In health, the gut microbiome functions as a stable ecosystem maintaining overall balance and ensuring its own survival against environmental stressors through complex microbial interaction. This balance and protection from stressors is maintained through interactions both within the bacterial ecosystem as well as with its host. As a consequence, the gut microbiome plays a critical role in various physiological processes including maintaining the structure and function of the gut barrier, educating the gut immune system, and modulating the gut motor, digestive/absorptive, as well as neuroendocrine system all of which are crucial for human health and disease pathogenesis. Pre- and probiotics, widely available and clinically established, offer various health benefits primarily by beneficially modulating the gut microbiome. However, their clinical outcomes can vary significantly due to differences in host physiology, diets, individual microbiome compositions, and other environmental factors. This perspective paper highlights emerging scientific insights into the importance of microbial micronutrient sharing, gut redox balance, keystone species, and the gut barrier in maintaining a diverse and functional microbial ecosystem, and their relevance to human health. We propose a novel approach that targets microbial ecosystems and keystone taxa performance by supplying microbial micronutrients in the form of colon-delivered vitamins, and precision prebiotics [e.g. human milk oligosaccharides (HMOs) or synthetic glycans] as components of precisely tailored ingredient combinations to optimize human health. Such a strategy may effectively support and stabilize microbial ecosystems, providing a more robust and consistent approach across various individuals and environmental conditions, thus, overcoming the limitations of current single biotic solutions.

Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality, with limited treatment options at advanced stages. The gut microbiota, a diverse community of microorganisms residing in the gastrointestinal tract, plays a pivotal role in regulating immune responses through the gut-liver axis. Emerging evidence underscores its impact on HCC progression and the efficacy of immunotherapy. This review explores the intricate interactions between gut microbiota and the immune system in HCC, with a focus on key immune cells and pathways involved in tumor immunity. Additionally, it highlights strategies for modulating the gut microbiota - such as fecal microbiota transplantation, dietary interventions, and probiotics - as potential approaches to enhancing immunotherapy outcomes. A deeper understanding of these mechanisms could pave the way for novel therapeutic strategies aimed at improving patient prognosis.

Afatinib, an oral molecular-targeted anticancer agent, is effective but causes significant gastrointestinal side effects. These effects are associated with EGFR inhibition in intestinal cells and changes in the microbiota.

To investigate the effects of afatinib on intestinal mucosal immunity in rats, focusing on IgA levels in the intestine and saliva, and to understand the innate and acquired immune responses to these side effects.

Male Wistar rats received afatinib (5.2 mg/kg) daily for 24 h (Day 1) and for 2 weeks (Day 14). Gene expression in the intestine was analyzed using quantitative polymerase chain reaction. IgA levels in the intestine and saliva were measured using enzyme-linked immunosorbent assay.

Afatinib suppressed α-defensin 5 and pIgR in the jejunum and ileum, indicating reduced innate immunity. It increased IgA levels in the intestine and saliva, suggesting altered acquired immunity. Salivary IgA levels significantly correlated with intestinal IgA levels.

Afatinib affects gastrointestinal mucosal immunity, suppresses innate defense, and alters IgA production. Salivary IgA could serve as a marker for monitoring these effects, aiding cancer therapy management.

The gastrointestinal (GI) tract is essential for nutrient absorption and protection against pathogens and toxins. Its epithelial lining undergoes continuous renewal every 3-5 days, driven by intestinal stem cells (ISCs). ISCs are primarily of two types: actively proliferating crypt base columnar cells (CBCs), marked by Lgr5 expression, and quiescent label-retaining cells (+4 LRCs), which act as reserves during stress or injury. Key signaling pathways, such as Wnt/β-catenin, Notch, bone morphogenetic proteins (BMPs), and epidermal growth factor (EGF), are crucial in maintaining epithelial homeostasis. These pathways regulate ISCs proliferation and their differentiation into specialized epithelial cells, including goblet cells, paneth cells, enteroendocrine cells, and enterocytes. Disruptions in ISCs signaling can arise from extrinsic factors (e.g., dietary additives, heavy metals, pathogens) or intrinsic factors (e.g., genetic mutations, metabolic changes). Such disruptions impair tight junction integrity, induce inflammation, and promote gut dysbiosis, often perpetuating a cycle of intestinal dysfunction. Chronic ISCs dysregulation is linked to severe intestinal disorders, including colorectal cancer (CRC) and inflammatory bowel disease (IBD). This review emphasizes the critical role of ISCs in maintaining epithelial renewal and how various factors disrupt their signaling pathways, jeopardizing intestinal health and contributing to diseases. It also underscores the importance of protecting ISCs function to mitigate the risk of inflammation-related disorders. It highlights how understanding these regulatory mechanisms could guide therapeutic strategies for preserving GI tract integrity and treating related conditions.

Sleep-disordered breathing (SDB) is characterized by recurrent reductions or interruptions in airflow during sleep, termed hypopneas and apneas, respectively. SDB impairs sleep quality and is linked to substantive health issues including cardiovascular and metabolic disorders, as well as cognitive decline. Recent evidence suggests a link between gut microbiota (GM) composition and sleep apnea. Indeed, GM, a community of microorganisms residing in the gut, has emerged as a potential player in various diseases, and several studies have identified associations between sleep apnea and GM diversity along with shifts in bacterial populations. Additionally, the concept of "leaky gut," a compromised intestinal barrier with potentially increased inflammation, has emerged as another key player in the potential bidirectional relationship between GM and sleep apnea. One of the potential effectors could be extracellular vesicles (EVs) underlying gut-brain communication pathways that are relevant to sleep regulation and function. Thus, therapeutic implications afforded by targeting the GM or exosomes for sleep apnea management have surfaced as promising areas of research. This review explores current understanding of the relationship between GM, exosomes and sleep apnea, highlighting key research dynamics and potential mechanisms. A comprehensive review of the literature was conducted, focusing on studies investigating GM composition, intestinal barrier function and gut-brain communication in relation to sleep apnea.

