatty acids, and inosine) on different immune cells (dendritic cells, CD4+T cells, and macrophages). It also highlights innovative intervention strategies and clinical trials of microbiota-based checkpoint blocking therapies for tumor immunity, and ongoing efforts to maintain the long-term immunogenicity of COVID-19 vaccines. Finally, the challenges to be overcome in this area are discussed. These provide an important basis for further research and clinical translation of gut microbiota.

Millions of microorganisms make up the complex microbial ecosystem found in the human gut. The immune system's interaction with the gut microbiota is essential for preventing inflammation and maintaining intestinal homeostasis. Numerous metabolic products that can cross-talk between immune cells and the gut epithelium are metabolized by the gut microbiota. Traumatic injury elicits a great and multifaceted immune response in the minutes after the initial offense, containing simultaneous pro- and anti-inflammatory responses. The development of innovative therapies that improve patient outcomes depends on the gut microbiota and immunological responses to trauma. The altered makeup of gut microbes, or gut dysbiosis, can also dysregulate immunological responses, resulting in inflammation. Major human diseases may become more common as a result of chronic dysbiosis and the translocation of bacteria and the products of their metabolism beyond the mucosal barrier. In this review, we briefly summarize the interactions between the gut microbiota and the immune system and human disease and their therapeutic probiotic formulations. We also discuss the immune response to traumatic injury.

Although the pathogenesis of inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), has not been fully elucidated, accumulating researches suggest that intestinal microbiota imbalance contributes to the development of IBD in patients and animal models. RDP58, a peptide-based computer-assisted rational design, has been demonstrated to be effective in protecting against a wide range of autoimmune and inflammatory diseases. However, the underlying mechanism by which RDP58 protects against IBD mediated by intestinal microbiota has yet to be elucidated.

The colitis model was induced by continuously administering 2.5 % (wt/vol) dextran sodium sulfate (DSS) solution for 7 days. The manifestations of colon inflammation were assessed via daily weight changes, colon length, tumor necrosis factor-alpha (TNF-α) level, disease activity index (DAI) score, pathology score, and intestinal barrier permeability. Intestinal microbiota analysis was carried out by 16S-rRNA sequencing. Colonic short chain fatty acids (SCFAs) and regulatory T cells (Tregs) were also detected. To further confirm the protective effect of RDP58 on intestinal microbiota, broad-spectrum antibiotic cocktail (ABX) treatment and fecal microbial transplantation (FMT) experiment were performed.

Oral administration of RDP58 ameliorated DSS-induced mice colitis by altering the diversity and composition of intestinal microbiota. Notably, RDP58 significantly upregulated SCFAs-producing microbiota, thereby promoting the generation of Tregs. ABX and FMT were performed to verify the above mechanism.

RDP58 ameliorated DSS-induced colitis through altering intestinal microbiota and enhancing SCFAs and Tregs production in intestinal microbiota dependent manner, potentially provide a novel therapy for IBD.

Rheumatoid Arthritis (RA) is an autoimmune condition responsible for the impairment of synovia and joints, endangering the functionality of individuals and contributing to mortality. Currently, obesity is increasing worldwide, and recent studies have suggested an association between such condition and RA. In this sense, obese individuals present a lower capacity for achieving remission and present more intense symptoms of the disease, demonstrating a link between both disorders. Different studies aim to understand the possible connection between the conditions; however, few is known in this sense. Therefore, knowing that obesity can alter the activity of multiple body systems, this work's objective is to evaluate the main modifications caused by obesity, which can be linked to the pathophysiology of RA, highlighting as relevant topics obesity's negative impact triggering systemic inflammation, intestinal dysbiosis, endocrine disbalances. Furthermore, the relationship between oxidative stress and obesity also deserves to be highlighted, considering the influence of reactive oxygen species (ROS) accumulation in RA exacerbation. Additionally, many of those characteristics influenced by obesity, along with the classic peculiarities of RA pathophysiology, can also be associated with purinergic signaling. Hence, this work suggests possible connections between the purinergic system and RA, proposing potential therapeutic targets against RA to be studied.

Bile acids are steroids formed at the interface of host metabolism and intestinal microbiota. While primary bile acids are generated in the liver from cholesterol metabolism, secondary bile acids represent the products of microbial enzymes. Close to 100 different enzymatic modifications of bile acids structures occur in the human intestine and clinically guided metagenomic and metabolomic analyses have led to the identification of an extraordinary number of novel metabolites. These chemical mediators make an essential contribution to the composition and function of the postbiota, participating to the bidirectional communications of the intestinal microbiota with the host and contributing to the architecture of intestinal-liver and -brain and -endocrine axes. Bile acids exert their function by binding to a group of cell membrane and nuclear receptors collectively known as bile acid-regulated receptors (BARRs), expressed in monocytes, tissue-resident macrophages, CD4+ T effector cells, including Th17, T regulatory cells, dendritic cells and type 3 of intestinal lymphoid cells and NKT cells, highlighting their role in immune regulation. In this review we report on how bile acids and their metabolitesmodulate the immune system in inflammations and cancers and could be exploiting for developing novel therapeutic approaches in these disorders.

The mucosal barrier's immune-brain interactions, pivotal for neural development and function, are increasingly recognized for their potential causal and therapeutic relevance to irritable bowel syndrome (IBS). Prior studies linking immune inflammation with IBS have been inconsistent. To further elucidate this relationship, we conducted a Mendelian randomization (MR) analysis of 731 immune cell markers to dissect the influence of various immune phenotypes on IBS. Our goal was to deepen our understanding of the disrupted brain-gut axis in IBS and to identify novel therapeutic targets.

