Regulated host-microbe interactions are a critical aspect of lifelong health. Colonic goblet cells protect from microorganisms via the generation of a mucus barrier structure. Bacteria-sensing sentinel goblet cells provide secondary protection by orchestrating mucus secretion when microbes breach the mucus barrier. Mucus deficiencies in germ-free mice implicate a role for the microbiota in programming barrier generation, but its natural ontogeny remains undefined. We now investigate the mucus barrier and sentinel goblet cell development in relation to postnatal colonization. Combined in vivo and ex vivo analyses demonstrate rapid and sequential microbiota-dependent development of these primary and secondary goblet cell protective functions, with dynamic changes in mucus processing dependent on innate immune signaling via MyD88 and development of functional sentinel goblet cells dependent on the NADPH/dual oxidase family member Duox2. Our findings identify new mechanisms of microbiota-goblet cell regulatory interaction and highlight the critical importance of the pre-weaning period for the normal development of protective systems that are key legislators of host-microbiota interaction.

The intestinal mucus barrier has emerged as a promising therapeutic target for inflammatory bowel disease. Understanding its regulatory mechanisms is critical for elucidating ulcerative colitis (UC) pathogenesis, improving diagnostics, guiding treatments, and preventing relapse. Chloride Channel Accessory 1 (Clca1), a constituent of the mucus layer, remains understudied in colitis. Here, we investigated Clca1's role in mucosal immunity and intestinal homeostasis using experimental colitis models. Clca1-deficient (Clca1-/-) mice displayed compromised mucus layer integrity, reduced neutrophil infiltration, and gut microbiota dysbiosis. Notably, Clca1-/- mice exhibited exacerbated colitis severity following dextran sulfate sodium (DSS) challenge, accompanied by a diminished goblet cell populations. Fecal microbiota transplantation (FMT) studies revealed that gut microbiota critically modulates divergent phenotypic outcomes between genotypes. Our findings establish Clca1 as a multifunctional regulator of mucus barrier integrity through mechanisms involving goblet cell maintenance, neutrophil-mediated immunity, and host-microbiota crosstalk. These results advance the understanding of UC pathogenesis and identify Clca1-associated pathways as potential targets for barrier restoration therapies.

Xiexin Tang (XXT) is a classic Chinese medicine formula that can be used to treat Atherosclerosis (AS). This study aimed to investigate the mechanism by which XXT regulated AS lipid levels. Firstly, the mixture components of XXT were analyzed by High-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Then, the AS model based on Apolipoprotein E knockout (ApoE-/-) mice was established. Cytokines related to lipid metabolism and bile acid metabolism were detected by Quantitative Real-time PCR (qRT-PCR). 16S rDNA gene sequencing was performed to analyze differential bacterial populations, and the mechanism of XXT regulation of bile acids affecting lipid metabolism was further explored by targeted metabolomics. Further, antibiotic-treated mice were used to investigate the role of gut microbiota in the anti-AS effect of XXT. The results showed that XXT attenuated the lipid levels and reversed the abnormal elevation of cytokines, such as hepatic lipid metabolism and inflammatory reaction in AS mice. XXT also repaired the gut barrier damage and reversed gut microbiota disorders in AS mice. Furthermore, the metabolic levels of bile acids were reshaped by XXT. Whereas, in the absence of gut microbiota, XXT failed to attenuate lipid levels and inhibit the expression of cytokines related to inflammation and bile acid metabolism in AS mice and failed to play a role in ultimately treating AS. In conclusion, XXT could effectively inhibit the inflammatory reaction and lipid accumulation in AS mice, and this effect was closely related to its remodeling of gut microbiota to regulate bile acid metabolism.

Depression affects millions, and current treatments have limitations, necessitating new approaches. Earlier research confirms Hyperforin's ability to reduce anhedonic behaviors in mice and modulate gut microbiota. This study aims to identify specific metabolic changes induced by Hyperforin that could illuminate its impact on gut microbiome metabolism, possibly uncovering novel metabolites for developing antidepressant therapies.

Following the chronic stress model, untargeted metabolomic analysis of fecal samples was conducted to identify metabolic changes induced by Hyperforin. Bioinformatics tools analyzed the origins of differentially expressed metabolites and their correlation with Akkermansia muciniphila and Muribaculum intestinale. The significant metabolite Carbocysteine was further investigated for its antidepressant effects using behavioral assays in a mouse model of depression. Additionally, the response of the colonic mucus barrier was evaluated using Periodic Acid-Schiff (PAS) staining, scanning electron microscopy (SEM), and enzyme-linked immunosorbent assays (ELISA).

Hyperforin significantly altered fecal metabolite profiles in stressed mice, with a notable shift in 239 metabolites mainly associated with co-metabolism pathways and microbiota-specific processes. Among these, Carbocysteine emerged as a key metabolite linked to beneficial bacteria Akkermansia muciniphila and Muribaculum intestinale, with its levels significantly elevated following Hyperforin treatment. Behavioral assessments indicated that Carbocysteine supplementation ameliorated depressive-like behaviors in the chronic restraint stress mouse model. It also enhanced colonic mucus production and integrity.

Our research highlights Hyperforin's role in modulating gut microbiota metabolism and identifies Carbocysteine as a potential antidepressant. These findings advance our understanding of the gut-brain axis (GBA) in depression and pave the way for developing new therapeutics.

Ulcerative colitis is a chronic inflammatory condition of the intestine characterized by mucosal damage and a compromised epithelial barrier. This study explored the protective and therapeutic potential of laminaran derived from the brown seaweed Undaria pinnatifida in promoting mucin secretion and restoring mucosal barrier integrity. Physicochemical analysis revealed laminaran as having a β-(1 → 3)-linked glucose backbone with β-(1 → 6)-linked branches and a molecular weight of 14.41 kDa. In vitro experiments revealed that laminaran enhanced the expression of mucin-related proteins in a lipopolysaccharide-induced LS174T model. Laminaran also upregulated the expression of sulfotransferases, which are essential for mucin sulfation, and promoted vesicular transport by increasing the expression of vesicle-associated membrane protein 8 and synaptosome-associated protein-23, facilitating mucin secretion. These effects are mediated through the protein kinase C (PKC) pathway, which involves PKCα and PKCβII. In an in vivo model, laminaran alleviated dextran sulfate sodium-induced colitis, increasing mucus thickness and overall intestinal barrier function. These results suggest that laminaran is a promising therapeutic agent for treating ulcerative colitis, suggesting a novel approach to restoring the mucosal barrier and reducing intestinal inflammation. This study lays the groundwork for developing laminaran-based treatments for ulcerative colitis and other intestinal diseases associated with epithelial barrier dysfunction.

