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Summary: The gastrointestinal tract serves as a pivotal physical barrier that prevents the translocation of exogenous substances from the intestinal lumen into the systemic circulation. Dysfunction of intestinal barrier function has been implicated in the pathogenesis of several diseases, such as metabolic disorders. Heat shock proteins (HSPs) play a critical role in maintaining the resilience and viability of epithelial cells when exposed to stressors. Evidence suggests that dietary fibre (DF), a known inducer of HSP production, may be a promising candidate for strengthening the intestinal barrier. Understanding the regulation of intestinal HSPs and the protective effect of DF is critical to defending against environmental threats and preserving human health. To date, six DFs—pectin, chicory, psyllium, guar gum, partially hydrolysed guar gum, and xylooligosaccharide—have been reported to have promotive effects on intestinal HSP induction. DF promotes intestinal HSP induction through gut microbiota‐dependent and independent mechanisms. DF is fermented by gut microbiota to produce short‐chain fatty acids, specifically butyrate and propionate, to promote HSP production. Meanwhile, DF also promotes intestinal HSP induction through direct interaction with intestinal epithelial cells, independent of gut microbiota activity, although the precise mechanism is still unclear. Regulation of intestinal HSP occurs by transcriptional modulation through activation of heat shock transcription factors, primarily heat shock factor 1, or at the post‐transcriptional level by modulation of the translation process. This review highlights recent advances in understanding the role of DF in improving intestinal barrier function, with particular emphasis on the regulatory mechanisms of intestinal HSPs. [ABSTRACT FROM AUTHOR]

• Hyperglycemic stress increases protein loss and spatial distribution of key intestinal barrier proteins in a mouse intestinal organoid model. • Small molecular weight hyaluronan (35 kDa), HA35, plays a protective effect on barrier function under high glucose conditions. • HA35 regulates apoptotic cell death in organoids grown under hyperglycemic stress. • The effects of HA35 on the intestinal barrier function are likely regulated by its receptor layilin via the layilin-integrin-FAK axis. Metabolic syndrome and diabetes in obese individuals are strong risk factors for development of inflammatory bowel disease (IBD) and colorectal cancer. The pathogenic mechanisms of low-grade metabolic inflammation, including chronic hyperglycemic stress, in disrupting gut homeostasis are poorly understood. In this study, we sought to understand the impact of a hyperglycemic environment on intestinal barrier integrity and the protective effects of small molecular weight (35 kDa) hyaluronan on epithelial barrier function. Intestinal organoids derived from mouse colon were grown in normal glucose media (5 mM) or high glucose media (25 mM) to study the impact of hyperglycemic stress on the intestinal barrier. Additionally, organoids were pretreated with 35 kDa hyaluronan (HA35) to investigate the effect of hyaluronan on epithelial barrier under high glucose stress. Immunoblotting as well as confocal imaging was used to understand changes in barrier proteins, quantitative as well as spatial distribution, respectively. Alterations in barrier function were measured using trans-epithelial electrical resistance and fluorescein isothiocyanate flux assays. Untargeted proteomics analysis was performed to elucidate mechanisms by which HA35 exerts a protective effect on the barrier. Intestinal organoids derived from receptor knockout mice specific to various HA receptors were utilized to understand the role of HA receptors in barrier protection under high glucose conditions. We found that high glucose stress decreased the protein expression as well as spatial distribution of two key barrier proteins, zona occludens-1 (ZO-1) and occludin. HA35 prevented the degradation or loss of ZO-1 and maintained the spatial distribution of both ZO-1 and occludin under hyperglycemic stress. Functionally, we also observed a protective effect of HA35 on the epithelial barrier under high glucose conditions. We found that HA receptor, layilin, was involved in preventing barrier protein loss (ZO-1) as well as maintaining spatial distribution of ZO-1 and occludin. Additionally, proteomics analysis showed that cell death and survival was the primary pathway upregulated in organoids treated with HA35 under high glucose stress. We found that XIAP associated factor 1 (Xaf1) was modulated by HA35 thereby regulating apoptotic cell death in the intestinal organoid system. Finally, we observed that spatial organization of both focal adhesion kinase (FAK) as well as F-actin was mediated by HA35 via layilin. Our results highlight the impact of hyperglycemic stress on the intestinal barrier function. This is of clinical relevance, as impaired barrier function has been observed in individuals with metabolic syndrome. Additionally, we demonstrate barrier protective effects of HA35 through its receptor layilin and modulation of cellular apoptosis under high glucose stress. [ABSTRACT FROM AUTHOR]

Alcohol consumption is not uncommon among people with HIV (PWH) and may exacerbate HIV-induced intestinal damage, and further lead to dysbiosis and increased intestinal permeability. This study aimed to determine the changes in the fecal microbiota and its association with alcohol consumption in HIV-infected patients. A cross-sectional survey was conducted between November 2021 and May 2022, and 93 participants were recruited. To investigate the alterations of alcohol misuse on fecal microbiology in HIV-infected individuals, we performed 16s rDNA gene sequencing on fecal samples from the low-to-moderate drinking (n = 21) and non-drinking (n = 72) groups. Comparison between groups using alpha and beta diversity showed that the diversity of stool microbiota in the low-to-moderate drinking group did not differ from that of the non-drinking group (all p > 0.05). The Linear discriminant Analysis effect size (LEfSe) algorithm was used to determine the bacterial taxa associated with alcohol consumption, and the results showed altered fecal bacterial composition in HIV-infected patients who consumed alcohol; Coprobacillus , Pseudobutyrivibrio , and Peptostreptococcaceae were enriched, and Pasteurellaceae and Xanthomonadaceae were depleted. In addition, by using the Kyoto Encyclopedia of Genes and Genomes (KEGG), functional microbiome features were also found to be altered in the low-to-moderate drinking group compared to the control group, showing a reduction in metabolic pathways (p = 0.036) and cardiovascular disease pathways (p = 0.006). Low-to-moderate drinking will change the composition, metabolism, and cardiovascular disease pathways of the gut microbiota of HIV-infected patients. • Alcohol use and gut microbial composition in PWH is an important area of research. • Alcohol consumption alters the composition of the gut microflora in PWH. • Alcohol consumption reduces metabolic pathways and cardiovascular disease pathways. [ABSTRACT FROM AUTHOR]

Sediment is the ultimate sink of environmental pollutants. A total of 128 surface sediment samples were collected from 8 rivers and 3 reservoirs in Maoming City, Guangdong Province. This study assessed the content and distribution of brominated flame retardants in sediments. The acute toxicity effects of tetrabromobisphenol A (TBBPA) and hexabromocyclododecane (HBCDs) in sediments were evaluated using Caenorhabditis elegans as model organisms. The concentration of TBBPA in sediments ranged from not detected (ND) to 12.59 µg/kg and was mainly distributed in the central area, which was affected by the emission of TBBPA from residential and factory. The concentration of HBCDs ranged from ND to 6.31 µg/kg, and the diastereoisomer distribution was consistent, showing a trend close to the South China Sea. The composition pattern of HBCDs in the surface sediments from rivers were 41.73%–62.33%, 7.89%–25.54%, and 18.76%–40.65% for α-, β-, and γ-HBCD, respectively, and in the sediments from reservoirs were 26.15%–45.52%, 7.44%–19.23%, and 47.04%–61.89% for α-, β-, and γ-HBCD, respectively. When the sum of concentrations of TBBPA and HBCD in sediments were above high levels, reactive oxygen species in nematodes significantly increased, resulting in an oxidative stress response. Intestinal permeability was also enhanced, causing intestinal damage. In addition, in terms of this study, TBBPA had a greater impact on biotoxicity compared to HBCDs, and more attention should be paid to the toxic effects of the river ecosystem organisms in Maoming City, Guangdong Province. This study can complement the pollution database in the study area and provide basic data for pollution control. [Display omitted] [ABSTRACT FROM AUTHOR]

I-FABP is an intracellular protein specifically and abundantly expressed in the epithelial cells of the mucosal layer of the tissue of the small and large intestine. Current research studies the role of intestinal barrier dysfunction as a predictor of autoimmune diseases, including the development of autoimmune thyroid diseases. The determination of new non-invasive markers for impaired integrity of the intestinal epithelium will be beneficial for clinical practice, and early interventions to protect the intestinal microbiota may prevent the development of autoimmune processes. The aim of the present review is to investigate the relationship between plasma levels of intestinal fatty acid binding protein (I-FABP), intestinal permeability and the presence of autoimmune diseases such as Hashimoto’s thyroiditis. [ABSTRACT FROM AUTHOR]