The current limitations of oral nanomedicines such as aminosalicylates, immunosuppressants, corticosteroids, and antibiotics include the toxic byproducts from nanocarrier synthesis, poor targeting and retention within the inflamed colon, delayed release at inflammation sites, susceptibility to gastric degradation, reduced efficacy under hypoxic conditions, MUC2 homeostasis disruption, and insufficiently addressing the disease's root causes. This research presents an innovative approach of using non-toxic, biodegradable, and biocompatible Maillard reaction-based nanoparticles (MPs) for targeted oral drug delivery in IBD therapy. Through the development of mucoadhevise chitosan-bovine serum albumin Maillard nanoparticles shielded with biocompatible, non-toxic, non-immunogenic, gastroprotective pectin (P@CMPs) encapsulating with chrysin, a flavonoid with anti-inflammatory and hyperoxia properties whose bioavailability is negatively affected by gastric degradation. P@CMPs had a spherical, uniform 300 nm hydrodynamic diameter, confirmed by TEM and FESEM. Chrysin encapsulation efficiency and loading capacity were ∼96 % and 16 %, respectively, demonstrating effective nanoparticle formulation The P@CMPs is designed to withstand the gastrointestinal environment, ensuring targeted delivery and prolonged retention in inflamed colonic regions. In a dextran sodium sulfate-induced colitis mouse model, P@CMPs markedly mitigated inflammation, suppressed proinflammatory cytokine levels, and augmented the expression of MUC2, a crucial factor for maintaining the integrity of the gut barrier. By employing non-toxic, biocompatible and biodegradable materials, our P@CMPs approach offers a promising avenue for advancing IBD treatment, addressing various challenges and precise oral delivery within the gastrointestinal system.

Ionizing radiation (IR) induced damages are common complications of radiotherapy for tumors, severely limiting the intensity and therapeutic efficacy of the radiotherapy program. Emerging data indicated that the cGAS-STING pathway has paradoxical effects on IR-induced damage. SR-717, as a non-nucleotide, small-molecule stimulator of interferon genes (STING) agonist, has been proven that it could activate the STING signaling pathway. In this work, we try to explore the radioprotection of the STING signaling pathway and figure out whether SR-717 could be a potential intestinal radioprotective agent. C57BL/6 mice were intraperitoneally treated with SR-717 or normal saline (NS). By analyzing the survival rate, body weight, and the number of peripheral blood cells after IR exposure, we found that SR-717 improved the survival rate and body weight of mice, protected the intestine from IR-induced damage as well as hematopoietic damage, and promoted the regeneration of intestinal stem cells (ISCs). Cell viability and apoptosis after irradiation were detected after stimulation of MODE-K cells with SR-717 or PBS. We found that SR-717 increased cell viability and inhibited apoptosis in vitro. The mechanism of SR-717 in intestinal radiation protection was investigated by RNA-seq. The results of RNA-seq and qRT-PCR suggested that SR-717 significantly activated the immune system via the STING-IL-6 signaling pathway. In addition, we discussed the role of TLR2 in SR-717-mediated anti-radiation activity, and TLR2 deletion significantly reversed the radioprotective effects of SR717. In conclusion, we proved STING signaling activation displayed anti-radiation activity and found SR-717 displayed anti-radiation activity via the STING-IL-6 signaling pathway, suggesting SR-717 could be a potential intestinal radioprotective agent.

AiiO-AIO6 is a quorum-sensing quenching enzyme that could decrease the virulence of pathogenic bacteria, and improve animal immunity. However, the precise regulatory mechanism of AiiO-AIO6 on intestinal immunity remains unknown. Thus, this study aimed to reduce this knowledge gap. After feeding with graded levels of AIO-AIO6 (0.0 (un-supplemented group), 2.5, 5.0, 7.5, 10.0, and 12.5 U/g) for 70 days, juvenile grass carp was selected from each group for a 6-day Aeromonas hydrophila challenge test. Meanwhile, some other fish selected from un-supplemented control group were injected with saline as un-challenged control. Results showed that A. hydrophila infection increased enteritis morbidity, and caused intestinal inflammation in grass carp compared with saline group, while AiiO-AIO6 supplementation decreased enteritis morbidity, mitigated inflammatory cell infiltration, pyroptosis, and apoptosis in the intestine after A. hydrophila infection. Furthermore, both 5.0 and 7.5 U/g AiiO-AIO6 decreased gene expressions of tumor necrosis factor-α and interleukin-1β, and elevated gene expressions of transforming growth factor-β1 and IL-10, potentially associating with decreased NF-κB p65 and increased PPARγ signaling in the intestine. Supplementing 5.0 or 7.5 U/g AiiO-AIO6 also mitigated intestinal pyroptosis, as indicated by reduced mRNA levels of NLRP3, PYCARD, caspase-1, GSDME a, and GSDME b, and decreased protein levels of N-GSDME and IL-1β. Additionally, AiiO-AIO6 alleviated intestinal apoptosis, demonstrated by reduced gene expressions of pro-apoptotic genes apoptotic protease activating factor-1, Bcl-2 associated X protein, Fas ligand, and caspase-3, as well as c-Jun N-terminal kinase and mitogen-activated protein kinase p38, and elevated gene expressions of anti-apoptotic factors, B-cell lymphoma-2, myeloid cell leukemia 1, and inhibitor of apoptosis protein. Altogether, optimal levels of AiiO-AIO6 attenuated intestinal inflammation probably relating to down-regulated NF-κB signaling, and reduced NLRP3 and GSDME-mediated pyroptosis, and finally reduced apoptosis in the intestine of grass carp.

