Mucosal Barrier Research Articles

Gingival spatial analysis reveals geographic immunological variation in a microbiota-dependent and -independent manner

In mucosal barriers, tissue cells and leukocytes collaborate to form specialized niches that support host-microbiome symbiosis. Understanding the spatial organization of these barriers is crucial for elucidating the mechanisms underlying health and disease. The gingiva, a unique mucosal barrier with significant health implications, exhibits intricate tissue architecture and likely contains specialized immunological regions. Through spatial transcriptomic analysis, this study reveals distinct immunological characteristics between the buccal and palate regions of the murine gingiva, impacting natural alveolar bone loss. The microbiota primarily affects gingival immunity in the buccal region. Additionally, a significant influence of the microbiota on the junctional epithelium facing the oral biofilm offers new insights into neutrophil recruitment. The microbiota also regulates the proliferation and barrier-sealing function of the gingival epithelium. This underscores the presence of immunological niches in the gingiva, with the microbiota differentially influencing them, highlighting the high complexity of this oral mucosal barrier.

Gut-Microbiota-Derived Butyric Acid Overload Contributes to Ileal Mucosal Barrier Damage in Late Phase of Chronic Unpredictable Mild Stress Mice

Intestinal mucosal barrier damage is regarded as the critical factor through which chronic unpredictable mild stress (CUMS) leads to a variety of physical and mental health problems. However, the exact mechanism by which CUMS induces intestinal mucosal barrier damage is unclear. In this study, 14, 28, and 42 d CUMS model mice were established. The indicators related to ileal mucosal barrier damage (IMBD), the composition of the ileal microbiota and its amino acid (AA) and short-chain fatty acid (SCFA) metabolic functions, and free amino acid (FAA) and SCFA levels in the ileal lumen were measured before and after each stress period. The correlations between them are analyzed to investigate how CUMS induces intestinal mucosal barrier damage in male C57BL/6 mice. With the progression of CUMS, butyric acid (BA) levels decreased (14 and 28 d) and then increased (42 d), and IMBD progressively increased. In the late CUMS stage (42 d), the degree of IMBD is most severe and positively correlated with significantly increased BA levels (p < 0.05) in the ileal lumen and negatively correlated with significantly decreased FAAs, such as aspartic, glutamic, alanine, and glycine levels (p < 0.05). In the ileal lumen, the abundance of BA-producing bacteria (Muribaculaceae, Ruminococcus, and Butyricicoccus) and the gene abundance of specific AA degradation and BA production pathways and their related enzymes are significantly increased (p < 0.05). In addition, there is a significant decrease (p < 0.05) in the abundance of core bacteria (Prevotella, Lactobacillus, Turicibacter, Blautia, and Barnesiella) that rely on these specific AAs for growth and/or are sensitive to BA. These changes, in turn, promote further colonization of BA-producing bacteria, exacerbating the over-accumulation of BA in the ileal lumen. These results were validated by ileal microbiota in vitro culture experiments. In summary, in the late CUMS stages, IMBD is related to an excessive accumulation of BA caused by dysbiosis of the ileal microbiota and its overactive AA degradation.

Neutral Polysaccharide from Platycodonis Radix-Ameliorated PM2.5-Induced Lung Injury by Inhibiting the TLR4/NF-κB p65 Pathway and Regulating the Lung and Gut Microbiome.

Platycodonis radix (PR) has been reported to play a protective role in lung injury. However, much less is known about the protective effect and mechanism of its main component PR polysaccharides (PRPs) in particulate matter (PM2.5)-induced lung injury. Here, a neutral polysaccharide (MW: 244.56 kDa) was isolated from PR, mainly composed of Rha, Ara, Gal, Glc, Xyl, and Man. PRPs significantly improved PM2.5-induced pulmonary edema, oxidative damage, and cell apoptosis and downregulated inflammatory factor levels in bronchoalveolar lavage fluid. Mechanistically, PRPs reduced intestinal mucosal barrier damage, thereby lowering serum lipopolysaccharide levels and inhibiting the overactivation of the TLR4/NF-κB signaling pathway in the lung tissue. Notably, PRPs could optimize the composition of pulmonary and intestinal microbiota. Oral administration of PRPs resulted in enrichment of short-chain fatty acid (SCFA)-producing bacteria, thereby upregulating the levels of acetate, butyrate, and isovalerate. Taken together, PRPs have great potential in preventing and repairing the lung injury caused by PM2.5.