The prolonged exposure to arsenic results in intestinal barrier dysfunction, which is strongly concerned with detrimental processes such as oxidative stress and the inflammatory response. Ferulic acid (FA), as a phenolic acid, possesses the capability to mitigate arsenic‐induced liver damage and cardiotoxic effects dependent on inhibition of oxidative stress and inflammatory responses. FA can mitigate testicular tissue damage and alveolar epithelial dysfunction, the mechanism of which may rely on nuclear factor erythroid 2‐related factor 2/heme oxygenase 1 (Nrf2/HO‐1) activation and nuclear factor‐kappa B (NF‐κB) pathway blocking. Based on the antioxidant and anti‐inflammatory properties of FA, we speculated that FA might have the potential to inhibit arsenic‐induced intestinal damage. To confirm this scientific hypothesis, mice exposed to sodium arsenite were treated with FA to observe colonic histopathology and TJ protein levels, and oxidative stress and TJ protein levels in Caco‐2 cells exposed to sodium arsenite were assessed after FA intervention. In addition, molecular levels of NF‐κB and Nrf2/HO‐1 pathway in colon and Caco‐2 cells were also detected. As shown in our data, FA inhibited arsenic‐induced colon injury, which was reflected in the improvement of mucosal integrity, the decrease of down‐regulated expression of tight junction (TJ) proteins (Claudin‐1, Occludin, and ZO‐1) and the inhibition of oxidative stress. Similarly, treatment with FA attenuated the inhibitory effect of arsenic on TJ protein expression in Caco‐2 cells. In addition to suppressing the activation of NF‐κB pathway, FA retrieved the activation of Nrf2/HO‐1 pathway in colon and intestinal epithelial cells induced by arsenic. In summary, our findings propose that FA has the potential to mitigate arsenic‐induced intestinal damage by preserving the integrity of intestinal epithelial TJs and suppressing oxidative stress. These results lay the groundwork for the potential use of FA in treating colon injuries caused by arsenic. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusion Accumulating evidence has suggested that neuropeptides such as orexin, ghrelin, or oxytocin act centrally in the brain to regulate intestinal barrier function through the vagus nerve. It has been reported that the vagal cholinergic anti‐inflammatory pathway was blocked by splenectomy. In the present study, we therefore examined the effect of splenectomy on neuropeptides‐induced improvement of increased intestinal permeability.Colonic permeability was determined in vivo by quantifying the absorbed Evans blue in colonic tissue for 15 min spectrophotometrically in rats.Splenectomy increased colonic permeability. The increased permeability by splenectomy was significantly blocked by vagal activation induced by carbachol or 2‐deoxy‐d‐glucose which was prevented by atropine, suggesting vagal activation could prevent colonic hyperpermeability in splenectomized rats. In the splenectomized rats, intracisternal injection of orexin, ghrelin, oxytocin, or butyrate failed to inhibit increased colonic permeability while intracisternal glucagon‐like peptide‐1 (GLP‐1) analogue, liraglutide, potently blocked the increased colonic permeability in a dose‐dependent manner. The liraglutide‐induced improvement of increased colonic permeability was blocked by atropine in splenectomized rats. Intracisternal injection of GLP‐1 receptor antagonist attenuated 2‐deoxy‐d‐glucose‐induced improvement of colonic hyperpermeability in splenectomized rats.The present results suggested that the spleen is important in the improvement of intestinal barrier function by brain orexin, ghrelin or oxytocin, and butyrate. On the other hand, GLP‐1 acts centrally in the brain to improve colonic hyperpermeability in a spleen‐independent manner. All these results suggest that dual mechanisms (spleen dependent or independent) may exist for the brain‐gut regulation in intestinal barrier function. [ABSTRACT FROM AUTHOR]

Background and Purpose Experimental Approach Key Results Conclusion and Implications Chicoric acid, a hydroxycinnamic acid, exhibits anti‐inflammation activities. However, the specific mechanisms underlying the effects of chicoric acid on dextran sulfate sodium (DSS)‐induced colitis remain unclear. Here, we aimed to elucidate the molecular mechanisms underlying the protective effects of chicoric acid in DSS‐induced colitis.Mice with DSS‐induced colitis (UC mice) were treated for a week with chicoric acid. Symptoms of colitis, colonic pathology, inflammation‐related indicators, and intestinal mucosal barrier function were evaluated. RNA sequencing was performed on colon tissues to obtain differentially expressed genes. The deubiquitinating enzyme USP9X was selected, and the inhibitory and targeting effects of chicoric acid on USP9X were subsequently determined. In vivo and in vitro, DSS‐induced colitis was treated with USP9X inhibitors WP1130 and EOAI3402143. Ubiquitination label‐free quantitative proteomic analysis was performed to identify protein peptides that may undergo de‐ubiquitination by USP9X. Co‐immunoprecipitation (Co‐IP), immunohistochemistry and western blotting were used to validate in vivo and in vitro results.Chicoric acid significantly alleviated clinical activity and histological changes, inhibited pro‐inflammatory cytokine production and improved integrity of the intestinal barrier in UC mice. Moreover, chicoric acid suppressed USP9X expression in colonic tissues from UC mice. Furthermore, USP9X contributed to promoting the onset of UC and that insulin‐like growth factor 2 mRNA‐binding protein 2 (IGF2BP2) was deubiquitinated by USP9X.Chicoric acid ameliorated DSS‐induced colitis by targeting the USP9X/IGF2BP2 axis, indicating that targeting the USP9X/IGF2BP2 axis presents a promising and innovative therapeutic approach for the treatment of UC. [ABSTRACT FROM AUTHOR]

Gut serves as the largest interface between humans and the environment, playing a crucial role in nutrient absorption and protection against harmful substances. The intestinal barrier acts as the initial defense mechanism against non-specific infections, with its integrity directly impacting the homeostasis and health of the human body. The primary factor attributed to the impairment of the intestinal barrier in previous studies has always centered on the gastrointestinal tract itself. In recent years, the concept of the “gut-organ” axis has gained significant popularity, revealing a profound interconnection between the gut and other organs. It speculates that disruption of these axes plays a crucial role in the pathogenesis and progression of intestinal barrier damage. The evaluation of intestinal barrier function and detection of enterogenic endotoxins can serve as “detecting agents” for identifying early functional alterations in the heart, kidney, and liver, thereby facilitating timely intervention in the disorders. Simultaneously, consolidating intestinal barrier integrity may also present a potential therapeutic approach to attenuate damage in other organs. Studies have demonstrated that diverse signaling pathways and their corresponding key molecules are extensively involved in the pathophysiological regulation of the intestinal barrier. Aberrant activation of these signaling pathways and dysregulated expression of key molecules play a pivotal role in the process of intestinal barrier impairment. Microgravity, being the predominant characteristic of space, can potentially exert a significant influence on diverse intestinal barriers. We will discuss the interaction between the “gut-organ” axes and intestinal barrier damage, further elucidate the signaling pathways underlying intestinal barrier damage, and summarize alterations in various components of the intestinal barrier under microgravity. This review aims to offer a novel perspective for comprehending the etiology and molecular mechanisms of intestinal barrier injury as well as the prevention and management of intestinal barrier injury under microgravity environment. [ABSTRACT FROM AUTHOR]

Periodontitis exacerbates Alzheimer's disease (AD) through multiple pathways. Both periodontitis and AD are intricately correlated to intestinal homeostasis, yet there is still a lack of direct evidence regarding whether periodontitis can regulate the progression of AD by modulating intestinal homeostasis. The current study induced experimental periodontitis in AD mice by bilaterally ligating the maxillary second molars with silk and administering Pg-LPS injections in APPswe/PS1ΔE9 (APP/PS1) mice. Behavioral tests and histological analyses of brain tissue were conducted after 8 weeks. Gut microbiota was analyzed and colon tissue were also evaluated. Then, fecal microbiota from mice with periodontitis was transplanted into antibiotic-treated mice to confirm the effects of periodontitis on AD and the potential mechanism was explored. The results indicated periodontitis exacerbated cognitive impairment and anxious behaviour in APP/PS1 mice, with increased Aβ deposition, microglial overactivation and neuroinflammation in brain. Moreover, the intestinal homeostasis of AD mice was altered by periodontitis, including affecting gut microbiota composition, causing colon inflammation and destroyed intestinal epithelial barrier. Furthermore, AD mice that underwent fecal transplantation from mice with periodontitis exhibited worsened AD progression and disrupted intestinal homeostasis. It also impaired intestinal barrier function, elevated peripheral inflammation, damaged blood-brain barrier (BBB) and caused neuroinflammation and synapses impairment. Taken together, the current study demonstrated that periodontitis could disrupt intestinal homeostasis to exacerbate AD progression potential via causing gut microbial dysbiosis, intestinal inflammation and intestinal barrier impairment to induce peripheral inflammation and damage BBB, ultimately leading to neuroinflammation and synapse impairment. It underscores the importance of maintaining both periodontal health and intestinal homeostasis to reduce the risk of AD. [ABSTRACT FROM AUTHOR]

Background: Chronic alcohol intake is associated with alterations of choline metabolism in various tissues. Here, we assessed if an oral choline supplementation attenuated the development of alcohol-related liver disease (ALD) in mice. Methods: Female C57BL/6 J mice (n = 8/group) were either pair-fed a liquid control diet, or a Lieber DeCarli liquid diet (5% ethanol) ± 2.7 g choline/kg diet for 29 days. Liver damage, markers of intestinal permeability and intestinal microbiota composition were determined. Moreover, the effects of choline on ethanol-induced intestinal permeability were assessed in an ex vivo model. Results: ALD development as determined by liver histology and assessing markers of inflammation (e.g., nitric oxide, interleukin 6 and 4-hydroxynonenal protein adducts) was attenuated by the supplementation of choline. Intestinal permeability in small intestine being significantly higher in ethanol-fed mice was at the level of controls in ethanol-fed mice receiving choline. In contrast, no effects of the choline supplementation were found on intestinal microbiota composition. Choline also significantly attenuated the ethanol-induced intestinal barrier dysfunction in small intestinal tissue ex vivo, an effect almost entirely abolished by the choline oxidase inhibitor dimbunol. Conclusion: Our results suggest that an oral choline supplementation attenuates the development of ALD in mice and is related to a protection from intestinal barrier dysfunction. [ABSTRACT FROM AUTHOR]