Microplastics (MPs) are emerging environmental pollutants that are increasingly being detected in various human tissues. However, their impact on ocular health is underexplored. This study investigated the presence of MPs in tear fluid and meibum of 45 patients with dry eye disease (DED). Various examinations were conducted, including the Schirmer I test, fluorescein tear film break-up time (FBUT) and other dry eye-related assessments. MPs were identified in the tear fluid and meibum and were categorized into five distinct types, with polyethylene (PE) being the most predominant. Notably, PE levels exhibited significant correlations with key DED parameters, such as Schirmer I test scores and FBUT. In in-vitro studies, PE exposure reduced the viability and induced apoptosis of human corneal epithelial cells and conjunctival epithelial cells in a dose-dependent manner. In mouse models, topical exposure to PE drops, which imitate airborne PE exposure, induced typical dry eye signs, reduced goblet cell numbers, and triggered conjunctival inflammation. PE-treated meibomian glands exhibited changes, but these changes were not statistically significant, possibly because of the limited duration of the study. This study is the first to confirm the presence of microplastics (MPs) in human tear fluid and meibum while also offering novel insights into the potential pathogenic effects of airborne MP exposure on ocular health.

Dysbiosis of the gut microbiota is emerging as a pivotal factor in the pathogenesis of colorectal cancer (CRC). Ginsenoside Rh4 (Rh4) is an active compound isolated from ginseng with beneficial effects in modulating intestinal inflammation and gut microbiota dysbiosis, but how Rh4 regulates the gut microbiota to alleviate CRC remains underexplored.

We investigated the impact of Rh4 on CRC and the mechanism of its action in inhibiting CRC via modulation of gut microbiota.

We used the AOM/DSS model and employed transcriptomics, genomics and metabolomics techniques to explore the inhibitory impact of Rh4 on CRC. Furthermore, we employed experiments involving antibiotic treatment and fecal microbiota transplantation (FMT) to investigate the role of the gut microbiota. Finally, we elucidated the pivotal role of key functional bacteria and metabolites regulated by Rh4 in CRC.

Our research findings indicated that Rh4 repaired intestinal barrier damage caused by CRC, alleviated intestinal inflammation, and inhibited the development of CRC. Additionally, Rh4 inhibited CRC in a gut microbiota-dependent manner. Rh4 increased the diversity of gut microbiota, enriched the probiotic Akkermansia muciniphila (A. muciniphila), and alleviated gut microbiota dysbiosis caused by CRC. Subsequently, Rh4 regulated A. muciniphila-mediated bile acid metabolism. A. muciniphila promoted the production of UDCA by enhancing the activity of 7α-hydroxysteroid dehydrogenase (7α-HSDH). UDCA further activated FXR, modulated the TLR4-NF-κB signaling pathway, thus inhibiting the development of CRC.

Our results confirm that Rh4 inhibits CRC in a gut microbiota-dependent manner by modulating gut microbiota-mediated bile acid metabolism and promoting the production of UDCA, which further activates the FXR receptor and regulates the TLR4-NF-κB signaling pathway. Our results confirm that Rh4 has the potential to be used as a modulator of gut microbiota for preventing and treatment of CRC.

Klebsiella pneumoniae (KP) infection often causes diarrhoea and intestinal barrier damage in young rabbits. The objective of this study was to explore whether selenomethionine (SeMet) can attenuate the jejunal injury caused by KP in rabbits. Therefore, we investigated the protective effect of SeMet by performing haematoxylin-eosin (HE), alcian blue periodic acid Schiff (AB-PAS), proliferating nuclear antigen (PCNA), TUNEL and immunofluorescence staining. In addition, the concentrations of Interleukin-1β (IL-1β), Interleukin-6 (IL-6), Tumor necrosisfactor-α (TNF-α) and Interleukin-10 (IL-10) in the jejunal tissue were detected by enzyme-linked immunosorbent assay (ELISA). The results showed that after KP infection, the productivity of rabbits decreased, and the mucosal barrier of the jejunum was damaged. Moreover, KP induced jejunal inflammation, activated the TLR4/NF-κB signalling pathway, and promoted the expression of the IL-1β, IL-6, and TNF-α. In addition, KP increased the apoptotic response of intestinal cells and upregulated the expression of caspase-3 and caspase-9. SeMet pretreatment significantly decreased the degree of intestinal epithelial cell apoptosis. Therefore, we showed that SeMet can reduce inflammation and enhance intestinal barrier function to improve the production performance of rabbits infected with KP.

Phytic acid (PA) is a common anti-nutritional factor found in plant-based protein sources. Our previous research demonstrated that dietary PA negatively affected the growth of grass carp. Intestinal health plays a vital role in the growth, development, and disease resistance of fish. Therefore, in order to comprehensively reveal the impact of PA on the intestines of fish, we further used the grass carp to investigate the impact of PA on the intestines of fish. The 540 grass carp (120.56 ± 0.51 g) were separated into 6 groups and provided with diets that included varying levels of PA (0, 0.8, 1.6, 2.4, 3.2, and 4.0 %) over 60 days. The findings suggested that a higher level of PA in diet, particularly at 3.2 %-4.0 %, led to a decrease in the goblet cell number as well as a reduced expression of mucin 2 and mucin 3 in the intestine. Concurrently, there was an increase in 8-hydroxy-2'-deoxyguanosine, active oxygen species, protein carbonyl, and malondialdehyde. These changes were accompanied by lower anti-superoxide anion activity, total antioxidant capacity, and anti-hydroxyl radical activity, as well as lower activity and gene expression of antioxidant enzymes. The DNA fragmentation in the intestine increased. Additionally, the bcl-2-associated X protein, Fas-ligand, apoptotic protease activating factor-1, cysteine aspartate protease (caspase) 8, caspase 9, and caspase 3 gene expression was increased, while the expression of B-cell lymphoma 2, myeloid cell leukemia-1b, and inhibitor of apoptosis protein was decreased. The gene expression of tight junction-associated molecules (such as claudin-b, -3c, and -7b and zonula occludens-2b) was decreased, whereas the expression of claudin-15b and myosin light chain kinase was increased. These data suggested that dietary PA may compromise the intestinal mucus barrier and the structural integrity of grass carp by inducing a goblet cell number decrease, causing oxidative damage, promoting apoptosis, and disrupting tight junctions. These results indicated that we must consider the potential threat posed by PA to the intestine of grass carp when utilizing plant-based protein sources.