The Influence and Mechanisms of Natural Plant Polysaccharides on Intestinal Microbiota-Mediated Metabolic Disorders

Natural plant polysaccharides are renowned for their broad spectrum of biological activities, making them invaluable in both the pharmaceutical and food industries. Their safety, characterized by low toxicity and minimal side effects, coupled with their potential therapeutic properties, positions them as crucial elements in health-related applications. The functional effectiveness of these polysaccharides is deeply connected to their structural attributes, including molecular weight, monosaccharide components, and types of glycosidic bonds. These structural elements influence how polysaccharides interact with the gut microbiota, potentially alleviating various metabolic and inflammatory disorders such as inflammatory bowel disease, diabetes, liver-associated pathologies, obesity, and kidney diseases. The polysaccharides operate through a range of biological mechanisms. They enhance the formation of short-chain fatty acids, which are pivotal in keeping intestinal health and metabolic balance. Additionally, they strengthen the intestinal mucosal barrier, crucial for deterring the ingress of pathogens and toxins into the host system. By modulating the immune responses within the gut, they help in managing immune-mediated disorders, and their role in activating specific cellular signaling pathways further underscores their therapeutic potential. The review delves into the intricate structure–activity relationships of various natural polysaccharides and their interactions with the intestinal flora. By understanding these relationships, the scientific community can develop targeted strategies for the use of polysaccharides in therapeutics, potentially leading to innovative treatments for a range of diseases. Furthermore, the insights gained can drive the advancement of research in natural polysaccharide applications, providing direction for novel dietary supplements and functional foods designed to support gut health and overall well-being.

The role of the mucosal barrier system in maintaining gut symbiosis to prevent intestinal inflammation.

In the intestinal tract, where numerous intestinal bacteria reside, intestinal epithelial cells produce and release various antimicrobial molecules that form a complex barrier on the mucosal surface. These barrier molecules can be classified into two groups based on their functions: those that exhibit bactericidal activity through chemical reactions, such as antimicrobial peptides, and those that physically hinder bacterial invasion, like mucins, which lack bactericidal properties. In the small intestine, where Paneth cells specialize in producing antimicrobial peptides, the chemical barrier molecules primarily inhibit bacterial growth. In contrast, in the large intestine, where Paneth cells are absent, allowing bacterial growth, the primary defense mechanism is the physical barrier, mainly composed of mucus, which controls bacterial movement and prevents their invasion of intestinal tissues. The expression of these barrier molecules is regulated by metabolites produced by bacteria in the intestinal lumen and cytokines produced by immune cells in the lamina propria. This regulation establishes a defense mechanism that adapts to changes in the intestinal environment, such as alterations in gut microbial composition and the presence of pathogenic bacterial infections. Consequently, when the integrity of the gut mucosal barrier is compromised, commensal bacteria and pathogenic microorganisms from outside the body can invade intestinal tissues, leading to conditions such as intestinal inflammation, as observed in cases of inflammatory bowel disease.

Altered O-Glycans in stimulated whole saliva from patients with primary Sjögren's syndrome and non-pSS sicca.

To investigate if salivary O-linked glycans are altered in primary Sjögren's syndrome (pSS), and thus contributing to explain symptoms of oral dryness, and an impaired oral mucosal barrier function leading to changes in microbial metabolism and colonization by both pathogenic and commensal microorganisms and increased prevalence of oral diseases. O-linked oligosaccharides from stimulated whole saliva (SWS) samples from 24 patients with pSS, 38 patients with non-pSS sicca, and 23 healthy controls were analyzed using liquid chromatography mass spectrometer (LC-MS). Non-fractionated reduced and alkylated saliva was dot-blotted to PVDF-membrane and O-linked oligosaccharides were released using reductive beta-elimination. The 50 most abundant glycans were identified and their intensity compared for each sample, reflecting the relative abundance of individual monosaccharide residues. Comparison of the compositions of O-glycans in SWS samples revealed higher relative levels of sialic acid (NeuAc) and lower levels of neutral amino-monosaccharides (HexNAc) in pSS and non-pSS sicca patients than in the healthy controls. MS2 fragmentation analysis of salivary O-glycans suggests that altered sulfation, fucosylation, sialylation and distribution of core types may all contribute to the observed alteration, directly or indirectly. Additionally, the short disaccharide sialyl-Tn was most abundant in the saliva samples from patients with pSS. Our findings indicate that the salivary mucin-type O-glycan profile is altered in pSS, reflecting a dysfunction of the post-translational modification of salivary mucins leading to rheological changes of saliva, oral dryness symptoms, and impaired oral mucosal barrier function. The pathophysiological significance of the aberrant O-glycosylation needs further elucidation.