Irinotecan (CPT-11) is a commonly prescribed chemotherapeutic for the treatment of colon cancer. Unfortunately, acute and delayed diarrhea are prominent side effects of CPT-11 use, and this limits its therapeutic potential. The curative effect of Huangqin decoction (HQD) on chemotherapy-induced diarrhea has been proven. This study investigated the efficacy of the components of HQD (baicalein, baicalin, and paeoniflorin) on CPT-11-induced diarrhea and their underlying mechanisms. Baicalein was found to be the most effective component in improving CPT-11-induced enterotoxicity by intestinal permeability test, ELISA, fluorescence co-localization, and IHC. The combination of baicalin, baicalin and paeoniflorin can obtain similar therapeutic effect to that of HQD. Mendelian randomization analysis, 16 s rRNA sequencing, and fluorescence imaging revealed that baicalein and baicalin significantly inhibited β-glucuronidase (β-GUS) activity. Bacterial abundance analysis and scanning electron microscopy showed that baicalein inhibited the proliferation of Escherichia coli by destroying its cell wall. The molecular dynamics and site-directed mutagenesis results revealed the structural basis for the inhibition of β-GUS by baicalein and baicalin. The results above provide a new idea for the development of drug therapy for adjuvant chemotherapy and theoretical guidance for the optimization of molecular structure targeting β-GUS. [ABSTRACT FROM AUTHOR]

Increasing researches reveal gut microbiota was associated with the development of tuberculosis (TB). How to prevent or reduce Mycobacterium tuberculosis colonization in the lungs is a key measure to prevent TB. However, the data on gut microbiota preventing Mycobacterium colonization in the lungs were scarce. Here, we established the clindamycin-inducing intestinal microbiome dysbiosis and fecal microbial transplantation models in mice to identify gut microbiota's effect on Mycobacterium's colonization in the mouse lungs and explore its potential mechanisms. The results showed that clindamycin treatment altered the diversity and composition of the intestinal bacterial and fungal microbiome, weakened the trans-kingdom network interactions between bacteria and fungi, and induced gut microbiome dysbiosis in the mice. Gut microbiota dysbiosis increases intestinal permeability and enhances the susceptibility of Mycobacterium colonization in the lungs of mice. The potential mechanisms were gut microbiota dysbiosis altered the lung transcriptome and increased Nos2 expression through the 'gut-lung axis'. Nos2 high expression disrupts the intracellular antimicrobial and anti-inflammatory environment by increasing the concentration of nitric oxide, decreasing the levels of reactive oxygen species and Defb1 in the cells, and promoting Mycobacteria colonization in the lungs of mice. The present study raises a potential strategy for reducing the risks of Mycobacteria infections and transmission by regulating the gut microbiome balance. [ABSTRACT FROM AUTHOR]

BACKGROUND RESULTS CONCLUSION Postweaning intestinal damage in piglets is a challenging issue in the livestock industry. Short‐chain fatty acids (SCFAs) are important metabolic products of the gut microbiota and are widely recognized for their role in maintaining normal colonic function and regulating the intestinal immune system. However, the effects of branched short‐chain fatty acid (BSCFA) isobutyrate on intestinal health remain largely unknown. This study aims to explore the potential of isobutyrate for alleviating postweaning intestinal damage.This study indicates that isobutyrate can alleviate diarrhea in weaned piglets, enhance their growth performance, and optimize the gut microbiota. This is mainly achieved through increasing the relative abundance of probiotic bacteria such as Lactobacillus, Megasphaera, and Prevotellaceae_UCG‐003, while concurrently reducing the relative abundance of potentially harmful bacteria such as Clostridium_sensu_stricto‐1 and Escherichia‐Shigella. It promotes the production of SCFAs, including acetate, isobutyrate, and butyrate. Furthermore, it activates G‐protein‐coupled receptors (GPR43/109A), inhibits the TLR4/MyD88 signaling pathway, strengthens the intestinal barrier function, and regulates the expression of related cytokines.In summary, exogenous isobutyrate can be considered a promising feed additive for improving the intestinal microbiota and regulating intestinal health in piglets. © 2024 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

The gastrointestinal tract's epithelial barrier plays a crucial role in maintaining health. This study aims to investigate the impact of glutamine supplementation on intestinal permeability, considering its importance for immune function and nutrient absorption. The study adhered to the PRISMA protocol for systematic reviews and meta-analyses. A systematic search was performed in four databases (PubMed, Scopus, Web of Science, and Google Scholar) until April 2023 to identify clinical trials on glutamine supplementation and gastrointestinal permeability. Eligibility criteria included randomized placebo-controlled trials measuring gut permeability post-glutamine supplementation. Studies were included regardless of language or publication date. Data extraction involved study characteristics, intervention details, and outcomes. Quality assessment was performed using the Cochrane tool, and statistical analysis utilized mean differences and standard deviations with a random effects model. Subgroup analysis was conducted to explore heterogeneity. The systematic review and meta-analysis included 10 studies from 1998 to 2014 with 352 participants. A total of 216 patients were enrolled in the intervention group, and 212 in the control group. The mean participant age was 46.52 years. The participants had different types of diseases in terms of their health status. Overall, glutamine supplementation did not significantly affect intestinal permeability (WMD: −0.00, 95% CI −0.04, 0.03). Subgroup analysis showed a significant reduction in intestinal permeability with doses over 30g/day (WMD: −0.01, 95% CI −0.10, −0.08). The glutamine supplements were administered orally in all included studies. The meta-analysis demonstrated a significant reduction in intestinal permeability with glutamine supplementation exceeding 30 mg/day for durations of less than 2 weeks. Further investigations with varying dosages and patient populations are warranted to enhance understanding and recommendations regarding glutamine supplementation's effects on gut permeability. [ABSTRACT FROM AUTHOR]

Insulin resistance (IR) is a pathogenic factor in numerous metabolic diseases. The gut microbiota plays a crucial role in maintaining the function of the intestinal barrier and overall human health, thereby influencing IR. Dysbiosis of the gut microbiota can contribute to the development of IR. Therefore, it is essential to maintain a balanced and diverse gut microbiota for optimal health. Akkermansia muciniphila, a widely present microorganism in the human intestine, has been shown to regulate gastrointestinal mucosal barrier integrity, reduce endotoxin penetration, decrease systemic inflammation levels, and improve insulin sensitivity. Reduced abundance of A. muciniphila is associated with an increased risk of IR and other metabolic diseases, highlighting its correlation with IR. Understanding the role and regulatory mechanism of A. muciniphila is crucial for comprehending IR pathogenesis and developing novel strategies for preventing and treating related metabolic disorders. Individual variations may exist in both the gut microbiota composition and its impact on IR among different individuals. Further investigation into individual differences between A. muciniphila and IR will facilitate advancements in personalized medicine by promoting tailored interventions based on the gut microbiota composition, which is a potential future direction that would optimize insulin sensitivity while preventing metabolic disease occurrence. In this review, we describe the physiological characteristics of A. muciniphila, emphasize its roles in underlying mechanisms contributing to IR pathology, and summarize how alterations in its abundance affect IR development, thereby providing valuable insights for further research on A. muciniphila, as well as new drug development targeting diabetes. [ABSTRACT FROM AUTHOR]

Introduction: The incidence of type-1 diabetes is on the rise, particularly in developed nations, and predominantly affects the youth. While genetic predisposition plays a substantial role, environmental factors, including alterations in the gut microbiota, are increasingly recognized as significant contributors to the disease. Methods: In this study, we utilized germ-free non-obese diabetic mice to explore the effects of microbiota colonization during early life on type-1 diabetes susceptibility. Results: Our findings reveal that microbiota introduction at birth, rather than at weaning, significantly reduces the risk of type-1 diabetes, indicating a crucial window for microbiota-mediated modulation of immune responses. This protective effect was independent of alterations in intestinal barrier function but correlated with testosterone levels in male mice. Additionally, early life colonization modulated T cell subset frequencies, particularly T helper cells and regulatory T cells, in the intestine, potentially shaping type-1 diabetes predisposition. Discussion: Our findings underscore the pivotal role of early-life microbial interactions in immune regulation and the development of autoimmune diseases. [ABSTRACT FROM AUTHOR]

A commentary published in Frontiers in Immunology explores the potential connection between gut dysbiosis and chronic pain. The study reviewed in the commentary found that individuals with chronic pain had imbalances in their gut microbiota, specifically a decrease in diversity and an increase in the genus Eggerthella. The commentary discusses the impact of Eggerthella on chronic pain, focusing on its involvement in dopamine metabolism and the regulation of female hormones. The findings suggest that combination therapies targeting both dopamine and estrogen pathways may be helpful in treating chronic pain. The article emphasizes the potential role of the gut microbiota in chronic pain and calls for further research to determine if it can be targeted for therapeutic interventions. [Extracted from the article]