Ulcerative colitis (UC) is an inflammatory bowel disease with an unknown cause. Previous studies have shown that Group 3 innate lymphoid cells (ILC3s) are crucial for maintaining intestinal mucosal immune homeostasis by producing key cytokines such as IL-22 and IL-17 A. While the RNA-binding protein Musashi-2 (MSI2) is recognized as essential for promoting intestinal epithelial regeneration post-injury, its impact on immune regulation remains unclear. Therefore, we aim to investigate the protective mechanisms associated with ILC3s-specific MSI2 deletion in a mouse model of ulcerative colitis.

Dextran sulfate sodium (DSS) was used to induce a mouse colitis model. Colitis severity was evaluated through weight loss, diarrhea, fecal traits, colon length, and pathological scoring. Transcriptome sequencing was utilized to identify differentially expressed genes in colon tissues. Flow cytometry was employed to measure the quantity and functionality of ILC3s. Western blot was conducted to analyze protein expression, while real-time polymerase chain reaction and enzyme-linked immunosorbent assay were employed to quantify inflammatory factors. Additionally, immunofluorescence, AB-PAS staining, and immunohistochemistry were employed to evaluate the integrity of the intestinal barrier.

Following DSS treatment, colon damage was milder in Msi2∆Rorc mice than in Msi2fl/fl mice. Transcriptomic analysis revealed the down-regulation of cytokines and pro-inflammatory factors in the colon tissue of Msi2∆Rorc mice. Flow cytometry showed that specific deletion of MSI2 reduced the infiltration of ILC3s in the intestinal lamina propria of Msi2∆Rorc mice and decreased IL-17 A production. The reduction of IL-17 A-mediated immune responses lessened inflammatory damage to the intestinal barrier, thereby reducing colitis severity.

Specific deletion of MSI2 alleviates DSS-induced colitis in mice by reducing ILC3s infiltration and IL-17 A secretion in the lamina propria of the colon. This decrease in inflammatory mediators and cell infiltration dampens the inflammatory response in the intestinal mucosa, helping to maintain the integrity of the intestinal barrier in mice with colitis. These findings enhance our understanding of UC pathogenesis and offer novel avenues for clinical diagnosis and treatment.

The gastrointestinal (GI) tract is composed of distinct sub-regions, which exhibit segment-specific differences in microbial colonization and (patho)physiological characteristics. Gut microbes can be collectively considered as an active endocrine organ. Microbes produce metabolites, which can be taken up by the host and can actively communicate with the immune cells in the gut lamina propria with consequences for cardiovascular health. Variation in bacterial load and composition along the GI tract may influence the mucosal microenvironment and thus be reflected its interstitial fluid (IF). Characterization of the segment-specific microenvironment is challenging and largely unexplored because of lack of available tools.

Here, we developed methods, namely tissue centrifugation and elution, to collect IF from the mucosa of different intestinal segments. These methods were first validated in rats and mice, and the tissue elution method was subsequently translated for use in humans. These new methods allowed us to quantify microbiota-derived metabolites, mucosa-derived cytokines, and proteins at their site-of-action. Quantification of short-chain fatty acids showed enrichment in the colonic IF. Metabolite and cytokine analyses revealed differential abundances within segments, often significantly increased compared to plasma, and proteomics revealed that proteins annotated to the extracellular phase were site-specifically identifiable in IF. Lipopolysaccharide injections in rats showed significantly higher ileal IL-1β levels in IF compared to the systemic circulation, suggesting the potential of local as well as systemic effect.

Collection of IF from defined segments and the direct measurement of mediators at the site-of-action in rodents and humans bypasses the limitations of indirect analysis of faecal samples or serum, providing direct insight into this understudied compartment.

Microcystis aeruginosa is a dominant and widely distributed cyanobacterium that plays a major role in the formation and recurrence of harmful algal blooms in lakes. While it is known to cause intestinal inflammation and appetite dysregulation in fish, the relationship between these effects and their underlying molecular mechanisms remains poorly understood. This study explored the impact of M. aeruginosa-induced intestinal inflammation on fish appetite, with a focus on the underlying molecular pathways, using Pseudorasbora parva exposed to M. aeruginosa for 96 h. We found a significant increase in inflammatory cells in the intestinal tract, accompanied by notable changes in glycerophospholipid and tryptophan metabolism, pathways associated with inflammation and appetite regulation. Key inflammatory markers interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-1 beta (IL-1β), Nuclear factor-kappaB (NF-κB), and tumor necrosis factor-alpha (TNF-α) were significantly elevated, while orexigenic factors orexins, ghrelin, acetylcholine (Ach), and dopamine (DA) were markedly reduced. In contrast, anorexigenic factors 5-Hydroxytryptamine (5-HT), gamma-aminobutyric acid (GABA), proopiomelanocortin (POMC), and glucagon-like peptide-1 (GLP-1) showed significant increases. Correlation analysis revealed that inflammatory markers were negatively correlated with orexigenic factors and positively correlated with anorexigenic factors. These findings indicate that M. aeruginosa-induced intestinal inflammation is a potential mechanism underlying reduced appetite in fish. This study provides novel insights into the toxic effects of M. aeruginosa on fish and offers a new perspective on the mechanisms by which it suppresses fish appetite, contributing to the broader understanding of the ecological and physiological impacts of cyanobacterial blooms.

The small intestine is essential for digestion, nutrient absorption, immune regulation, and microbial balance. Its epithelial lining, containing specialized cells like Paneth and tuft cells, is crucial for maintaining intestinal homeostasis. Paneth cells produce antimicrobial peptides and growth factors that support microbial regulation and intestinal stem cells, while tuft cells act as chemosensors, detecting environmental changes and modulating immune responses. Along with immune cells such as intraepithelial lymphocytes, innate lymphoid cells, T cells, and macrophages, they form a strong defense system that protects the epithelial barrier. Disruptions in this balance contribute to chronic inflammation, microbial dysbiosis, and compromised barrier function-key features of inflammatory bowel disease, celiac disease, and metabolic syndromes. Furthermore, dysfunctions in the small intestine and immune cells are linked to systemic diseases like obesity, diabetes, and autoimmune disorders. Recent research highlights promising therapeutic strategies, including modulation of epithelial and immune cell functions, probiotics, and gene editing to restore gut health and address systemic effects. This review emphasizes the pivotal roles of small intestinal epithelia and immune cells in maintaining intestinal homeostasis, their involvement in disease development, and emerging treatments for intestinal and systemic disorders.