Bidirectional communications between the gut and the brain play an important role in the regulation of food intake, pain perception, mood, and cognitive function. The involved communication pathways are modulated by signals generated by the gut microbiome. Alterations in these communications have been implicated in several chronic brain and gut disorders, including food addiction, mood disorders, neurodevelopmental and neurodegenerative disorders, and functional and inflammatory bowel disorders. The gut microbiome holds great promise for the development of novel therapies normalizing altered brain-gut interactions.

The urgency of emerging pollutants driven by human activities presents an increasing threat to the health of fish. The mucosal system, serving as a primary barrier against environmental pollutants, has emerged as a central focus in toxicological research. Alterations in the mucosal microbiota can impact health at both local and systemic levels. This review explores the toxic effects of emerging pollutants on the mucosal immunity of teleost fish, reflects on the reasons behind the limited focus on adaptive immunity studies, and highlights changes in microbial composition, gene expression, histology, and overall mucosal organ function. Furthermore, we summarize the mechanisms through which these pollutants disrupt the mucosal barriers of teleosts, emphasizing interactions between the mucosal microbiota, physical barriers, and immune defenses. The relevant methodologies and potential solutions to the current challenges have been summarized. While current research predominantly centers on the intestines and gills, further studies are needed to investigate the toxic effects of emerging pollutants on other mucosal organs and to elucidate how microbiota influence host health through neuro-immune communication. This review aims to provide a comprehensive overview of mucosal immunity, serving as a theoretical foundation for the assessment of related ecological risks.

Prolonged postoperative ileus (PPOI) is a common complication following total mesorectal excision. Early detection and prompt intervention are crucial for the treatment of rectal cancer.

We conducted a retrospective study. After applying propensity score matching, we collected and compared the clinical characteristics of 164 patients in both the PPOI group and the non-PPOI group using univariate analysis. Significant factors identified were then evaluated in a multivariable logistic regression analysis. Moreover, we analyzed the clinical features and treatment strategies.

The incidence of PPOI after laparoscopic TME was 18.3% in our trial. Univariate analysis revealed significant differences in several factors between the two groups, including prophylactic anaerobic antibiotic therapy (p < 0.001), preoperative bowel obstruction (p = 0.006), preoperative nutritional support therapy (p < 0.001), and the type of stoma (p < 0.001). However, further multivariable logistic regression analysis indicated that prophylactic anaerobic antibiotic therapy was not an independent risk factor for PPOI. Among the patients who experienced PPOI, the majority, 135 patients (82.3%), presented with Clavien-Dindo grades I-II. Overall, 81.7% and 85.4% of patients received oral probiotics and vancomycin treatment, respectively. Only 48 patients (29.3%) required gastric tube insertion, while 27 patients (16.5%) needed a transnasal ileus tube due to ineffective drug treatment.

Our study suggests that selecting the appropriate preoperative nutritional support strategy and type of stoma is crucial in reducing the incidence of PPOI. When PPOI occurs, a multi-stage treatment protocol may be beneficial for recovery.

This comprehensive review delves into the pivotal role of intestinal epithelial cells in the context of various diseases. It provides an in-depth analysis of the diverse types and functions of these cells, explores the influence of multiple signaling pathways on their differentiation, and elucidates their critical roles in a spectrum of diseases. The significance of the gastrointestinal tract in maintaining overall health is extremely important and cannot be exaggerated. This complex and elongated organ acts as a crucial link between the internal and external environments, making it vulnerable to various harmful influences. Preserving the normal structure and function of the gut is essential for well-being. Intestinal epithelial cells serve as the primary defense mechanism within the gastrointestinal tract and play a crucial role in preventing harmful substances from infiltrating the body. As the main components of the digestive system, they not only participate in the absorption and secretion of nutrients and the maintenance of barrier function but also play a pivotal role in immune defense. Therefore, the health of intestinal epithelial cells is of vital importance for overall health.

The acceptable daily intake (ADI) and maximum residue limits in food for chlorpyrifos (CPF), a widely used organophosphorus pesticide, may damage the intestine. Here, we evaluated damage to the intestine by CPF at the ADI (0.01 mg/kg bodyweight/day) and at 10 times the ADI (10ADI; 0.1 mg/kg bodyweight/day) in mice after 8 weeks of exposure and evaluated the resulting immune response to an enterotoxigenic Escherichia coli (ETEC) infection. CPF at the ADI dose significantly disrupted the intestinal integrity and intestinal stem cell functionality, which may be associated with reduced indole-3-propionic acid levels. However, mice in the 10ADI group exhibited only elevated pro-inflammatory cell and cytokine levels. During ETEC infection, intestinal mucosal immunity was activated by the 10ADI dose, as indicated by increased regulatory T cells and IL-10 levels, which were associated with decreased fecal butyric acid content. Our study demonstrated that the effects of pesticide residues appear to be dose-specific, bringing attention to the health risk at the ADI level.