To leverage publicly available data to perform MR analysis on 731 immune cell markers and explore their impact on IBS. We aimed to uncover immunophenotypic associations with IBS that could inform future drug development and therapeutic strategies.

We performed a comprehensive two-sample MR analysis to evaluate the causal relationship between immune cell markers and IBS. By utilizing genetic data from public databases, we examined the causal associations between 731 immune cell markers, encompassing median fluorescence intensity, relative cell abundance, absolute cell count, and morphological parameters, with IBS susceptibility. Sensitivity analyses were conducted to validate our findings and address potential heterogeneity and pleiotropy.

Bidirectional false discovery rate correction indicated no significant influence of IBS on immunophenotypes. However, our analysis revealed a causal impact of IBS on 30 out of 731 immune phenotypes (P < 0.05). Nine immune phenotypes demonstrated a protective effect against IBS [inverse variance weighting (IVW) < 0.05, odd ratio (OR) < 1], while 21 others were associated with an increased risk of IBS onset (IVW ≥ 0.05, OR ≥ 1).

Our findings underscore a substantial genetic correlation between immune cell phenotypes and IBS, providing valuable insights into the pathophysiology of the condition. These results pave the way for the development of more precise biomarkers and targeted therapies for IBS. Furthermore, this research enriches our comprehension of immune cell roles in IBS pathogenesis, offering a foundation for more effective, personalized treatment approaches. These advancements hold promise for improving IBS patient quality of life and reducing the disease burden on individuals and their families.

Weaning is a critical transitional point in the life cycle of piglets. Early weaning can lead to post-weaning syndrome, destroy the intestinal barrier function and microbiota homeostasis, cause diarrhea and threaten the health of piglets. The nutritional components of milk and solid foods consumed by newborn animals can affect the diversity and structure of their intestinal microbiota, and regulate post-weaning diarrhea in piglets. Therefore, this paper reviews the effects and mechanisms of different nutrients, including protein, dietary fiber, dietary fatty acids and dietary electrolyte balance, on diarrhea and health of piglets by regulating intestinal function. Protein is an essential nutrient for the growth of piglets; however, excessive intake will cause many harmful effects, such as allergic reactions, intestinal barrier dysfunction and pathogenic growth, eventually aggravating piglet diarrhea. Dietary fiber is a nutrient that alleviates post-weaning diarrhea in piglets, which is related to its promotion of intestinal epithelial integrity, microbial homeostasis and the production of short-chain fatty acids. In addition, dietary fatty acids and dietary electrolyte balance can also facilitate the growth, function and health of piglets by regulating intestinal epithelial function, immune system and microbiota. Thus, a targeted control of dietary components to promote the establishment of a healthy bacterial community is a significant method for preventing nutritional diarrhea in weaned piglets.

This study sought to compare the behavior of Treg subsets displaying different coexpression patterns of Neuropilin-1 (Nrp1) and Helios, under the influence of gut stress unrelated to hematopoietic stem cell transplantation, pretransplantation conditioning, and posttransplant gastrointestinal acute graft versus host disease (GI-aGvHD). Host CD4+/CD25hi/Foxp3+ Treg cells, identified by flow cytometry, were isolated from various tissues of mice affected by these stressors. Expression of CD25, CTLA-4, CD39, OX40, integrin-β7, LAG3, TGFβ/LAP, granzyme-A, -B, and interleukin-10 was compared in four Treg subsets displaying Helios or Nrp1 only, both or none. Fluorescence-activated cell sorter-sorted Treg subsets, displaying markers affected in a conditioning- and GI-aGVHD-restricted manner, were further investigated by transcriptome profiling and T-cell suppression assays. We found that conditioning by irradiation greatly diminished the relative frequency of Helios+/Nrp1+ Treg, shifting the balance toward Helios-/Nrp1- Treg in the host. Upregulation of integrin-β7 and OX40 occurred in GI-aGvHD-dependent manner in Helios+/Nrp1+ cells but not in Helios-/Nrp1- Treg. Sorted Treg subsets, confirmed to overexpress Nrp1, Helios, OX40, or integrin-β7, displayed superior immunosuppressive activity and enrichment in activation-related messenger RNA transcripts. Our data suggest that conditioning-induced shrinkage of the Nrp1+/Helios+ Treg subset may contribute to the development of GI-GvHD by impairing gut homing and decreasing the efficiency of Treg-mediated immunosuppression.

The gut microbiota plays a critical role in the progression of human diseases, especially cancer. In recent decades, there has been accumulating evidence of the connections between the gut microbiota and cancer immunotherapy. Therefore, understanding the functional role of the gut microbiota in regulating immune responses to cancer immunotherapy is crucial for developing precision medicine. In this review, we extract insights from state-of-the-art research to decipher the complicated crosstalk among the gut microbiota, the systemic immune system, and immunotherapy in the context of cancer. Additionally, as the gut microbiota can account for immune-related adverse events, we discuss potential interventions to minimize these adverse effects and discuss the clinical application of five microbiota-targeted strategies that precisely increase the efficacy of cancer immunotherapy. Finally, as the gut microbiota holds promising potential as a target for precision cancer immunotherapeutics, we summarize current challenges and provide a general outlook on future directions in this field.