Background: Enterotoxigenic Escherichia coli (E. coli) is a threat to humans and animals that causes intestinal disorders. Antimicrobial resistance has urged alternatives, including Lactobacillus postbiotics, to mitigate the effects of enterotoxigenic E. coli. Methods: Forty-eight newly weaned pigs were allotted to NC: no challenge/no supplement; PC: F18+ E. coli challenge/no supplement; ATB: F18+ E. coli challenge/bacitracin; and LPB: F18+ E. coli challenge/postbiotics and fed diets for 28 d. On d 7, pigs were orally inoculated with F18+ E. coli. At d 28, the mucosa-associated microbiota, immune and oxidative stress status, intestinal morphology, the gene expression of pattern recognition receptors (PRR), and intestinal barrier function were measured. Data were analyzed using the MIXED procedure in SAS 9.4. Results: PC increased (P < 0.05) Helicobacter mastomyrinus whereas reduced (P < 0.05) Prevotella copri and P. stercorea compared to NC. The LPB increased (P < 0.05) P. stercorea and Dialister succinatiphilus compared with PC. The ATB increased (P < 0.05) Propionibacterium acnes, Corynebacterium glutamicum, and Sphingomonas pseudosanguinis compared to PC. The PC tended to reduce (P = 0.054) PGLYRP4 and increased (P < 0.05) TLR4, CD14, MDA, and crypt cell proliferation compared with NC. The ATB reduced (P < 0.05) NOD1 compared with PC. The LPB increased (P < 0.05) PGLYRP4, and interferon-γ and reduced (P < 0.05) NOD1 compared with PC. The ATB and LPB reduced (P < 0.05) TNF-α and MDA compared with PC. Conclusions: The F18+ E. coli challenge compromised intestinal health. Bacitracin increased beneficial bacteria showing a trend towards increasing the intestinal barrier function, possibly by reducing the expression of PRR genes. Lactobacillus postbiotics enhanced the immunocompetence of nursery pigs by increasing the expression of interferon-γ and PGLYRP4, and by reducing TLR4, NOD1, and CD14. [ABSTRACT FROM AUTHOR]

Background: Aflatoxin B1 (AFB1) is a prevalent contaminant in agricultural products, presenting significant risks to animal health. CotA laccase from Bacillus licheniformis has shown significant efficacy in degrading mycotoxins in vitro test. The efficacy of Bacillus CotA laccase in animals, however, remains to be confirmed. A 2 × 2 factorial design was used to investigate the effects of Bacillus CotA laccase level (0 or 1 U/kg), AFB1 challenge (challenged or unchallenged) and their interactions on ducks. The purpose of this study was to evaluate the efficacy of Bacillus CotA laccase in alleviating AFB1 toxicosis of ducks. Results: Bacillus CotA laccase alleviated AFB1-induced declines in growth performance of ducks accompanied by improved average daily gain (ADG) and lower feed/gain ratio (F/G). Bacillus CotA laccase ameliorated AFB1-induced gut barrier dysfunctions and inflammation testified by increasing the jejunal villi height/crypt depth ratio (VH/CD) and the mRNA expression of tight junction protein 1 (TJP1) and zonula occluden-1 (ZO-1) as well as decreasing the expression of inflammation-related genes in the jejunum of ducks. Amino acid metabolome showed that Bacillus CotA laccase ameliorated AFB1-induced amino acid metabolism disorders evidenced by increasing the level of glutamic acid in serum and upregulating the expression of amino acid transport related genes in jejunum of ducks. Bacillus CotA laccase ameliorated AFB1-induced liver injury testified by suppressing oxidative stress, inhibiting apoptosis, and downregulating the expression of hepatic metabolic enzyme related genes of ducks. Moreover, Bacillus CotA laccase degraded AFB1 in digestive tract of ducks, resulting in the reduced absorption level of AFB1 across intestinal epithelium testified by the decreased level of AFB1-DNA adduct in the liver, and the reduced content of AFB1 residues in liver and feces of ducks. Conclusions: Bacillus CotA laccase effectively improved the growth performance, intestinal health, amino acid metabolism and hepatic aflatoxin metabolism of ducks fed AFB1 diets, highlighting its potential as an efficient and safe feed enzyme for AFB1 degradation in animal production. [ABSTRACT FROM AUTHOR]

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Background: Oral dose formulations must be soluble in gastrointestinal fluids for systemic absorption. The solubility of meloxicam was determined in 16 different age-specific simulated gastric and intestinal media that mirrored the microenvironments in pediatrics and adults. Methods: The solubility of meloxicam in the 16 different age-specific simulated gastric and intestinal biorelevant media was assessed using the standard US pharmacopeial method. The molecular descriptors of meloxicam were used to assess its intestinal permeability. Results: Meloxicam exhibited low solubility in the age-specific simulated gastric media for fasted and fed states and in pediatrics and adults. Similarly, meloxicam exhibited low solubility in the age-specific simulated media that mirrored neonates fed cow milk-based formula. On the other hand, meloxicam exhibited high solubility in the rest of the age-specific pediatric and adult intestinal media that simulated the fasted and fed states. The pediatric-to-adult solubility ratios were outside the 80–125% range in 7 (58.3%) and was borderline in 1 (8.3%) out of the 12 calculated ratios. These findings indicated that the solubility of meloxicam showed clinically significant differences in 8 (66.7%) of the compared media. Conclusion: Meloxicam exhibited low solubility in the age-specific simulated gastric media and high solubility in the simulated intestinal media for adults and pediatrics. Moreover, the pediatric-to-adult solubility ratios may have clinically significant implications. These differences can be translated into a higher likelihood of failing to demonstrate bioequivalence of different formulations containing meloxicam and variabilities in the performance of these formulations. [ABSTRACT FROM AUTHOR]

Endotoxemia is closely related to many diseases. As the largest endotoxin reservoir in the human body, the gut microbiota should be a key target for alleviating endotoxemia. The intestinal microbiota is believed to cause endotoxemia directly or indirectly by modifying the intestinal barrier function through dysbiosis, changing intestinal mucosal permeability and bacterial translocation. Diet is known to be the main environmental factor affecting the intestinal microbiota, and different diets and food components have a large impact on the gut microbiota. The Mediterranean diet, which received much attention in recent years, is believed to be able to regulate the gut microbiota, thereby maintaining the function of the intestinal barrier and alleviating endotoxemia. In this review, we focus on the relationship between the gut microbiota and endotoxemia, and how the Mediterranean dietary (MD) pattern can interfere with endotoxemia through the gut microbiota. [ABSTRACT FROM AUTHOR]

Background: Recently, there has been increasing interest in the possible role of the gut microbiota (GM) in the onset of migraine. Our aim was to verify whether bacterial populations associated with intestinal dysbiosis are found in pediatric patients with migraine. We looked for which metabolic pathways, these bacteria were involved and whether they might be associated with gut inflammation and increased intestinal permeability. Methods: Patients aged between 6 and 17 years were recruited. The GM profiling was performed by the 16S rRNA metataxonomics of faecal samples from 98 patients with migraine and 98 healthy subjects. Alpha and beta diversity analyses and multivariate and univariate analyses were applied to compare the gut microbiota profiles between the two group. To predict functional metabolic pathways, we used phylogenetic analysis of communities. The level of indican in urine was analyzed to investigate the presence of metabolic dysbiosis. To assess gut inflammation, increased intestinal permeability and the mucosal immune activation, we measured the plasmatic levels of lipopolysaccharide, occludin and IgA, respectively. Results: The α-diversity analysis revealed a significant increase of bacterial richness in the migraine group. The β-diversity analysis showed significant differences between the two groups indicating gut dysbiosis in patients with migraine. Thirty-seven metabolic pathways were increased in the migraine group, which includes changes in tryptophan and phenylalanine metabolism. The presence of metabolic dysbiosis was confirmed by the increased level of indican in urine. Increased levels of plasmatic occludin and IgA indicated the presence of intestinal permeability and mucosal immune activation. The plasmatic LPS levels showed a low intestinal inflammation in patients with migraine. Conclusions: Pediatric patients with migraine present GM profiles different from healthy subjects, associated with metabolic pathways important in migraine. [ABSTRACT FROM AUTHOR]

Background: Our previous study has demonstrated a decreased colonic CD8+CD39+ T cells, enrichment of granzyme A (GZMA), was found in pediatric-onset colitis and inflammatory bowel disease (IBD) characterized by impaired intestinal barrier function. However, the influence of GZMA on intestinal barrier function remains unknown. Methods: Western blotting(WB), real-time PCR (qPCR), immunofluorescence (IF) and in vitro permeability assay combined with intestinal organoid culture were used to detect the effect of GZMA on intestinal epithelial barrier function in vivo and in vitro. Luciferase, immunoprecipitation (IP) and subcellular fractionation isolation were performed to identify the mechanism through which GZMA modulated intestinal epithelial barrier function. Results: Herein, we, for the first time, demonstrated that CD8+CD39+ T cells promoted intestinal epithelial barrier function through GZMA, leading to induce Occludin(OCLN) and Zonula Occludens-1(ZO-1) expression, which was attributed to enhanced CDX2-mediated cell differentiation caused by increased glutathione peroxidase 4(GPX4)-induced ferroptosis inhibition in vivo and in vitro. Mechanically, GZMA inhibited intestinal epithelial cellular PDE4B activation to trigger cAMP/PKA/CREB cascade signaling to increase CREB nuclear translocation, initiating GPX4 transactivity. In addition, endogenous PKA interacted with CREB, and this interaction was enhanced in response to GZMA. Most importantly, administration of GZMA could alleviate DSS-induced colitis in vivo. Conclusion: These findings extended the novel insight of GZMA contributed to intestinal epithelial cell differentiation to improve barrier function, and enhacement of GZMA could be a promising strategy to patients with IBD. [ABSTRACT FROM AUTHOR]