Di(2-ethylhexyl) phthalate (DEHP), a ubiquitous plasticizer, has raised concerns due to its potential role in exacerbating food allergy through chronic human exposure. The study aimed to investigate the potential effects of DEHP on ovalbumin (OVA)-induced food allergy and elucidate the underlying mechanisms related to intestinal barrier homeostasis. In OVA-sensitized BALB/c mice, DEHP exposure significantly exacerbated allergic responses by functioning as an immunoadjuvant, as evidenced by heightened anaphylactic symptoms, elevated serum levels of inflammatory mediators (IgE, IgG, IgG1, IgG2), and increased concentrations of histamine and monocyte chemoattractant protein-1 (MCP-1). Furthermore, DEHP disrupted intestinal barrier integrity and impaired mucin secretion. Administration of high-dose DEHP significantly downregulated the expression of tight junction proteins and mucins. Histopathological analysis revealed goblet cell depletion and diminished mucin production. The results suggest that DEHP exacerbated food allergy through a multifactorial mechanism involving intestinal barrier dysfunction and immune dysregulation. This study establishes a critical association between oral DEHP exposure and food allergy pathogenesis, providing insights into the interplay of environmental pollutants, intestinal immunity, and food allergy manifestation.

Ulcerative colitis (UC) is an inflammatory bowel disease characterized by chronic inflammation and ulcerative erosion of the colonic mucosa. Because of the complex causes, UC is often difficult to completely cure, greatly increasing the risk of bowel cancer and other diseases. In the UC environment, excessive production of reactive oxygen species (ROS) and high levels of inflammatory factors lead to the continuous deterioration of inflammation. We developed Mn-PEGCG nanoparticles (NPs) based on the metal-polyphenol network for the preventive treatment of UC. Mn-PEGCG NPs were synthesized by the polymerization of epigallocatechin gallate (EGCG) and further complexation with Mn2+. After oral administration, Mn-PEGCG NPs are more likely to reach the inflammation site of the colon through electrostatic interaction, effectively clear ROS, reduce the production of pro-inflammatory cytokines, exert antioxidant and anti-inflammatory effects, and protect colon cells from oxidative stress damage. In addition, it can play the role of EGCG in promoting the expression of tight junction protein and enhancing the intestinal epithelial barrier. In a mouse model of UC, oral administration of Mn-PEGCG NPs reduced intestinal inflammation, alleviated pathological structural damage in mice, and promoted mucus secretion and tight junction protein expression, thereby strengthening the intestinal barrier. Mn-PEGCG NPs can effectively alleviate inflammation and repair the intestinal barrier to maintain the stability of the intestinal environment, which is an ideal treatment strategy for UC.

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.

Huangqin decoction (HQD), a traditional Chinese antidiarrheal formula, is effective in treating chemotherapy-induced diarrhea (CID). However, its underlying mechanism has not been fully clarified.

This study aimed to determine whether the underlying mechanism of HQD against CID is related to the activation of AMPK/mTOR-mediated autophagy inhibiting endoplasmic reticulum (ER) stress.

Network pharmacology was used to screen potential targets and pathways. The CID mouse model was induced by intraperitoneal injection of 75 mg/kg irinotecan consecutively for four days. The effectiveness of HQD against CID was evaluated through diarrhea score, intestinal epithelial permeability, etc. The histopathological changes of colon were evaluated by HE staining. Alcian blue and immunofluorescence staining were used to assess mucous layer and the expression of MUC2, TJP-1, Occludin, and LC3, relatively. The level of GRP78 and CHOP was assessed by RT-qPCR and WB. Furthermore, the levels of LC3II/I, Beclin-1, P62, AMPK, p-AMPK, mTOR, p-mTOR were evaluated by WB.

Network pharmacology highlighted that the therapeutic effects of HQD against CID may be related to ER stress, autophagy, AMPK, and mTOR signaling pathways, etc. Subsequently, we conducted animal experiments to validate the predicted results. HQD improved CID by attenuating diarrhea, intestinal permeability, etc. HQD could effectively repair intestinal mucous barrier by activating AMPK/mTOR-mediated autophagy to inhibit ER stress.

Irinotecan disrupted the intestinal barrier causing diarrhea, while HQD could repair intestinal barrier via inducing AMPK/mTOR-mediated autophagy inhibiting ER stress, thereby exerting therapeutic effects against CID.

Sleep deprivation (SD) disrupts intestinal homeostasis through excessive reactive oxygen species (ROS) accumulation. Tibetan tea is a potential dietary intervention for inflammation, it's effect on SD-induced intestinal inflammation remains unclear. This study investigates the alleviating effects of Tibetan tea water-soluble extract (TTE) on intestinal dysfunction in SD mice. After TTE supplementation, the physiological activity, inflammatory cytokines, and oxidative stress levels were assessed in SD-induced intestinal dysfunction mice. SD increased ROS levels and pro-inflammatory cytokines in plasma and small intestine, causing intestinal injury characterized by reduced goblet cells, decreased Mucin2 (MUC2) expression, and impaired tight junction proteins. Conversely, TTE reversed these disorders and improved mucosal injury in the small intestine. Furthermore, TTE modulated gut microbiota by enriching probiotics linked to SCFA production and restored SD-induced metabolic disturbances in the small intestine and systemic circulation, particularly affecting tricarboxylic acid (TCA) cycle, urea cycle, and TAG-related metabolites. Overall, TTE remarkably ameliorated SD-induced intestinal dysfunction through reducing ROS, restoring intestinal barrier function, and regulating the gut microbiome, which suggested that Tibetan tea could contribute to the treatment of intestinal inflammation.

The gut microbiome is altered in MS and may contribute to disease by disrupting the intestinal barrier. The colonic mucus barrier, which is primarily composed of mucin protein 2 (MUC2), plays a crucial role in providing a barrier between colonic epithelial cells and the microbiome. Disruption of intestinal epithelial and mucus barriers has been reported in inflammatory bowel disease (IBD) and Parkinson's disease (PD) but has not been studied in the context of the microbiome in multiple sclerosis (MS).

We investigated the epithelial tight junction protein zonulin occludins 1 (ZO-1), mucus protein MUC2, inflammatory stool markers (calprotectin), and gut microbiota composition in a cohort of subjects with relapsing and progressive MS.