Radix Fici Hirtae (RFH), a traditional Chinese medication, is said to be useful in controlling immunity. However, it remained unclear whether its polysaccharides components are associated with these immunomodulatory properties. Herein, two polysaccharides, designated RFHP-1 and RFHP-2, were isolated from RFH using water-soluble alcohol precipitation and column chromatography. Structural characterization by monosaccharide content analysis, methylation, and nuclear magnetic resonance spectroscopy (NMR) revealed that the main chain of RFHP-1 was formed by the interconnection of →4)-α-D-Glcp-(1→, →3,6)-β-D-Glcp-(1→, →3)-β-D-Glcp-(1→, and →4,6)-α-D-Glcp-(1→, and the main chain of RFHP-2 was formed by the interconnection of →4)-α-D-Glcp-(1→, →3,6)-β-D-Galp-(1→, →3)-β-D-Galp-(1→, →4,6)-α-D-Glcp-(1→ and →6)-β-D-Galp-(1→. Both RFHP-1 and RFHP-2 raised the CD4/CD8 ratio and improved the expression of immune factors in immunocompromised mice. By activating the NF-κB pathway (promote phosphorylation of p65 and IκB), RFHP-1 and RFHP-2 both promoted release cytokines (NO, TNF-a, IL-6, and IFN-γ) at RAW 264.7 macrophages. The results of molecular docking (-8.4 kcal/mol vs. -6.0 kcal/mol) and isothermal titration calorimetry (ITC) (-7.75 kcal/mol vs. -7.46 kcal/mol) demonstrated that RFHP-1 exhibited stronger binding affinity with MD2, suggesting greater immunoactivating potential. These findings indicate that RFHP polysaccharides, particularly RFHP-1, may serve as promising candidates for development as dietary supplements for individuals with compromised immune systems.

Intestinal microbiota and the host's immune system form a symbiotic alliance that sustains normal development and function in the human gut. Changes such as dietary habits among societies in developed countries have led to the development of unbalanced microbial populations in the gut, likely contributing to the dramatic increase in inflammatory diseases in the last few decades. Recent advances in DNA sequencing technologies have tremendously helped to characterize the microbiome associated with disease, both in identifying global alterations and discovering specific biomarkers that potentially contribute to disease pathogenesis, as evidenced by animal studies. Beyond bacterial alterations, non-bacterial components such as fungi, viruses, and microbial metabolites have been implicated in these diseases, influencing immune responses and gut homeostasis. Multi-omics approaches integrating metagenomics, metabolomics, and transcriptomics offer a more comprehensive understanding of the microbiome's role in disease pathogenesis, paving the way for innovative diagnostic and therapeutic strategies. Unraveling the metagenomic profiles associated with disease may facilitate earlier diagnosis and intervention, as well as the development of more personalized and effective therapeutic strategies. This review synthesizes recent and relevant microbiome research studies aimed at characterizing the microbial signatures associated with inflammatory bowel disease, colorectal cancer, and celiac disease.

The tissues of origin and molecular mechanisms underlying human complex diseases remain incompletely understood. Previous studies have leveraged transcriptomic data to interpret genome-wide association studies (GWASs) for identifying disease-relevant tissues and fine-mapping causal genes. However, according to the central dogma, proteins more directly reflect cellular molecular activities than RNA. Therefore, in this study, we integrated proteomic data with GWAS to identify disease-associated tissues and genes.

We compiled proteomic and paired transcriptomic data for 12,229 genes across 32 human tissues from the GTEx project. Using three tissue inference approaches-S-LDSC, MAGMA, and DESE-we analyzed GWAS data for six representative complex diseases (bipolar disorder, schizophrenia, coronary artery disease, Crohn's disease, rheumatoid arthritis, and type 2 diabetes), with an average sample size of 260 K. We systematically compared disease-associated tissues and genes identified using proteomic versus transcriptomic data.

Tissue-specific protein abundance showed a moderate correlation with RNA expression (mean correlation coefficient = 0.46, 95% CI: 0.42-0.49). Proteomic data accurately identified disease-relevant tissues, such as the association between brain regions and schizophrenia and between coronary arteries and coronary artery disease. Compared to GWAS-based gene association estimates alone, incorporating proteomic data significantly improved gene association detection (AUC difference test, p = 0.0028). Furthermore, proteomic data revealed unique disease-associated genes that were not identified using transcriptomic data, such as the association between bipolar disorder and CREB1.

Integrating proteomic data enables accurate identification of disease-associated tissues and provides irreplaceable advantages in fine-mapping genes for complex diseases.

Polygonatum cyrtonema polysaccharides (PCP) exhibit ameliorative effects on colitis. However, whether the protective effects of PCP depend on the gut microbiota and how PCP regulates intestinal immune responses to alleviate colitis remain unclear. Therefore, this study investigated the effect of PCP against colitis focusing on the regulation of intestinal immune response. The PCP structure was reclassified as fructan. PCP treatment significantly reduced the symptoms of colitis. PCP restored IgA, ZO-1, Occludin, and MUC2 expression to enhance intestinal barrier function. Oral PCP administration markedly inhibited excessive inflammation-mediated immune response by modulating inflammatory cytokines secretion and Th17/Tregs cell balance and restored gut microbial composition. Interestingly, PCP still had a significant ameliorating effect on intestinal inflammation in colitis mice with gut microbial depletion by antibiotics. In the Caco-2/RAW264.7 co-culture inflammation model, PCP treatment improved the intestinal epithelial barrier function by regulating the inflammatory immune response through signal transduction pathways. Overall, these findings suggested that the alleviating effects of PCP on colitis are independent of gut microbiota, and that PCP can directly modulate the inflammatory immune response and intestinal barrier function, which in turn regulates gut microbiota. These findings will provide new insights into the action mechanism of natural polysaccharides in relieving colitis.