[Display omitted] • EA alleviates depression-like behaviors in CUMS rats. • EA reduces intestinal damage and adjusting GM in CUMS rats. • Changes in the 4 lipid metabolites were associated with EA-induced changes in GM. This study aims to investigate the effect of electroacupuncture (EA) treatment on depression, and the potential molecular mechanism of EA in depression-like behaviors rats. A total of 40 male Sprague Dawley rats were divided into three groups: normal control, chronic unpredictable mild stress (CUMS), and EA (CUMS + EA). The rats in CUMS and EA groups underwent chronic stress for 10 weeks, and EA group rats received EA treatment for 4 weeks starting from week 7. Body weight and behavioral tests, including the sucrose preference test (SPT), the forced swimming test (FST), and the open field test (OFT) were monitored. Gut microbiota composition was assessed via 16S rDNA sequencing, and lipid metabolism was analyzed by using UPLC-Q-TOF/MS technology. In comparison to CUMS group, EA could improve the behavior including bodyweight, immovability time, sucrose preference index, crossing piece index and rearing times index. After 4 weeks of EA treatment, 5-HT in hippocampus, serum and colon of depressive rats were simultaneously increased, indicating a potential alleviation of depression-like behaviors. In future studies revealed that EA could regulate the distribution and functions of gut microbiota, and improve the intestinal barrier function of CUMS rats. The regulation of intestinal microbial homeostasis by EA may further affect lipid metabolism in CUMS rats, and thus play an antidepressant role. This study suggested that EA has potential antidepressant effects by regulating gut microbiota composition and abundance, subsequently affecting lipid metabolism. [ABSTRACT FROM AUTHOR]

Introduction: Visceral pain represents the most common digestive issue, frequently resulting from long-term inflammation, such as inflammatory bowel diseases. The lack of effective drugs prompted search of new therapeutic approaches. In this regard, gamma-aminobutyric acid (GABA) and Melissa officinalis (Mo) appear as excellent candidates as they were recognized to have several positive effects on the digestive system. The aim of this research was to evaluate the effects of a compound containing GABA and Mo (GABA-Mo 5:1) in inflammation-induced intestinal damage and visceral pain. Methods: Colitis was induced in rats by intrarectal 2,4-dinitrobenzenesulfonic acid (DNBS) administration. DNBS-treated animals received GABA-Mo (80 mg/kg BID), starting 3 days before DNBS administration, until 14 days after colitis induction (preventive protocol), or starting 7 days after DNBS until day 21 (curative protocol). Visceral pain was assessed by measuring the visceromotor response (VMR) and the abdominal withdrawal reflex (AWR) to colorectal distension on day 7, 14 (both protocols) and 21 (curative protocol) after DNBS administration. Results: In the preventive protocol, GABA-Mo reduced AWR at day 14 but had no effect on VMR. In the spinal cord, treatment with GABA-Mo significantly prevented microglia reactivity (Iba-1 positive cells). In the colon, the supplement significantly decreased malondialdehyde (MDA, index of oxidative stress) and IL-1ß levels and counteracted the decreased expression of claudin-1. Moreover, GABA-Mo normalized the increased levels of plasma lipopolysaccharide binding protein (LBP, index of altered intestinal permeability). In the curative protocol, GABA-Mo significantly counteracted visceral hypersensitivity persistence in DNBS-treated animals (day 14 and 21). In the spinal cord, GABA-Mo significantly reduced GFAP positive cell density (astrocytes). Histological evaluations highlighted a mild but significant effect of GABA-Mo in promoting healing from DNBS-induced colon damage. Colonic MDA and myeloperoxidase (index of leukocyte infiltration) levels were reduced, while the decreased colonic claudin-1 expression was normalized. In addition, the increased levels of plasma LBP were normalized by GABA-Mo administration. Discussion: In conclusion GABA-Mo, particularly in the curative protocol, was able to reduce visceral pain and intestinal inflammation, likely through a reinforcement of intestinal barrier integrity, thus representing a suitable approach for the management of abdominal pain, especially in the remission stages of colitis. [ABSTRACT FROM AUTHOR]

Numerous studies highlight the potential of natural antioxidants, such as those found in foods and plants, to prevent or treat nonalcoholic fatty liver disease (NAFLD). Inflammation is a key factor in the progression from high‐fat diet‐induced NAFLD to nonalcoholic steatohepatitis (NASH). Injured liver cells and immune cells release inflammatory cytokines, activating hepatic stellate cells. These cells acquire a profibrogenic phenotype, leading to extracellular matrix accumulation and fibrosis. Persistent fibrosis can progress to cirrhosis. Fatty infiltration, oxidative stress, and inflammation exacerbate fatty liver diseases. Thus, many plant‐derived antioxidants, like silymarin, silibinin, curcumin, resveratrol, berberine, and quercetin, have been extensively studied in experimental models and clinical patients with NAFLD. Experimentally, these compounds have shown beneficial effects in reducing lipid accumulation, oxidative stress, and inflammatory markers by modulating the ERK, NF‐κB, AMPKα, and PPARγ pathways. They also help decrease metabolic endotoxemia, intestinal permeability, and gut inflammation. Clinically, silymarin and silibinin have been found to reduce transaminase levels, while resveratrol and curcumin help alleviate inflammation in NAFLD patients. However, these phytocompounds exhibit poor water solubility, leading to low oral bioavailability and hindering their biological efficacy. Additionally, inconclusive clinical results highlight the need for further trials with larger populations, longer durations, and standardized protocols. Significance Statement: This review explores hepatoprotective phytochemicals for nonalcoholic fatty liver disease at the molecular level. Existing literature supports that silymarin, silibinin, resveratrol, curcumin, and berberine exhibit antioxidant and anti‐inflammatory properties by inhibiting inflammatory pathways, while also mitigating metabolic endotoxemia, intestinal permeability, and gut inflammation. However, their poor solubility and limited oral bioavailability in clinical settings reduce their potential benefits for patients with nonalcoholic fatty liver disease. [ABSTRACT FROM AUTHOR]

Background: Immune stressors, such as lipopolysaccharides (LPS), profoundly affect microbiota balance, leading to gut dysbiosis. This imbalance disrupts the metabolic phenotype and structural integrity of the gut, increasing intestinal permeability. During puberty, a critical surge in estrogen levels is crucial for mammary gland development. However, inflammation originating from the gut in this period may interfere with this development, potentially heightening breast cancer risk later. The long‐term effects of pubertal inflammation on mammary development and breast cancer risk are underexplored. Such episodes can dysregulate cytokine levels and microRNA expression, altering mammary cell gene expression, and predisposing them to tumorigenesis. Methods: This study hypothesizes that prebiotics, specifically Lentinula edodes Cultured Extract (AHCC), can counteract LPS's adverse effects. Using BALB/c mice, an acute LPS dose was administered at puberty, and breast cancer predisposition was assessed at 13 weeks. Cytokine and tumor‐related microRNA levels, tumor development, and cancer stem cells were explored through immunoassays and qRT‐PCR. Results: Results show that LPS induces lasting effects on cytokine and microRNA expression in mammary glands and tumors. AHCC modulates cytokine expression, including IL‐1β, IL‐17A/F, and IL‐23, and mitigates LPS‐induced IL‐6 in mammary glands. It also regulates microRNA expression linked to tumor progression and suppression, particularly counteracting the upregulation of oncogenic miR‐21, miR‐92, and miR‐155. Although AHCC slightly alters some tumor‐suppressive microRNAs, these changes are modest, highlighting a complex regulatory role that warrants further study. Conclusion: These findings underscore the potential of dietary interventions like AHCC to mitigate pubertal LPS‐induced inflammation on mammary gland development and tumor formation, suggesting a preventive strategy against breast cancer. [ABSTRACT FROM AUTHOR]

Background: Considering the increasing worldwide prevalence of inflammatory bowel disease (IBD), the early diagnosis of this disease is extremely important. However, non-invasive diagnostic methods remain limited, while invasive techniques are the most commonly used in daily practice. Therefore, there is a serious need to find new non-invasive biomarkers of IBD. Methods: The serum profiles of occludin, claudin-2, and zonulin were assessed in IBD patients using the ELISA method. The levels of the analyzed biomarkers were measured before and after a year of anti-inflammatory treatment, which was a tumor necrosis factor α (TNF-α) inhibitor (adalimumab) in patients with ulcerative colitis (UC) and conventional therapy in patients with Crohn's disease (CD). Results: In IBD patients, the serum level of occludin (p < 0.001) decreased compared to healthy individuals, while the level of claudin-2 (p < 0.001) increased. Additionally, zonulin (p < 0.01) concentration increased in CD patients compared to the control group. The highest diagnostic ability was presented by occludin measurements with the area under the curve (AUC) of 0.959 (95% CI 0.907–1) in UC and 0.948 (95% CI 0.879–1) in CD. Claudin-2 also demonstrated very good ability in diagnosing UC and CD with AUC values of 0.864 (95% CI 0.776–0.952) and 0.896 (95% CI 0.792–0.999), respectively. The ability of zonulin to diagnose CD was estimated as good with an AUC of 0.74 (95% CI 0.598–0.881). Moreover, a significant correlation was identified between C-reactive protein (CRP), claudin-2 (r = −0.37; p < 0.05), and zonulin (r = −0.44; p < 0.05) in UC patients. Treatment with adalimumab improved the level of occludin, claudin-2, and zonulin in UC patients, while anti-inflammatory conventional therapy decreased the concentration of zonulin in CD. Conclusions: Occludin and claudin-2 measurements present significant utility in diagnosing both UC and CD, while zonulin assessments may be useful in CD diagnosis. Additionally, claudin-2 and zonulin measurements may be helpful in evaluating the intensity of the inflammatory process. Anti-TNF-α treatment improved the value of occludin, claudin-2, and zonulin, indicating its beneficial effect on the integrity of tight junctions in UC. [ABSTRACT FROM AUTHOR]