MUC2 was decreased in stool of subjects with both relapsing and progressive MS. ZO-1 was elevated in the serum of subjects with progressive MS but was not altered in the stool. Inflammatory markers typically elevated in IBD and PD, including calprotectin, were not altered in MS stool, suggesting disease specificity of altered gut physiology in MS. Microbiota with known mucus degrading capacity were elevated in the stool of subjects with MS and negatively correlated with mucus protein levels.

Taken together, these findings suggest reduced gut barrier function in MS which is linked to increased mucin degrading bacteria.

This work was supported by grants from the National MS Society, the NIH/NINDS, the Nancy Davis Race to Erase MS Young Investigator Award, the Water Cove Charitable Foundation, and the Clara E. and John H. Ware Jr.

Intestinal health is crucial for digestive and absorptive functions, which are associated with fish growth performance. Searching for nutraceuticals and bioactive ingredients to improve intestinal health has become urgent for the aquaculture industry. In the present study, the effects of eicosapentaenoic acid (EPA) on intestinal function were investigated in turbot with induced intestinal damage caused by lipopolysaccharide (LPS). Juvenile turbot (initial weight 100 ± 5 g) were subjected to a 10-day enforced feeding regimen. Each fish was fed twice daily with either a 100 mg amino acid mixture (CON), an additional 1 mg of LPS (LPS), or an additional combination of 1 mg LPS and 1.7 mg EPA (LE). The results indicated that EPA supplementation restored intestinal villi integrity and the mucosal barrier. The number of goblet cells and the gene expression of MUC-2 were increased by EPA. Additionally, EPA suppressed the expression of inflammatory factors (MyD88 and NF-κB p65) and pro-inflammatory cytokines (TNFα, IL-1β, and IFN-γ). Meanwhile, post-feeding plasma free amino acid levels as well as intestinal protein synthesis were improved by EPA supplementation. The target of rapamycin (TOR) signaling pathway was significantly activated by EPA. Furthermore, EPA supplementation positively influenced intestinal microbiota, reducing the abundance of prevalent pathogens while enhancing the abundance of probiotics. Collectively, the administration of EPA effectively mitigates LPS-induced damage to the intestinal barrier, inflammatory response, and dysbiosis of microbiota through modulation of the TOR signaling pathway.

Traumatic brain injury (TBI) occurs in 2-3 million Americans each year and is a leading cause of death and disability. Among the many physiological consequences of TBI, the hypothalamic pituitary axis (HPA) is particularly vulnerable, including a reduction in growth hormone (GH) and insulin-like growth factor (IGF-1). Clinical and preclinical supplementation of IGF-1 after TBI has exhibited beneficial effects. IGF-1 receptors are prominently observed in many tissues, including in the brain and in the gastrointestinal (GI) system. In addition to causing damage in the brain, TBI also induces GI system damage, including inflammation and alterations to intestinal permeability and the gut microbiome. The goal of this study was to assess the effects of systemic IGF-1 treatment in a rat model of TBI on GI outcomes. Because GI dysfunction has been linked to hippocampal dysfunction, we also examined proliferation and immature granule cells in the hippocampal dentate gyrus. 10-week-old male rats were treated with an intraperitoneal (i.p.) dose of IGF-1 at 4 and 24 h after lateral fluid percussion injury (FPI). At 3- and 35-days post-injury (DPI), gut permeability, gut dysmorphia, the fecal microbiome, and the hippocampus were assessed. FPI-induced permeability of the blood-gut-barrier, as measured by elevated gut metabolites in the blood, and this was prevented by the IGF-1 treatment. Gut dysmorphia and alterations to the microbiome were also observed after FPI and these effects were ameliorated by IGF-1, as was the increase in immature granule cells in the hippocampus. These findings suggest that IGF-1 can target gut dysfunction and damage after TBI, in addition to its role in influencing adult hippocampal neurogenesis.

Proline rich-39 (PR-39) is a natural antimicrobial protein with good antibacterial and anti-inflammatory activities. The miniature Wuzhishan pig (WZSP) has important similarities to humans in anatomical structure, physiological characteristics, and nutrient metabolism that make it an important model animal for biomedical research. This study aimed to investigate the protective effect and therapeutic mechanism of PR-39 on intestinal barrier function using the LPS-induced enteritis model in WZSPs. We found that PR-39 treatment reversed the decrease in growth performance and peripheral organ damage, regulated serum indices (IL-1β, IL-6, TNF-α, IL-10, TGF-β, IgA, IgG, DAO, D-LA) and enhanced the antioxidant capacity (MDA, CAT, GSH-Px, T-AOC) of piglets. PR-39 protected the integrity of the jejunal barrier by upregulating the density of goblet cells and the expression of tight junction proteins ZO-1, Claudin-1, and Occludin. Additionally, PR-39 increased the abundance of jejunal probiotics (e.g., Lactococcus), and increased the cecal abundance of Lactobacillus johnsonii, then promoted the production of 7-keto deoxycholic acid to activate the bile acid receptor TGR5, which in turn inhibited the NF-κB-MLCK-MLC signaling pathway and the secretion of proinflammatory factors by macrophages. In summary, these findings suggest that PR-39 supplementation may be an effective strategy to improve the intestinal damage and dysfunction.

Neonatal hypoxia, a prevalent complication during the perinatal period, poses a serious threat to the health of newborns. The intestine, as one of the most metabolically active organs under stress conditions, is particularly vulnerable and susceptible to hypoxic injury. Using a neonatal hypoxic mouse model, we systematically investigated hypoxia-induced intestinal barrier damage and underlying mechanisms. Hypoxia caused significant structural abnormalities in the ileum and distal colon of neonatal mice, including increased numbers of F4/80+ cells (p = 0.0031), swollen mucus particles (p = 0.0119), and disrupted tight junction. At the genetic level, hypoxia caused dysregulation of the expression of genes involved in intestinal barrier function, including antimicrobial activity, immune response, intestinal motility, and nutrient absorption. Further 16 S rDNA sequencing revealed hypoxia-driven gut microbiota dysbiosis with general reduced microbial abundance and diversity (Chao1 = 0.1143, Shannon = 0.0571, and Simpson = 0.3429). Structural dysbiosis of the gut microbiota consequently perturbed metabolic homeostasis, especially enhancing the activity of glycolipid metabolism. Notably, results showed that hypoxia may interfere with neurotransmitter metabolism, thereby increasing the risk of neurological disorders.