The barrier to HIV cure is the HIV reservoir, which is composed of latently infected CD4+ T cells and myeloid cells that carry stably integrated and replication-competent provirus. The gastrointestinal tract (GIT) contains a substantial part of the HIV reservoir and its immunophysiology could be especially conducive for HIV persistence and reactivation. However, the exact cellular microenvironment and molecular mechanisms that govern the renewal of provirus-harboring cells and proviral reactivation in the GIT remain unclear. In this review, we outline the evidence supporting an overarching hypothesis that interferon activity driven by specialized enterocytes creates a microenvironment that fosters proliferation of latently infected CD4+ T cells and sporadic HIV reactivation from these cells. First, we describe unique immunologic features of the gastrointestinal associated lymphoid tissue (GALT), specifically highlighting IFN activity in specialized enterocytes and potential interactions between these cells and neighboring HIV susceptible cells. Then, we will describe dysregulation of IFN signaling in HIV infection and how IFN dysregulation in the GALT may contribute to the persistence and reactivation of the latent HIV reservoir. Finally, we will speculate on the clinical implications of this hypothesis for HIV cure strategies and outline the next steps.

IgA nephropathy (IgAN), as the most common chronic glomerulonephritis worldwide, is often triggered by mucosal infections and follows a chronic progression, with the majority of patients ultimately progressing to end-stage renal disease (ESRD) during their lifetimes. Since the mystery of its complete pathogenesis has not been fully solved, the resulting lack of effective early diagnosis and treatment greatly affects the prognosis of patients. Given the well-defined pathological feature of IgA deposition in the mesangial region, the source and role of pathogenic IgA has been focused on. Starting from the microbiology and immunity of the gut, we systematically review both the physiological and the pathological process of microbiome-B cell-IgA axis, from microbial-induced IgA production to the role of IgA in the intestinal immune milieu, and ultimately end up with the various aspects of microbiome-B cell-IgA axis in the pathogenesis of IgAN as well as the corresponding therapeutic initiatives available. Our retrospective review helps researchers to systematically understand the complex role between intestinal flora dysbiosis and pathogenic IgA in IgAN. This understanding provides a foundation for in-depth explorations to uncover more detailed pathogenic mechanisms and to develop more precise and effective diagnostic and therapeutic approaches.

Stroke-associated pneumonia (SAP), a highly lethal complication following stroke, is closely linked to dysregulation of the "brain-gut-lung axis." Accumulating evidence indicates that stroke triggers intestinal alterations through the brain-gut axis, while multiple studies confirm that gut-derived changes can mediate pneumonia through the gut-lung axis. However, the mechanisms connecting stroke-induced intestinal dyshomeostasis to SAP remain incompletely elucidated, and the multiorgan interaction mechanisms of the "brain-gut-lung axis" in SAP pathogenesis require further exploration.

This systematic literature review systematically searched databases, including PubMed, using the keywords "stroke," "gastrointestinal microbiome," and "bacterial pneumonia," incorporating 80 mechanistic studies. Key findings reveal that stroke initiates a cascade of "neuro-microbial-immune" pathway interactions along the brain-gut-lung axis, leading to intestinal dyshomeostasis characterized by microbiota and metabolite alterations, barrier disruption, immune dysregulation, inflammatory responses, and impaired gut motility. These intestinal perturbations ultimately disrupt pulmonary immune homeostasis, promoting SAP development. In addition, stroke directly induces vagus nerve injury through the brain-gut axis, resulting in impaired swallowing and cough reflexes that exacerbate aspiration-related pulmonary infection risks.

Elucidating the role of the brain-gut-lung axis in SAP pathogenesis provides critical insights into its underlying mechanisms. This paradigm highlights intestinal homeostasis modulation and vagus nerve stimulation as promising therapeutic strategies for SAP prevention and management, advancing a multitargeted approach to mitigate poststroke complications.

Human pluripotent stem cell-derived tissue engineering offers great promise for designer cell-based personalized therapeutics, but harnessing such potential requires a deeper understanding of tissue-level interactions. We previously developed a cell replacement manufacturing method for ectoderm-derived skin epithelium. However, it remains challenging to manufacture the endoderm-derived esophageal epithelium despite possessing a similar stratified epithelial structure. Here, we employ single-cell and spatial technologies to generate a spatiotemporal multi-omics cell census for human esophageal development. We identify the cellular diversity, dynamics, and signal communications for the developing esophageal epithelium and stroma. Using Manatee, a machine-learning algorithm, we prioritize the combinations of candidate human developmental signals for in vitro derivation of esophageal basal cells. Functional validation of Manatee predictions leads to a clinically compatible system for manufacturing human esophageal mucosa.

The oral delivery of DNA/RNA nanoparticles represents a transformative approach in immunotherapy and vaccine development. These nanoparticles enable targeted immune modulation by delivering genetic material to specific cells in the gut-associated immune system, triggering both mucosal and systemic immune responses. Unlike parenteral administration, the oral route offers a unique immunological environment that supports both tolerance and activation, depending on the formulation design. This review explores the underlying mechanisms of immune modulation by DNA/RNA nanoparticles, their design and delivery strategies, and recent advances in their application. Emphasis is placed on strategies to overcome physiological barriers such as acidic pH, enzymatic degradation, mucus entrapment, and epithelial tight junctions. Special attention is given to the role of gut-associated lymphoid tissue in mediating immune responses and the therapeutic potential of these systems in oral vaccine platforms, food allergies, autoimmune diseases, and chronic inflammation. Despite challenges, recent advances in nanoparticle formulation support the translation of these technologies into clinical applications for both therapeutic immunomodulation and vaccination.