Background Immunoglobulin A nephropathy (IgAN) is a major cause of primary glomerulonephritis characterized by mesangial deposits of galactose-deficient IgA1 (Gd-IgA1). Toll-like receptors (TLRs), particularly TLR4, are involved in the pathogenesis of IgAN. The role of gut microbiota on IgAN patients was recently investigated. However, whether gut microbial modifications of Gd-IgA1 through TLR4 play a role in IgAN remains unclear. Methods We recruited subjects into four groups, including 48 patients with untreated IgAN, 22 treated IgAN patients (IgANIT), 22 primary membranous nephropathy and 31 healthy controls (HCs). Fecal samples were collected to analyze changes in gut microbiome. Gd-IgA1 levels, expression of TLR4, B-cell stimulators and intestinal barrier function were evaluated in all subjects. C57BL/6 mice were treated with a broad-spectrum antibiotic cocktail to deplete the gut microbiota and then gavaged with fecal microbiota transplanted from clinical subjects of every group. Gd-IgA1 and TLR4 pathway were detected in peripheral blood mononuclear cells (PBMCs) from IgAN and HCs co-incubated with lipopolysaccharide (LPS) and TLR4 inhibitor. Results Compared with the other three groups, different compositions and decreased diversity demonstrated gut dysbiosis in the untreated IgAN group, especially the enrichment of Escherichia-Shigella. Elevated Gd-IgA1 levels were found in untreated IgAN patients and correlated with gut dysbiosis, TLR4, B-cell stimulators, indexes of intestinal barrier damage and proinflammatory cytokines. In vivo , mice colonized with gut microbiota from IgAN and IgANIT patients mimicked the IgAN phenotype with the activation of TLR4/MyD88/nuclear factor-κB pathway and B-cell stimulators in the intestine, and had with enhanced proinflammatory cytokines. In vitro , LPS activated TLR4/MyD88/NF-κB pathway, B-cell stimulators and proinflammatory cytokines in PBMCs of IgAN patients. This process may induce the overproduction of Gd-IgA1, which was inhibited by TLR4 inhibitors. Conclusions Our results illustrated that the gut–kidney axis is involved in the pathogenesis of IgAN. Gut dysbiosis could stimulate the overproduction of Gd-IgA1 via TLR4 signaling pathway production and B-cell stimulators. [ABSTRACT FROM AUTHOR]

Simple Summary: The use of fermented agricultural by-products as novel feed additives to improve animal health and livestock production has attracted attention due to their enhanced nutritional values after fermentation. Blueberry pomace, rich in bioactive substances, has health benefits. This study investigated the effects of fermented blueberry pomace on intestinal health in late-phase laying hens. The findings indicated that dietary fermented blueberry pomace supplementation could improve small intestinal barrier function and modulate cecal microbiota in laying hens during the late laying period and thus could be a potential feed additive in poultry production. This study aimed to investigate the effects of fermented blueberry pomace (FBP) on the intestinal barrier function and cecal microbiome of aged laying hens. A total of 320 Yukou Jingfen No. 8 laying hens (345-day-old) were randomly divided into a control group, 0.25% FBP group, 0.5% FBP group, or 1.0% FBP group. The results showed that the villus height (VH) in the jejunum of the 0.25–0.5% FBP groups and villus surface area in the jejunum of the 0.25% FBP group were higher (p < 0.05), while 0.25% FBP supplementation displayed a higher (p = 0.070) VH in the ileum compared to the control group. Mucin-2 expression was upregulated (p < 0.05) in the jejunum of the 0.5% FBP group and the ileum of the 0.25–0.5% FBP groups. Compared to the control group, interleukin (IL)-4 and IL-13 expressions were upregulated (p < 0.05) in the 1.0% FBP group. Microbiota analysis revealed that Prevotella abundance in the cecum of the 0.5–1.0% FBP groups was higher (p < 0.05) than in the 0.25% FBP group. In addition, microbial function prediction analysis showed that cecal microbiota in the 0.25% FBP group were mainly enriched by alanine/aspartate/glutamate metabolism and methane metabolism. Moreover, Spearman's correlation analysis revealed the potential correlations between the abundance of the cecal microbiota and intestinal-barrier-function-related gene expressions, as well as the short-chain fatty acid content, of laying hens. In summary, dietary FBP supplementation enhanced intestinal barrier function by improving intestinal morphology, upregulating gene expressions related to barrier function, and altering the cecal microbiota of aged laying hens. [ABSTRACT FROM AUTHOR]

Cannabidiol (CBD) is a major non-psychotropic phytocannabinoid that exists in the Cannabis sativa plant. CBD has been found to act on various receptors, including both cannabinoid and non-cannabinoid receptors. In addition, CBD has antioxidant effects that are independent of receptors. CBD has demonstrated modulatory effects at different organ systems, such as the central nervous system, immune system, and the gastrointestinal system. Due to its broad effects within the body and its safety profile, CBD has become a topic of therapeutic interest. This literature review summarizes previous research findings with regard to the effect of CBD on the gastrointestinal (GI) system, including its effects at the molecular, cellular, organ, and whole-body levels. Both pre-clinical animal studies and human clinical trials are reviewed. The results of the studies included in this literature review suggest that CBD has significant impact on intestinal permeability, the microbiome, immune cells and cytokines. As a result, CBD has been shown to have therapeutic potential for GI disorders such as inflammatory bowel disease (IBD). Furthermore, through interactions with the gut, CBD may also be helpful in the treatment of disorders outside the GI system, such as non-alcoholic liver disease, postmenopausal disorders, epilepsy, and multiple sclerosis. In the future, more mechanistic studies are warranted to elucidate the detailed mechanisms of action of CBD in the gut. In addition, more well-designed clinical trials are needed to explore the full therapeutic potential of CBD on and through the gut. [ABSTRACT FROM AUTHOR]

This study aimed to investigate the effects of dietary bacteriophage administration on diarrhea and intestinal impairment induced by enterotoxigenic Escherichia coli (ETEC) in a newly weaned mouse model. Forty-four newly weaned C57BL/6 mice were divided into four treatment groups, where they were provided either the control diet or the bacteriophage-supplemented diet, with or without ETEC infection. The results show that the bacteriophage administration resulted in increased body weight, decreased diarrhea score, and improved jejunal histopathology in ETEC-infected mice. The bacteriophage administration enhanced the intestinal barrier function of the ETEC-infected mice, as indicated by the reduced serum DAO level and the increased expression of Claudin-1, Occludin, and ZO-1 at both the mRNA and protein levels in the jejunum. Also, the bacteriophage administration resulted in a decrease in serum TNF-α and IL-1β levels, a down-regulation of TNF-α and IL-6 mRNA levels in the jejunum, and the inhibition of jejunal TLR-4/NF-κB pathway activation induced by ETEC infection. Moreover, the bacteriophage administration increased the levels of acetic acid, propionic acid, butyric acid, and total short-chain fatty acids in the caecum content. The bacteriophage administration increased the Shannon index, increased the abundance of Bacteroidota and Muribaculaceae, and decreased the abundance of Verrucomicrobiota and Akkermansiaceae in the colon contents of the ETEC-infected mice. Spearman's correlation analysis indicates that the protective effects of bacteriophage on ETEC-induced intestinal impairment, inflammation, and intestinal barrier function are associated with regulating the abundance of Bacteroidota and Muribaculaceae in the colon contents of mice. Collectively, bacteriophage administration alleviates ETEC-induced diarrhea and intestinal impairment through regulating intestinal inflammation and gut microbiota in newly weaned mice. [ABSTRACT FROM AUTHOR]

Ursolic acid (UA) has demonstrated significant immunomodulatory and hepatoprotective effects; however, the underlying mechanisms remain unclear. This study aims to analyze the impact of UA on the gut microbiome, metabolome, and liver transcriptome, investigate UA's role in maintaining gut immune homeostasis and liver health, and evaluate the potential contributions of gut microbes and their metabolites to these beneficial effects. Our findings indicate that UA enhances immune balance in the jejunum, fortifies intestinal barrier function, and promotes overall gut health. UA modulates the intestinal microbiota and its metabolic processes, notably increasing the abundance of beneficial bacteria such as Odoribacter and Parabacteroides, along with their metabolites, including ornithine and lactucin. Additionally, UA inhibits the expression of interleukin-1 receptor 1 (IL1R1) and calcium (Ca2+) voltage-gated channel auxiliary subunit beta 2 (CACNB2) while enhancing the synthesis pathways of retinol and ascorbic acid, thereby exerting a protective influence on liver function. In summary, UA enhances intestinal immune homeostasis and promotes liver health, with these advantageous effects potentially mediated by beneficial bacteria (Odoribacter and Parabacteroides) and their metabolites (ornithine and lactucin). [ABSTRACT FROM AUTHOR]