Consumption of sugar-sweetened beverages (SSBs) have been linked to metabolic dysfunction, obesity, diabetes and enhanced risk of cardiovascular diseases across all age-groups globally. Decades of work that have provided insights into pathophysiological manifestations of sucrose overfeeding have employed paradigms that rarely mimic human consumption of SSBs. Thus, our understanding of multiorgan cross-talk and molecular and/or cellular mechanisms, which operate across scales and drive physiological derangement is still poor. By employing a paradigm of sucrose water feeding in mice that closely resembles chronic SSB consumption in humans (10% sucrose in water), we have unraveled hitherto unknown tissue-specific mechanistic underpinnings, which contribute towards perturbed physiology. Our findings illustrate that systemic impaired glucose homeostasis, mediated by hepatic gluconeogenesis and insulin resistance, does not involve altered gene expression programs in the liver. We have discovered the pivotal role of the small intestine, which in conjunction with liver and muscles, drives dyshomeostasis. Importantly, we have uncovered rewiring of molecular mechanisms in the proximal intestine that is either causal or consequential to systemic ill-effects of chronic sucrose water consumption including dysfunction of liver and muscle mitochondria. Tissue-specific molecular signatures, which we have unveiled as the primary outcome, clearly indicate that inefficient utilization of glucose is exacerbated by enhanced uptake by the gut. Besides providing systems-wide mechanistic insights, we propose that consumption of SSBs causes intestinal 'molecular addiction' for deregulated absorption of hexose-sugars, and drives diseases such as diabetes and obesity.

The organophosphorus pesticide chlorpyrifos (CPF) is widely utilized in agriculture to protect crops from pests and diseases. Concerns regarding its extensive use have emerged due to the substance's persistence, bioaccumulation, endocrine disruption, and associated toxicity, which may lead to various adverse reactions. In this study, 32 male C57BL/6 J mice were orally administered varying doses of CPF over a period of two weeks. Metabolic perturbations resulting from subacute exposure to CPF were assessed using LC-MS/MS-based untargeted metabolomics, alongside biochemical analysis and histopathological techniques. The 16S rRNA gene sequencing method was employed to evaluate changes in the gut microbial community within the cecal contents of mice exposed to CPF. In vivo studies have shown that CPF exposure induced dose-dependent damage and dysregulation of the intestinal microbiota in mouse colonic tissues. This was characterized by significant alterations in the gut microbiota, increased intestinal permeability and elevated levels of lipopolysaccharides. These changes may have compromised intestinal barrier function and facilitated the transfer of intestinal microbial metabolites and endotoxins to the liver, subsequently leading to liver injury. Collectively, this study elucidates a potential mechanism by which CPF triggers liver injury through alterations in the intestinal microbial community and increased intestinal permeability. These findings not only enhance our understanding of the toxicological effects of CPF but also contribute to the assessment of health risks associated with CPF exposure.

Aging-related cognitive impairment has emerged as a major health-threatening factor among the elderly, and cyanidin-3-glucoside (C3G) is a prominent anthocyanin with biological activities, including antioxidant, anti-inflammatory, and alleviation of neurodegeneration. However, the role of C3G in alleviating natural aging-induced cognitive impairment and the underlying mechanisms thereof remain unclear. In this study, experimental methods mainly included biochemical analysis, pathological analysis, immunofluorescence staining, transmission electron microscopy analysis, western blot, as well as the determination of the gut microbiota composition and detection of metabolites. We found that C3G may exert neuroprotective effects and promote brain health by alleviating brain atrophy and neuroinflammation, enhancing brain antioxidant capacity, regulating neurotransmitter expression and hypothalamic-pituitary-adrenal axis activity, and attenuating blood-brain barrier and hippocampal synaptic damage. Furthermore, C3G also promotes gut health by decreasing inflammatory responses and intestinal tissue crypt damage, upregulating the expression of tight junction proteins, and attenuating intestinal damage. Notably, C3G regulated the microbiota composition in different intestinal segments and intestinal mucosa, as well as the metabolic homeostasis of gut microbiota metabolites, such as short-chain fatty acids (SCFAs), amino acids, and bile acids. Substantially increased levels of SCFAs could activate the extracellular signal-regulated kinase (ERK)/cAMP response element-binding protein (CREB)/brain-derived neurotrophic factor (BDNF) signaling pathway by acting on the G protein-coupled receptors. Correlation analysis indicated that increased gut microbiota, such as Faecalibaculum and Bifidobacterium, and elevated SCFAs were positively correlated with behavioral improvement and brain health. In conclusion, our findings reveal that C3G has the potential to improve natural aging-induced cognitive impairment by modulating the gut microbiota and its metabolite SCFAs, thereby activating the ERK/CREB/BDNF pathway.

In the process of aging, adverse changes such as weakened intestinal barrier function, increased chronic inflammation, and decreased gut microbiota diversity often occur. We explored the protective effects of Oat β-glucan (BG) on the gut homeostasis of naturally aging mice. The study shows that daily intervention with 400 mg/kg BG effectively modulates the intestinal mucosal structure, mechanical barrier function [Zonula occludens-1 (ZO-1), occludin, and claudin], and anti-inflammatory [Tumor Necrosis Factor-α (TNF-α), Interleukin-6 (IL-6), and IL-1β], as well as antioxidant responses in aging mice. Spearman correlation analyses showed that BG supplementation increased acetate levels by 1.8-fold, propionate levels by 2.5-fold, and butyrate-derived GABA levels by 2.5-fold. Additionally, BG supplementation improved the gut microbiota, increasing the abundance of beneficial bacteria like Bacteroidota, Prevotellaceae, Coprobacillaceae, and Faecalibacterium. These microbes metabolize BG to produce short-chain fatty acids (SCFAs), activating butanoate and propanoate metabolic pathways to maintain intestinal homeostasis. In conclusion, this study identifies the therapeutic effects of BG in regulating intestinal barrier homeostasis and gut microbiota, providing new insights for nutritional intervention strategies in the elderly.