Fucoidan Supplementation Relieved Kidney Injury and Modulated Intestinal Homeostasis in Hyperuricemia Mice.

Hyperuricemia is a metabolic disease characterized by an excessively increased level of uric acid (UA) in the blood, with an increasing prevalence and often associated with kidney damage. Gut microbiota and endotoxins of gut origin are key mediators in the gut-kidney axis that can cause renal impairment. The study was to reveal the protective effects of fucoidan on renal injury caused by hyperuricemia. The hyperuricemia model was established in C57BL/6J mice. After 10 weeks of fucoidan supplementation, we found that the levels of serum UA and creatinine were reduced, and the levels of renal tumor necrosis factor α, interleukin-18 (IL-18), IL-6, and interleukin-1β (IL-1β) were also decreased. Fucoidan inhibited the expressions of phosphorylated NF-κB p65, NLRP3, and activated caspase-1 in the kidneys. Fucoidan also regulated the expressions of Bcl-2 family proteins and decreased the activation of caspase-3, thereby exerting antiapoptotic effect. In addition, fucoidan could reduce the expressions of glucose transporter 9 (GLUT9) and urate transporter 1 (URAT1) proteins, thereby promoting the excretion of UA from the kidneys. Moreover, the protective effect of fucoidan on renal injury may be related to maintaining intestinal homeostasis. Fucoidan reduced serum lipopolysaccharide and improved the intestinal mucosal barrier function. Fucoidan decreased the abundances of Blautia, Muribaculaceae, and Dubosiella, and increased the abundances of Lactobacillus. High-dose fucoidan supplementation increased the content of butyric acid and enhanced the expression of ATP binding box transporter G2 (ABCG2) via the AMPK/AKT/CREB pathway in ileum. Conclusion: Fucoidan could protect against hyperuricemia-induced renal injury by inhibiting renal inflammation and apoptosis and modulating intestinal homeostasis in hyperuricemia mice.

Traditional Chinese Medicine: A Promising Treatment Option for Intestinal Fibrosis.

Intestinal fibrosis, a common complication of inflammatory bowel disease, in particular in Crohn's disease, arises from chronic inflammation, leading to intestinal narrowing, structural damage, and functional impairment that significantly impact patients' quality of life. Current treatment options for intestinal fibrosis are limited, with surgery being the primary intervention. Traditional Chinese Medicine (TCM) has emerged as a promising approach in preventing and treating intestinal fibrosis. However, there is a scarcity of literature summarizing the mechanisms underlying TCM's efficacy in this context. To address this gap, we conducted a comprehensive review, uncovering multiple mechanisms through which TCM mitigates intestinal fibrosis. These mechanisms include immune cell balance regulation, suppression of inflammatory responses, reduction of inflammatory mediators, alleviation of colon tissue damage, restoration of intestinal function, modulation of growth factors to inhibit fibroblast activation, dynamic regulation of TIMPs and MMPs to reduce extracellular matrix deposition, inhibition of epithelial-mesenchymal transition and endothelial-mesenchymal transition, autophagy modulation, maintenance of the intestinal mucosal barrier, prevention of tissue damage by harmful factors, and regulation of cell proliferation and apoptosis. This study aims to bridge existing knowledge gaps by presenting recent evidence supporting the utilization of TCM in both clinical and experimental research settings.

α2,6-linked sialylated oligosaccharides riched in goat milk alleviate food allergy by regulating the gut flora and mucin O-glycosylation

The nutritious goat milk has low allergenicity. Oligosaccharides represent one of the crucial functional constituents in goat milk, which are structurally similar to human milk oligosaccharides (HMOs). Currently, the anti-allergic activity of GMOs has not been reported. In this study, GMOs were efficiently separated into neutral (NGMOs) and sialylated (SGMOs) fractions, following by qualitative and quantitative analysis at the isomer level using online LC-MS/MS. Fifteen NGMOs and 28 SGMOs were detected in goat milk, with 10 SGMOs reported for the first time. Distinctly, α2,6-linked SGMOs were 3.9 times more abundant in goat milk than in bovine milk, with the total relative content of 6′SL, 3′SLN and 6′NGL in SGMOs approach to 60%, which is more similar to HMOs. Orally administering GMOs, especially α2,6-linked sialylated oligosaccharides, significantly alleviated food allergy in ovalbumin-induced BALB/c mice. SGMOs restored the balance of Lachnospiraceae, Erysipelotrichaceae, and Bacteroidaceae, reconstructed the intestinal mucosal barrier, especially restored the levels of fucosylation, sialylation, and sulfation of mucin O-glycans, increased the expression of four core type 2 O-glycans (F1H2N2, F2H2N2, S1F2H2N2, and A1F1H2N2) significantly. This is the first comprehensive study of the anti-allergic activity of GMOs, and the results lay the foundation for the development of GMOs-based natural anti-allergic components.