Type 1 Diabetes Mellitus (T1DM) is a chronic autoimmune disease that results in the destruction of pancreatic β cells, leading to hyperglycaemia and the need for lifelong insulin therapy. Although genetic predisposition and environmental factors are considered key contributors to T1DM, the exact causes of the disease remain partially unclear. Recent evidence has focused on the relationship between the gut, the oral cavity, immune regulation, and systemic inflammation. In individuals with T1DM, changes in the gut and oral microbial composition are commonly observed, indicating that dysbiosis may contribute to immune dysregulation. Gut dysbiosis can influence the immune system through increased intestinal permeability, altered production of short chain fatty acids (SCFAs), and interactions with the mucosal immune system, potentially triggering the autoimmune response. Similarly, oral dysbiosis may contribute to the development of systemic inflammation and thus influence the progression of T1DM. A comprehensive understanding of these relationships is essential for the identification of biomarkers for early diagnosis and monitoring, as well as for the development of therapies aimed at restoring microbial balance. This review presents a synthesis of current research on the connection between T1DM and microbiome dysbiosis, with a focus on the gut and oral microbiomes in pediatric populations. It explores potential mechanisms by which microbial dysbiosis contributes to the pathogenesis of T1DM and examines the potential of microbiome-based therapies, including probiotics, prebiotics, synbiotics, and faecal microbiota transplantation (FMT). This complex relationship highlights the need for longitudinal studies to monitor microbiome changes over time, investigate causal relationships between specific microbial species and T1DM, and develop personalised medicine approaches. [ABSTRACT FROM AUTHOR]

Irritable bowel syndrome (IBS) is a common chronic functional bowel disorder and is strongly associated with an increased risk of depression and anxiety. The brain–gut axis plays an important role in the pathophysiologic changes in IBS, yet effective treatments for IBS are still lacking. Sinisan, originating from the Treatise on Typhoid Fever by the medical sage Zhang Zhongjing, is a classic formula in the Eight Methods of Traditional Chinese Medicine (TCM) that focuses on dispersing the liver and regulating the spleen, relieving depression and transmitting evils, and has been widely used in the treatment of liver-depression and spleen-deficiency, diarrhea, and related liver and stomach disorders. However, the therapeutic effect of sinisan in IBS has not been clarified. The aim of this study was to investigate the effects of sinisan on stress-induced intestinal dysfunction and depressive behavior in IBS mice. We established a diarrhea-predominant irritable bowel syndrome (IBS-D) mouse model using a 4% acetic acid enema combined with restraint stress, and analyzed the results using behavioral tests, relevant test kits, hematoxylin-eosin (HE) staining, immunofluorescence (IF), Western blot (WB), and quantitative fluorescence polymerase chain reaction (qRT-PCR). The results showed that sinisan administration significantly alleviated intestinal dysfunction and depressive-like behaviors in IBS-D mice, improved mild colonic inflammation and intestinal mucosal permeability, up-regulated the expression of tight junction proteins ZO-1 and occludin. Sinisan significantly alleviated intestinal dysfunction and depressive-like behaviors in IBS-D mice by decreasing the expression of TNF-α, promoting the expression of tight junction proteins (occludin, ZO-1) expression, and inhibiting the Tlr4/Myd88 signaling pathway, thereby attenuating the inflammatory response, protecting the intestinal barrier, and alleviating symptoms in the IBS-D mouse model. Taken together, sinisan may ameliorate intestinal inflammation and the intestinal barrier by regulating 5-HT expression and the Tlr4/Myd88 pathway, thereby alleviating stress-induced intestinal dysfunction and depressive behaviors in IBS-D mice. [ABSTRACT FROM AUTHOR]

Increased intestinal permeability is a manifestation of cystic fibrosis (CF) in people with CF (pwCF) and in CF mouse models. CF transmembrane conductance regulator knockout (Cftr KO) mouse intestine exhibits increased proliferation and Wnt/β-catenin signaling relative to wild-type mice (WT). Since the Rho GTPase Cdc42 plays a central role in intestinal epithelial proliferation and tight junction remodeling, we hypothesized that Cdc42 may be altered in the Cftr KO crypts. Immunofluorescence showed distinct tight junction localization of Cdc42 in Cftr KO fresh crypts and enteroids, the latter indicating an epithelial-autonomous feature. Quantitative PCR and immunoblots revealed similar expression of Cdc42 in the Cftr KO crypts/enteroids relative to WT, whereas pulldown assays showed increased GTP-bound (active) Cdc42 in proportion to total Cdc42 in Cftr KO enteroids. Cdc42 activity in the Cftr KO and WT enteroids could be reduced by inhibition of the Wnt transducer Disheveled. With the use of a dye permeability assay, Cftr KO enteroids exhibited increased paracellular permeability to 3 kDa dextran relative to WT. Leak permeability and Cdc42 tight junction localization were reduced to a greater extent by inhibition of Wnt/β-catenin signaling with endo-IWR1 in Cftr KO relative to WT enteroids. Increased proliferation or inhibition of Cdc42 activity with ML141 in WT enteroids had no effect on permeability. In contrast, inhibition of Cdc42 with ML141 increased permeability to both 3 kDa dextran and tight junction impermeant 500 kDa dextran in Cftr KO enteroids. These data suggest that increased constitutive Cdc42 activity may alter the stability of paracellular permeability in Cftr KO crypt epithelium. NEW & NOTEWORTHY: Increased tight junction localization and GTP-bound activity of the Rho GTPase Cdc42 was identified in small intestinal crypts and enteroids of cystic fibrosis (CF) transmembrane conductance regulator knockout (Cftr KO) mice. The increase in epithelial Cdc42 activity was associated with increased Wnt signaling. Paracellular flux of an uncharged solute (3 kDa dextran) in Cftr KO enteroids indicated a moderate leak permeability under basal conditions that was strongly exacerbated by Cdc42 inhibition. These findings suggest increased activity of Cdc42 in the Cftr KO intestine underlies alterations in intestinal permeability. [ABSTRACT FROM AUTHOR]

Opioid receptors are found throughout the gastrointestinal tract, including the large intestine. Many patients treated with opioids experience opioid-induced constipation (OIC). Laxatives are not effective in most patients, and in those who do initially respond, the efficacy of laxatives generally diminishes over time. In addition, OIC does not spontaneously resolve for most patients. However, complications of opioids extend far beyond simply slowing gastrointestinal transit. Opioid use can affect intestinal permeability through a variety of mechanisms. Toll-like receptors are a crucial component of innate immunity and are tightly regulated within the gut epithelium. Pathologic m-opioid receptor (MOR) and toll-like receptor signaling, resulting from chronic opioid exposure, disrupts intestinal permeability leading to potentially harmful bacterial translocation, elevated levels of bacterial toxins, immune activation, and increased cytokine production. Peripherally active MOR antagonists, including methylnaltrexone, are effective at treating OIC. Benefits extend beyond simply blocking the MOR; these agents also act to ameliorate opioid-induced disrupted intestinal permeability. In this review, we briefly describe the physiology of the gastrointestinal epithelial border and discuss the impact of opioids on gastrointestinal function. Finally, we consider the use of peripherally activeMORantagonists to treat disrupted intestinal permeability resulting from opioid use and discuss the potential for improved morbidity and mortality in patients treated with methylnaltrexone for opioid-induced bowel disorders. [ABSTRACT FROM AUTHOR]

Gastrointestinal first‐pass metabolism plays an important role in bioavailability and in drug–drug interactions. Physiologically‐based pharmacokinetic (PBPK) modeling is a powerful tool to integrate these processes mechanistically. However, a correct bottom‐up prediction of GI first‐pass metabolism is challenging and depends on various model parameters like the level of enzyme expression and the basolateral intestinal mucosa permeability (Pmucosa). This work aimed to investigate if cytochrome P450 (CYP) 3A4 expression could help predict the first‐pass effect using PBPK modeling or whether additional factors like Pmucosa do play additional roles using PBPK modeling. To this end, a systematic review of the absolute CYP3A expression in the human gastrointestinal tract and liver was conducted. The resulting CYP3A4 expression profile and two previously published profiles were applied to PBPK models of seven CYP3A4 substrates (alfentanil, alprazolam, felodipine, midazolam, sildenafil, triazolam, and verapamil) built‐in PK‐Sim®. For each compound, it was assessed whether first‐pass metabolism could be adequately predicted based on the integrated CYP3A4 expression profile alone or whether an optimization of Pmucosa was required. Evaluation criteria were the precision of the predicted interstudy bioavailabilities and area under the concentration–time curves. It was found that none of the expression profiles provided upfront an adequate description of the extent of GI metabolism and that optimization of Pmucosa as a compound‐specific parameter improved the prediction of most models. Our findings indicate that a pure bottom‐up prediction of gastrointestinal first‐pass metabolism is currently not possible and that compound‐specific features like Pmucosa must be considered as well. [ABSTRACT FROM AUTHOR]