Bangle, a perennial herb belonging to the ginger family with antiinflammatory properties, has been under-researched in ulcerative colitis. This study aimed to investigate the effects of Bangle extract (BaE) on inflammation and autophagy in the colons of mice with dextran sulfate sodium (DSS)-induced colitis. Male C57BL/6J mice were assigned to four groups: control, DSS + 0% BaE, DSS + 1% BaE, and DSS + 3% BaE. The BaE groups were fed BaE diets for 3 weeks, followed by an additional week of BaE diets and 3% DSS in the water. The control group received a standard chow diet and water for 4 weeks. Plasma leucine-rich α2-glycoprotein (LRG) levels, macrophage count, and the levels of nuclear factor kappa B (NFκB) p65, tumor necrosis factor-α (TNF-α), adenosine monophosphate-activated protein kinase (AMPK), peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), mechanistic target of rapamycin (mTOR), and autophagy markers were analyzed. In the DSS + 0% BaE group, LRG levels, macrophage count, NFκB p65 protein, and TNF-α mRNA levels were significantly higher compared to the control group. However, in the DSS + 3% BaE group, these levels were significantly reduced. Additionally, PGC-1α and phosphorylated AMPK levels were increased, while phosphorylated mTOR levels decreased, and autophagy marker microtubule-associated protein 1 light chain 3B (LC3B)-II levels were increased in the DSS + 3% BaE group. BaE may ameliorate colonic inflammation and upregulate autophagy via the modulation of the AMPK/mTOR/NFκB pathway in DSS-induced colitis.

Development of innovative in vitro test methods for the detection of potential health risks related to contaminants is imperative to food safety. Here we present an extended implementation for the intestinal model based on the human Caco-2/HT29-MTX-E12 co-culture which produces mucus and exhibits barrier function when differentiated. To simulate the presence of the microbiome, SiO2-based mesoporous rod-shaped nanoparticles (bacteria-like; bacNPs, 200 × 450 nm) were included adding an extra dimension to the system. Smaller SiO2-based mesoporous rod-shaped nanoparticles (srNPs, 35 × 160 nm) were used to mimic particulate matter present in the intestine as for the chyme transit. Synthetized and utilized to reproduce elements of the intestinal lumen, nanorods supported testing the interaction with the intestinal cells and mucus at the nanoscale. To start exploring the applicability of the model, the mycotoxin fumonisin B1 (10-100 μM) produced by Fusarium spp. was chosen as a test substance due to its wide occurrence and hazardous potential. As fumonisins are known to hamper lipid metabolism, palmitic acid (25-100 μM) - one of the most prevalent fatty acids in our diets - was additionally used. Significantly for the reproduction of in vivo physiology, srNPs penetrated through the mucus layer resulting in the modulation of intercellular distances and paracellular permeability in conjunction with exposure to fumonisin B1. This enabled the quantification of a response which was not detectable using exclusively the Caco-2/HT29-MTX-E12 model and paves the way toward the creation of systems that more efficiently support the screening of food contaminants in vitro.

Disruption of the intestinal epithelial barrier, driven by imbalances in gut mucosal immunity and microbial homeostasis, is central to the onset and progression of inflammatory bowel disease (IBD). This study introduces a CO-releasing polyoxometalates (POMs) nanozyme (PMC), synthesized by coordinating pentacarbonyl manganese bromide with molybdenum-based POM nanoclusters. PMC demonstrates targeted accumulation at IBD-affected sites, efficient scavenging of reactive oxygen species (ROS), and responsive CO release, resulting in multiple therapeutic effects. Extensive in vitro and in vivo studies have validated the exceptional capacity of PMC to repair intestinal barrier, attributed to their potent antioxidant and anti-inflammatory properties, thereby achieving significant therapeutic efficacy in ulcerative colitis treatment. 16S rRNA sequencing indicated that PMC efficiently remodeled the gut microbiota composition. Single-cell RNA sequencing indicates a reduction in pro-inflammatory M1 macrophages, alongside suppressed ROS and inflammatory signaling pathways. Concurrently, an increase in reparative M2 macrophages and intestinal stem cells is observed, in addition to significant activation of the VEGF signaling pathway in macrophages and the NOTCH pathway in stem cells, underscoring the potential of PMC to restore immune balance and promote tissue repair. This study positions PMC as a promising, multifunctional therapeutic agent for IBD treatment owing to its robust intestinal barrier-restoring capability.

Irinotecan (CPT11)-induced diarrhea affects 80-90% of cancer patients due to β-glucuronidase (GUS) converting 7-ethyl-10-hydroxycamptothecin glucuronide (SN38G) to 7-ethyl-10-hydroxycamptothecin (SN38). It remains unclear whether SN38 impacts the homeostasis between gut microbiota and mucosal stem cell niche. This study explores the crosstalk between gut microbiota and intestinal stem cells (ISCs) in intestinal mucositis triggered by CPT11 chemotherapy. CPT11-treated mice exhibited significant colon shortening, inflammatory infiltration, intestinal barrier dysfunction, and ISC impairment, which correlated with gut dysbiosis, enrichment of GUS-expressing bacteria, and intraluminal SN38 accumulation. In contrast, antidiarrheal (Xianglian pill) treatment alleviated SN38-induced enterotoxicity and reduced GUS-expressing bacterial populations. Microbiome profiling of clinical patients and mucositis mice revealed a strong correlation between CPT11/SN38 enterotoxicity and GUS-expressing bacteria, particularly Lactobacillus reuteri. PLS-PM modeling further linked L. reuteri to impaired epithelial regeneration, which is validated using a 3D intestinal organoid model. L. reuteri hindered ISC differentiation into secretory lineages within the organoids. Furthermore, L. reuteri colonization in mice exacerbated mucositis and disrupted epithelial differentiation, while its elimination ameliorated colitis symptoms and preserved crypt cell stemness. These findings suggest that selectively targeting GUS-expressing bacteria, particularly L. reuteri, to protect the regenerative epithelial stem/progenitor pool may serve as an effective strategy for mitigating CPT11-induced enterotoxicity.