Interleukin-26 (IL-26) belongs to the IL-10 cytokine family and exerts diverse biological functions in regulating immune responses in vertebrates. Although IL-26 has been extensively studied in mammals, the functions of IL-26 remain largely unexplored in lower vertebrates. In this study, we determined the tissue and cell sources of IL-26 using a monoclonal antibody (mAb) generated against grass carp (Ctenopharyngodon idella, Ci) IL-26, and investigated the responses of IL-26 producing cells to bacterial infection. We showed that the CiIL-26 mAb specifically recognized the recombinant CiIL-26 proteins expressed in the Escherichia coli and HEK293 cells. Flow cytometry analysis revealed that the CiIL-26 mAb could detect the intracellular CiIL-26 expressed in the HEK293 cells and CIK cells stimulated with inactivated Aeromonas hydrophila (A. hydrophila). Using confocal microscopy, we analyzed IL-26+ cells in various tissues of grass carp following infection with A. hydrophila. It was shown that the IL-26+ cells were significantly increased in the gills, head kidney, posterior intestine and spleen. Remarkably, for the first time, we observed that most IL-26+ cells were CD3γ/δ+ T cells and MCSFR+ monocytes/macrophages, which could be induced by A. hydrophila. Our findings highlight the essential roles of CD3γ/δ+/IL-26+ T cells and MCSFR+/IL-26+ macrophages in the immune defense against bacterial infections in fish.

This study aimed to clarify the role and mechanism of tetrahedral framework nucleic acids (tFNAs) in regulating M2 macrophages to reduce intestinal injury. An intestinal injury model was established by intraperitoneal injection of lipopolysaccharides (LPS) in mice to explore the alleviating effects of tFNAs on intestinal injury. Inflammatory factors were detected by quantitative polymerase chain reaction (qPCR) and enzyme-linked immunosorbent assay (ELISA). The intestinal barrier and permeability were assessed using western blotting and immunohistochemistry. Macrophages in the gut were localised and quantified using immunofluorescence. Western blotting was used to investigate the role and mechanism of tFNAs in regulating macrophages and alleviating inflammation in the injured intestines. These results show that tFNAs attenuated sepsis-induced intestinal injury. tFNAs can also promote the intestinal barrier reconstruction and reduce intestinal permeability. In vivo, tFNAs accelerated the aggregation of M2 macrophages at an early stage of injury and reduced the number of M1 macrophages in the intestine. In addition, tFNAs enhanced the clearance ability of intestinal macrophages. They activated the signalling and transcription activating factor 1(STAT1) and cytokine signalling inhibitory factor 1/3 (SOCS1/3) pathways by increasing the expression of the phagocytic receptor Mertk. These findings indicated that tFNAs can alleviate sepsis-induced intestinal injury by regulating M2 macrophages, providing a new option for treating intestinal injury.

Inflammatory bowel disease (IBD) comprises chronic inflammatory conditions with complex mechanisms and diverse manifestations, posing significant clinical challenges. Traditional animal models and ethical concerns in human studies necessitate innovative approaches. This review provides an overview of human intestinal architecture in health and inflammation, emphasizing the role of microfluidics and on-chip technologies in IBD research. These technologies allow precise manipulation of cellular and microbial interactions in a physiologically relevant context, simulating the intestinal ecosystem microscopically. By integrating cellular components and replicating 3D tissue architecture, they offer promising models for studying host-microbe interactions, wound healing, and therapeutic approaches. Continuous refinement of these technologies promises to advance IBD understanding and therapy development, inspiring further innovation and cross-disciplinary collaboration.

BackgroundProbiotics, as common regulators of the gut microbiota, have been used in research to alleviate clinical symptoms of atopic dermatitis (AD).ObjectiveOur research team has previously identified a potential relieving effect of Clostridium butyricum on the treatment of AD, but the specific mechanism of how Clostridium butyricum alleviates AD has not yet been confirmed.MethodsIn this study, we explored the relieving effect of Clostridium butyricum on AD through in vivo and in vitro experiments. AD mice induced by 2,4-dinitrofluorobenzene (DNFB) were orally administered with 1 × 108 CFU of Clostridium butyricum for three consecutive weeks.ResultsOral administration of Clostridium butyricum reduced ear swelling, alleviated back skin lesions, decreased mast cell and inflammatory cell infiltration, and regulated the levels of inflammation-related cytokines. Clostridium butyricum activated the intestinal immune system through the TLR4/MyD88/NF-κB signaling pathway, suppressed the expression of inflammatory factors IL-10 and IL-13, and protected the damaged intestinal mucosa.ConclusionClostridium butyricum administration improved the diversity and abundance of the gut microbiota, enhanced the functionality of the immune system, and protected the epidermal barrier.