Purpose: Metformin (MTF) shows promise in protecting against physical decline in osteoarthritis (OA), but how it works remains unclear. We studied MTF's effects on gut permeability and its link to physical performance in OA patients. Methods: We studied four groups: control (n = 72), OA non-diabetic (n = 58), OA diabetic on MTF (n = 55), and OA diabetic on other anti-diabetics (n = 57). We measured zonulin levels, as intestinal permeability marker, hand-grip strength (HGS), Oxford knee scoring (OKS) to determine OA severity, and short performance physical battery (SPPB) to determine physical functions. Results: Patients suffering from OA showed a reduction in HGS and SPPB scores with raised plasma zonulin than controls, irrespective of disease severity. MTF decreased plasma zonulin levels and improved OKS, gait speed, HGS, and SPPB scores in OA patients. However, OA patients taking other anti-diabetic medications demonstrated higher levels of plasma zonulin, reduced HGS, and SPPB scores. Furthermore, a robust correlation of plasma zonulin and HGS, OKS, gait speed, and SPPB scores in OA patients on MTF was observed. Moreover, we found reduced oxidative stress and inflammation associated with these alterations in OA patients treated with MTF. Conclusion: MTF improves HGS and physical performance by lowering zonulin levels, preserving gut permeability in OA patients. [ABSTRACT FROM AUTHOR]

Inflammatory bowel diseases (IBD) are often associated with dysregulated gut microbiota and excessive inflammatory microenvironment. Probiotic therapy combined with inflammation management is a promising approach to alleviate IBD, but the efficacy is hindered by the inferior colonization of probiotics in mucus-depleted inflammatory bowel segments. Here, we present modified montmorillonite armed probiotic Escherichia coli Nissle 1917 (MMT-Fe@EcN) with enhanced intestinal colonization and hydrogen sulfide (H 2 S) scavenging for synergistic alleviation of IBD. The montmorillonite layer that can protect EcN against environmental assaults in oral delivery and improve on-site colonization of EcN in the mucus-depleted intestinal segment due to its strong adhesive capability and electronegativity, with a 22.6-fold increase in colonization efficiency compared to EcN. Meanwhile, MMT-Fe@EcN can manage inflammation by scavenging H 2 S, which allows for enhancing probiotic viability and colonization for restoring the gut microbiota. As a result, MMT-Fe@EcN exhibits extraordinary therapeutic effects in the dextran sulfate sodium-induced mouse colitis models, including alleviating intestinal inflammation and restoring disrupted intestinal barrier function, and gut microbiota. These findings provide a promising strategy for clinical IBD treatment and potentially other mucus-depletion-related diseases. We present modified montmorillonite armed probiotic Escherichia coli Nissle 1917 (MMT-Fe@EcN) with enhanced intestinal colonization and hydrogen sulfide (H 2 S) scavenging for synergistic alleviation of IBD. [Display omitted] • Montmorillonite coating enhanced on-site mucus-depleted intestinal colonization of probiotics. • Fe3+-modified Montmorillonite can scavenge elevated H 2 S and alleviate inflammatory factors, which allows for enhancing probiotic viability and colonization for restoring the gut microbiota. • Improved probiotic colonization and intestinal microenvironment regulation exhibited synergistic alleviation of inflammatory bowel disease. [ABSTRACT FROM AUTHOR]

Diacylglycerol O -acyltransferase 1 (DGAT1) is a key enzyme for fat absorption step in the enterocytes. We previously reported that DGAT1 inhibition increased plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities in corn oil-loaded rats via protein kinase C (PKC) activation. In the present study, we investigated the mechanism with respect to the morphology and permeability of the small intestine, focusing on PKC function, and found that shortening of the intestinal villi and a decrease in the number of tdT-mediated dUTP-biotin nick-end labeling-positive cells in the tips of the villi were observed in the jejunum of DGAT1 inhibitor-treated rats loaded with corn oil. These results suggested that the tips of the villi were shed into the intestinal lumen. Next, fluorescein isothiocyanate-dextran, 110 kDa (FD-110) was administered intraduodenally to DGAT1 inhibitor-treated rats loaded with corn oil and we found that plasma FD-110 concentrations increased, indicating that the intestinal permeability to molecules with a molecular weight of approximately 110,000 (e.g., ALT and AST) increased. Taken together, the present results suggested that DGAT1 inhibitor-treatment in combination with corn oil causes ALT and AST to leak from the enterocytes into the blood by shedding the tips of the intestinal villi and increasing intestinal permeability. • DGAT1 inhibitor shortens the intestinal villi in corn oil-loaded rats. • DGAT1 inhibitor reduces the number of TUNEL-positive cells in corn oil-loaded rats. • DGAT1 inhibitor increases intestinal permeability in corn oil-loaded rats. • DGAT1 inhibitor decreases TJ-related protein mRNA levels in corn oil-loaded rats. • Plasma ALT and AST increase by shedding the villi and increasing permeability. [ABSTRACT FROM AUTHOR]

With the aging global population, Alzheimer's disease (AD) has become a significant social and economic burden, necessitating the development of novel therapeutic strategies. This study investigates the therapeutic potential of nicotinamide mononucleotide (NMN) synbiotics, a combination of NMN, Lactiplantibacillus plantarum CGMCC 1.16089, and lactulose, in mitigating AD pathology. APP/PS1 mice were supplemented with NMN synbiotics and compared against control groups. The effects on amyloid-β (Aβ) deposition, intestinal histopathology, tight junction proteins, inflammatory cytokines, and reactive oxygen species (ROS) levels were assessed. NMN synbiotics intervention significantly reduced Aβ deposition in the cerebral cortex and hippocampus by 67% and 60%, respectively. It also ameliorated histopathological changes in the colon, reducing crypt depth and restoring goblet cell numbers. The expression of tight junction proteins Claudin-1 and ZO-1 was significantly upregulated, enhancing intestinal barrier integrity. Furthermore, NMN synbiotics decreased the expression of proinflammatory cytokines IL-1β, IL-6, and TNF-α, and reduced ROS levels, indicative of attenuated oxidative stress. The reduction in Aβ deposition, enhancement of intestinal barrier function, decrease in neuroinflammation, and alleviation of oxidative stress suggest that NMN synbiotics present a promising therapeutic intervention for AD by modulating multiple pathological pathways. Further research is required to elucidate the precise mechanisms, particularly the role of the NLRP3 inflammasome pathway, which may offer a novel target for AD treatment. [ABSTRACT FROM AUTHOR]

(1) Background: This study aimed to evaluate the effect of an extruded whole-grain sorghum beverage containing L. paracasei on body composition, lipid profiles, and intestinal health in overweight and obese adults. (2) Methods: A chronic, single-blind randomized controlled pilot study was conducted with 30 volunteers allocated to three groups (n = 10/group): extruded sorghum beverage (ESB), extruded sorghum beverage with L. paracasei (ESPB), and control beverage (CB) (waxy maize starch). The chemical composition of the beverages was analyzed. Volunteers consumed the beverages for ten weeks at breakfast, along with individual dietary prescriptions. Body composition, biochemical markers, gastrointestinal symptoms, stool consistency, intestinal permeability, short-chain fatty acids, fecal pH, and stool L. paracasei DNA concentration were analyzed at the beginning and end of the intervention period. (3) Results: The ESB showed better composition than the CB, particularly in terms of resistant starch content, total phenolic compounds, condensed tannins, and antioxidant capacity. Both the ESB and the ESPB had an effect on body composition (estimated total visceral fat and waist volume), biochemical markers (Castelli index I), and intestinal health (Bristol scale, diarrhea score, valeric acid, and L. paracasei DNA concentration). No changes were observed in the CB group after the intervention. (4) Conclusions: Whole-grain sorghum beverages demonstrated good nutritional value, and consumption of these beverages, with or without L. paracasei, provided health benefits, including improvements in body composition, Castelli index I scores, and intestinal health, in overweight and obese adults. [ABSTRACT FROM AUTHOR]

Osteoporosis is a disease characterized by abnormal bone metabolism, where bone resorption outpaces bone formation. In this study, we investigated the key functional components of Lactobacillus plantarum AR495 in mitigating ovariectomy (OVX)-induced osteoporosis in mice. The results indicated that both Lactobacillus plantarum AR495 and its fermentation broth significantly reduced urinary calcium and deoxypyridinoline (DPD) levels in the mice. These interventions inhibited bone resorption and improved trabecular bone architecture by modulating the nuclear factor κB (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG) signaling pathway. Additionally, the L. plantarum AR495 and fermentation broth groups inhibited the RANKL/TRAF-6 and TLR4/MYD88 pathways, leading to enhanced bone metabolism, improved intestinal barrier function, and reduced intestinal inflammation. In vitro experiments revealed that AR495 fermentation supernatant fractions larger than 100 kDa and those between 50–100 kDa significantly decreased the activity of the osteoclast marker TRAP, regulated the expression of the TLR4/MYD88 pathway, and inhibited osteoclast formation, thereby alleviating the OVX-induced osteoporosis phenotype. These findings suggest that these components may be primary functional elements of L. plantarum AR495 in the treatment of osteoporosis. [ABSTRACT FROM AUTHOR]

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This document is an editorial titled "Interactions between bioactive food ingredients and intestinal microbiota, volume II" published in the journal Frontiers in Microbiology. The editorial discusses the importance of understanding how different diets affect the gut microbiome and explores the connections between diet, host, and microbes for precision nutrition and microbiome-based therapies. It summarizes 15 publications in Volume II of the Research Topic, which include studies on the effects of various substances on the gut microbiome in healthy humans and patients with colorectal cancer and kidney disease. The editorial also highlights studies on mouse models of colitis to investigate the therapeutic potential of natural compounds and interventions for gut health. The research suggests that substances like puerarin, ursolic acid, red quinoa polysaccharide, okra polysaccharides, and hemp seed can improve gut health by restoring the composition and abundance of gut microbiota. The document concludes by stating that further research in this field is expected to have significant implications for human health. [Extracted from the article]