Thlaspi arvense (TA), commonly known as "Ximi" or "Subaijiang," is a traditional Chinese medicinal herb used to prevent and treat ulcerative colitis (UC). However, the precise mechanisms underlying its therapeutic effects remain unclear, necessitating further investigation to identify potential pharmaceutical applications for UC management. This study aims to elucidate the efficacy and mechanisms of TA and its active constituents in UC treatment.

This study first evaluated the effects of varying TA doses on 3% dextran sulfate sodium (DSS)-induced UC. Gut microbiota alterations in UC mice were analyzed via 16S rRNA sequencing, with correlation analyses to reveal the relationship between gut microbiota and cytokines. Then, network pharmacology was utilized to identified potential TA targets for UC treatment. Protein-protein interaction (PPI) networks, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were employed to explore TA's mechanisms. Molecular docking and dynamics simulations validated interactions between TA's active compounds and UC-related targets. Finally, TNF pathway modulation by TA and its active component, isovitexin, was verified in vitro and in vivo.

TA alleviated DSS-induced weight loss in a dose-dependent manner, reduced disease activity indices, and preserved intestinal mucosal barrier integrity. Subsequently, fluorescence in situ hybridization (FISH) revealed TA suppressed microbial translocation in intestinal tissues. To further characterize inflammatory responses, ELISA demonstrated that TA modulated levels of key cytokines (TNF-α, IL-1β, IL-6, IL-10) and oxidative stress markers (SOD, MDA), indicating systemic anti-inflammatory effects. Building on these findings, 16S rRNA sequencing analyses showed that TA regulated gut microbiota alpha/beta diversity and inhibited infectious disease-related pathways. Notably, correlation heatmaps highlighted a strong association between TNF-α levels and Escherichia-Shigella abundance, with high-dose TA significantly reducing this pathogenic bacterial genus. To systematically explore molecular mechanisms, network pharmacology identified 220 potential TA targets for UC treatment. Consistent with experimental data, PPI and KEGG analyses implicated TNF-α, IL-6, and AKT as key targets, primarily through TNF signaling pathway modulation. To validate these predictions, molecular docking confirmed stable interactions between TA compounds and identified targets, while dynamics simulations specifically emphasized isovitexin's high affinity for TNF-α. Finally, experiments in vivo demonstrated TA's inhibition of TNF-α-mediated NF-κB pathway activation, and in vitro studies confirmed that isovitexin directly mitigated TNF-α-induced intestinal epithelial damage. Furthermore, TA demonstrated potent inhibition of TNF-α-mediated NF-κB inflammatory pathway activation in intestinal tissues, while its active constituent isovitexin effectively mitigated TNF-α-induced epithelial cell damage, collectively highlighting their complementary anti-inflammatory mechanisms.

Collectively, Thlaspi arvense (TA) ameliorates ulcerative colitis through synergistic mechanisms involving gut microbiota modulation, inflammatory pathway suppression, and intestinal barrier preservation. By remodeling microbial communities to reduce Escherichia-Shigella colonization and microbial translocation. TA concurrently inhibits TNF-α/NF-κB-driven inflammation, and oxidative stress regulation. Furthermore, its active constituent isovitexin directly attenuates TNF-α-induced epithelial damage, demonstrating multi-scale therapeutic efficacy. These findings establish TA's multi-target pharmacology spanning host-microbe interactions and intracellular signaling, while providing a rationale for standardizing TA-based formulations and advancing isovitexin as a precision therapeutic agent for inflammatory bowel diseases.

Inflammatory bowel diseases (IBDs) constitute chronic inflammatory disease of the gastrointestinal tract, with escalating global prevalence. There is a pressing demand for safe and effective treatments for IBDs. Fibroblast growth factor 1 (FGF1) variant FGF1ΔHBS, characterised by reduced mitogenic capacity, has shown promising therapeutic potential in various inflammatory conditions, including obesity and diabetic nephropathy. Hence, exploring the therapeutic impact of FGF1ΔHBS on colitis is warranted.

The protective role of FGF1ΔHBS was evaluated using a dextran sulphate sodium (DSS)-induced colitis model in mice. RNA-seq analysis was performed on colonic tissues. Inflammatory factor expression was examined by quantitative real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay. Flow cytometry and immunofluorescence staining were employed to confirm the inhibitory effect of FGF1ΔHBS on neutrophil recruitment. Western blotting was performed to explore the mitogen-activated protein kinase (MAPK) signalling pathway.

FGF1ΔHBS significantly alleviated DSS-induced colitis, as indicated by reduced Disease Activity Index scores and less histological injury to the colon. Additionally, FGF1ΔHBS decreased the expression of pro-inflammatory factors. Mechanistically, FGF1ΔHBS inhibited neutrophil-associated chemokine expression in intestinal epithelial cells by suppressing the MAPK signalling pathway, thereby reducing neutrophil recruitment and attenuating neutrophil-mediated intestinal inflammation.

FGF1ΔHBS protects against DSS-induced colitis in mice by inhibiting neutrophil recruitment through MAPK activity suppression, suggesting a potential therapeutic strategy for preventing IBDs.

The colonic mucus layer acts as a physicochemical barrier to pathogen invasion and as a habitat for mucus-associated microbes. This mucosal microbiome plays a crucial role in moderating mucus production, maintaining barrier integrity, and shaping the host immune response. However, unchecked mucin foraging may render the host vulnerable to disease. To better understand these dynamics in the mucus layer, it is essential to advance fundamental knowledge on how commensals bind to and utilize mucin as well as their interactions with both the host and their microbial neighbors. We present an overview of approaches for surveying mucus-associated bacteria and assessing their mucin-utilizing capacity, alongside a discussion of the limitations of existing methods. Additionally, we highlight how diet and host secretory immunoglobulin A interact with the mucosal bacterial community in the colon. Insights into this subset of the microbial community can guide therapeutic strategies to optimally support and modulate mucosal barrier integrity.