Fluxapyroxad is the most commonly used succinate dehydrogenase inhibitor fungicide. This work investigated its adverse effects on colitis susceptibility and explored the underlying mechanisms based on a mouse model. After 13 weeks of exposure at the acceptable daily intake (ADI) level, fluxapyroxad exacerbated the susceptibility to colitis, impaired the intestinal barrier, and elevated proinflammatory cytokines and chemokines of the colon in mice. It was found that this toxic effect was caused by the disruption of the gut microbiome. Specifically, the abundance of Lachnospiraceae and Muribaculaceae decreased, while Desulfovibrionaceae and Eggerthellaceae increased. Altered microbiota reduced fecal indole derivatives, including indole-3-lactic acid (ILA), indole-3-acetic acid (IAA), and indole-3-acrylic acid (IArA), inhibiting aryl hydrocarbon receptor (AHR) activation, disrupting immune homeostasis by overactivating Th17 cells and insufficient Treg cell differentiation, and causing mild colonic inflammation. Oral antibiotic-treated mice and fecal transfer experiments validated the pathway. Susceptibility to colitis induced by fluxapyroxad was not detected in the oral antibiotic-treated mice. Fecal transfer of the disordered gut microbiota caused by fluxapyroxad could aggravate the severity of colitis in recipient oral antibiotic-treated mice that did not receive fluxapyroxad exposure. In conclusion, chronic fluxapyroxad exposure at the ADI level exacerbated colitis via a gut microbiota-indole derivatives-Treg/Th17 cell balance axis, offering a new risk assessment perspective of fluxapyroxad.

Functional dyspepsia (FD) is a chronic gastrointestinal disorder without a readily identifiable organic cause, resulting in bothersome upper abdominal symptoms. It is a highly prevalent disorder of which the pathophysiology remains mostly elusive, despite intensive research efforts. However, recent studies have found alterations in the microenvironment of the duodenum in patients with FD. In this review we summarize the duodenal microenvironment in homeostatic conditions and the alterations found in patients with FD, highlighting the similarities and discrepancies between different studies. The most consistent findings, being an impaired duodenal barrier and duodenal immune activation, are reviewed. We discuss the potential triggers for these observed alterations, including psychological comorbidities, luminal alterations and food related triggers. In summary, this review presents the evidence of molecular and cellular changes in patients with FD, with an impaired duodenal barrier and activated mucosal eosinophils and mast cells, challenging the notion that FD is purely functional, and offering different targets for potential future treatments.

The intestine is an important immune organ of aquatic animals and it plays an essential role in maintaining body health and anti-oxidative stress. To investigate the toxic effects of deltamethrin in intestinal tissue of Chinese mitten crabs (Eriocheir sinensis), 120 healthy crabs were randomly divided into two experimental groups (blank control group and deltamethrin-treated group), with three replicates in each group. After being treated with deltamethrin for 24 h, 48 h, 72 h, and 96 h, intestinal tissues were collected aseptically to assess the effects of deltamethrin on oxidative stress, immunity, apoptosis-related genes, and the structure of microflora in intestinal tissues. Additionally, correlations between gut microbiota composition and intestinal tissue damage-associated genes were analyzed. The results demonstrated that prolonged exposure to deltamethrin induced oxidative stress damage in intestinal tissue. Compared with the blank control group, the expression of autophagy-related genes B-cell lymphoma/Leukemia-2 (bcl-2), c-Jun N-terminal kinase (jnk), Microtuble-associated protein light chain 3 (lc3c), Cysteine-dependent Aspartate-specific Protease 8 (caspase 8), BECN1(beclin1), oxidative stress damage-related genes MAS1 proto-oncogene (mas), Glutathione Peroxidase (gpx), kelch-like ECH-associated protein 1 (keap1), Sequestosome 1 (p62), Interleukin-6 (il-6), and immune-related genes Lipopolysaccharide-induced TNF-alpha Factor (litaf), Heat shock protein 90 (hsp90) and prophenoloxidase (propo) in the deltamethrin treatment group were significantly up-regulated at 96 h (p < 0.05 or p < 0.01). Additionally, 16S rRNA sequencing showed that the diversity of intestinal flora in the deltamethrin-treated group was significantly higher compared with the blank control group (p < 0.01). Analysis of the differences in the composition of intestinal flora at the genus level showed that the relative abundance of Candidatus Bacilloplasma in the deltamethrin treatment group was significantly lower than that in the blank control group (p < 0.01). In contrast, the relative abundances of Flavobacterium, Lachnospiraceae_NK4A136_group, Acinetobacter, Chryseobacterium, Lacihabitans, Taibaiella, Hydrogenophaga, Acidovorax, and Undibacterium were significantly higher than those in the blank control group (p < 0.05 or p < 0.01). Pearson correlation analysis revealed that Malaciobacter, Shewanella, and Prevotella exhibited significant positive correlations with gene indicators (jnk, gpx, lc3c, litaf, hsp90), while Dysgonomonas, Vibrio, and Flavobacterium demonstrated significant negative correlations with multiple gene indicators (caspase 8, p62, il-16, keap1, jnk, etc). These results demonstrate that deltamethrin significantly impacts the gut microbiota, immune function, and antioxidant capacity of E. sinensis. The changes in gut microbiota have correlations with the biomarkers of intestinal tissue injury genes, indicating that gut microbiota plays a crucial role in deltamethrin-induced intestinal tissue damage. These insights contribute to a better understanding of the ecological risks associated with deltamethrin exposure in aquatic organisms.

Intrinsic enteric neurons (iENs) form a crucial neuronal network within the myenteric and submucosal plexus of the gastrointestinal tract, primarily responsible for regulating gut peristalsis. The mechanisms by which iENs sense and integrate dietary and microbial signals to regulate intestinal homeostasis and inflammation remain unclear. Here, we showed that environmental sensor aryl hydrocarbon receptor (AHR) was expressed in different iEN subsets in the ileum and colon and that AHR ligands differentially modulated iEN activity in these regions. Genetic perturbation of Ahr in neurons increased iEN activation in the ileum but, conversely, decreased it in the colon in response to different intestinal pathogens. Furthermore, neuronal AHR deficiency enhanced the clearance of bacterial pathogens, which was associated with increased proliferation and abundance of group 3 innate lymphoid cells in the ileum. Together, our findings demonstrate the region-specific functions of AHR in neurons in response to infections.

Inflammation can generate pathogenic Th17 cells and cause an inflammatory dysbiosis. In the context of inflammatory bowel disease (IBD), these inflammatory Th17 cells and dysbiotic microbiota may perpetuate injury to intestinal epithelial cells. However, many models of IBD like T-cell transfer colitis and IL-10-/- mice rely on the absence of regulatory pathways, so it is difficult to tell if inflammation can also induce protective Th17 cells.

We subjected C57BL6, RAG1-/-, or JH-/- mice to systemic or gastrointestinal (GI) Citrobacter rodentium (Cr). Mice were then subjected to 2.5% dextran sodium sulfate (DSS) to cause epithelial injury. Fecal microbiota transfer was performed by bedding transfer and co-housing. Flow cytometry, qPCR, and histology were used to assess mucosal and systemic immune responses, cytokines, and tissue inflammation. 16s sequencing was used to assess gut bacterial taxonomy.

Transient inflammation with GI but not systemic Cr was protective against subsequent intestinal injury. This was replicated with sequential DSS collectively indicating that transient inflammation provides tissue-specific protection. Inflammatory Th17 cells that have a tissue-resident memory (TRM) signature expanded in the intestine. Experiments with reconstituted RAG1-/-, JH-/- mice, and cell trafficking inhibitors showed that inflammation-induced Th17 cells were required for protection. Fecal microbiota transfer showed that the inflammation-trained microbiota was necessary for protection, likely by maintaining protective Th17 cells in situ.

Inflammation can generate protective Th17 cells that synergize with the inflammation-trained microbiota to provide host resiliency against subsequent injury, indicating that inflammation-induced Th17 TRM T cells are heterogenous and contain protective subsets.

The global eradication of canine-mediated human rabies remains an ongoing public health priority. While conventional oral rabies vaccines (ORVs) have demonstrated partial success in interrupting zoonotic transmission, current formulations necessitate improvements in both immunogenic profiles and mechanistic clarity. Herein, we present a recombinant vesicular stomatitis virus (VSV)-vectored vaccine candidate (rVSVΔG-ERA-G) engineered to express the glycoprotein of the rabies virus (RABV) ERA strain, substituting the native VSV glycoprotein. Preclinical evaluation across multiple mammalian species (Mus musculus, Canis lupus familiaris, Felis catus, Vulpes lagopus, and Nyctereutes procyonoides) revealed rapid seroconversion and sustained neutralizing antibody responses. Challenge experiments demonstrated 100% survival efficacy in pre-exposure prophylaxis models, with partial protection observed in post-exposure scenarios. Safety assessments confirmed significant attenuation of neurotropism and absence of horizontal transmission or environmental shedding. Furthermore, evidence showed that rVSVΔG-ERA-G is recognized by Peyer's patches (PPs), where a cascade activation of immune cells occurred. From another perspective, the absence of functional microfold cells in PPs hampered the initiation and progression of immune responses. This proof-of-concept study establishes rVSVΔG-ERA-G as an ORV candidate with enhanced biosafety and cross-species immunogenicity. The elucidation of M cell-dependent mucosal priming mechanisms provides a rational framework for optimizing the targeted delivery of ORVs.

Ulcerative colitis (UC) is a refractory inflammatory disease that affects the rectum and colon, with pivotal involvement of the rectal environment in relapse initiation. This study was conducted in two phases to examine the differences in gene expression between the rectum and colon and to identify relapse factors.

In ***Study 1, RNA sequencing was performed on biopsies from the colon and rectum of patients with active UC, those with remission UC, and controls. In Study 2, the mucosal impedance (MI) values reflecting mucosal barrier function and the mRNA expression of tight junction proteins and inflammatory cytokines were examined in 32 patients with remission UC and 22 controls. Relapse was monitored prospectively.

In Study 1, comprehensive genetic analysis using RNA sequencing revealed distinct gene profiles in the rectum and sigmoid colon of patients with remission UC. The rectum of these patients exhibited an enriched immune response and apical junction phenotype with persistent upregulation of CLDN2 gene expression. In Study 2, even in patients with remission UC, the MI values in the rectum, but not in the sigmoid colon, were significantly decreased, whereas they were negatively correlated with CLDN2, IL-1β, and IL-6 expressions.

The status of the rectum in patients with remission UC differs from that of the colon, with microinflammation and impaired mucosal barrier function, which are associated with the upregulation of CLDN2, playing a role in relapse.

The mechanisms underlying the antihypertensive effect of dietary fibers remain poorly understood. This study investigates whether dietary fiber supplementation can prevent cardiovascular damage and high blood pressure in a genetic model of neurogenic hypertension. Six-week-old male spontaneously hypertensive rats (SHR) and their respective normotensive control, Wistar Kyoto rats (WKY), were divided into four groups: Untreated WKY, untreated SHR, SHR treated with resistant starch (SHR + RS), and SHR treated with inulin-type fructans (SHR + ITF) for 12 weeks. Additionally, a faecal microbiota transplantation (FMT) experiment was conducted, transferring faecal content from treated SHR donors to recipient SHRs. A diet rich in RS fiber reduced vascular oxidative stress, inflammation, and high blood pressure. These protective effects were associated with a reshaped gut microbiota, leading to increased short-chain fatty acid production, reduced endotoxemia, decreased sympathetic activity, and a restored balance between Th17 and Treg lymphocytes in mesenteric lymph nodes and aorta. Elevated plasma levels of acetate and butyrate in the SHR + RS group correlated with increased expression of aortic GPR41, GRP43 and PPARδ. Conversely, ITF treatment failed to prevent hypertension or endothelial dysfunction in SHR. FMT from the SHR + RS group to recipient SHR partially replicated these beneficial effects. This study highlights the antihypertensive benefits of dietary insoluble RS fiber, which are attributed to enhanced short-chain fatty acids production in the gut. This leads to improved gut permeability, reduced sympathetic tone, and diminished vascular T-cell accumulation. Therefore, dietary interventions with RS fiber may offer promising therapeutic strategies for preventing hypertension.