Immunoglobulin A Antibodies: From Protection to Harmful Roles.

Immunoglobulin A (IgA) is the most abundantly produced antibody in humans. IgA is a unique class of immunoglobulin due to its multiple molecular forms, and a defining difference between the two subclasses: IgA1 has a long hinge-region that is heavily O-glycosylated, whereas the IgA2 hinge-region is shorter but resistant to bacterial proteases prevalent at mucosal sites. IgA is essential for immune homeostasis and education. Mucosal IgA plays a crucial role in maintaining the integrity of the mucosal barrier by immune exclusion of pathobionts while facilitating colonization with certain commensals; a large part of the gut microbiota is coated with IgA. In the circulation, monomeric IgA that has not been engaged by antigen plays a discrete role in dampening inflammatory responses. Protective and harmful roles of IgA have been studied over several decades, but a new understanding of the complex role of this immunoglobulin in health and disease has been provided by recent studies. Here, we discuss the physiological and pathological roles of IgA with a special focus on the gut, kidneys, and autoimmunity. We also discuss new IgA-based therapeutic approaches.

Sishen Pill & Tongxieyaofang ameliorated ulcerative colitis through the activation of HIF-1α acetylation by gut microbiota-derived propionate and butyrate

BackgroundUlcerative colitis (UC) is a chronic inflammatory bowel disease closely related to gut microbiota dysbiosis and intestinal homeostasis imbalance. Sishen Pill&Tongxieyaofang (SSP-TXYF) has a long history of application in traditional Chinese medicine and is widely used in UC clinics. However, its mechanism of action is still unclear. PurposeThis study aimed to explore the potential regulatory role of SSP-TXYF in protecting against UC through metabolites produced by the intestinal microbiota, and elucidate its underlying molecular mechanism. Study design and Methods16S rRNA and UPLC-QE-Orbitrap-MS were used to assess the microbiota and short-chain fatty acids (SCFAs). A rat model of 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced gut microbiota dysbiosis was used to study the effects of SSP-TXYF on UC in vivo. Intestinal epithelial cells-6 (IEC-6) were treated with lipopolysaccharide (LPS). The intestinal mucosal barrier (IMB) functions were investigated by alcian blue staining and western blot analysis. The mechanism of SSP-TXYF influenced the HIF-1α acetylation pathway was examined by real-time fluorescence quantitative PCR (qPCR), Western blotting, and Co-immunoprecipitation. ResultsUsing 16S rRNA gene-based microbiota analysis, we found that SSP-TXYF ameliorated TNBS-induced gut microbiota dysbiosis. We found that SSP-TXYF significantly inhibited the decreased abundance of Firmicutes in UC rats, in addition, the abundance of Actinobacteria was also improved. The mechanism of SSP-TXYF-treated TNBS-induced UC resulted from improved IMB functions via the activation of hypoxia-inducible factor-1 (HIF-1α) acetylation. Notably, SSP-TXYF Enriched microbiota-derived metabolites propionate and butyrate, which could activate HIF-1α acetylation in IEC. Furthermore, exogenous treatment of propionate and butyrate reproduced similar protective effects as SSP-TXYF to UC through improving HIF-1α-dependent IMB functions. ConclusionsOverall, our findings suggest that the gut microbiota-propionate/butyrate-HIF-1α-IMB axis plays an important role in SSP-TXYF-maintaining intestinal homeostasis, which may represent a novel approach for UC prevention via the intervention of any link in this axis.

Terpenoids, a Rising Star in Bioactive Constituents for Alleviating Food Allergy: A Review about the Potential Mechanism, Preparation, and Application.

Food allergies affect approximately 2.5% of the global population, with a notable increase in prevalence observed each year. Terpenoids, a class of natural bioactive constituents, have been widely utilized in the management of immune- and inflammation-related disorders, and their potential in alleviating food allergies is increasingly being recognized. This article summarizes various terpenoids derived from plant, fungal, and marine sources. Among them, triterpenoids, such as oleanolic acid, ursolic acid, and lupeol, possess the highest proportion and bioactivity in alleviating food allergy. Additionally, the mechanisms by which terpenoids may mitigate allergic diseases were categorically outlined, focusing on their roles in epithelial mucosal barrier function, immunomodulatory effects during the sensitization phase, inhibition of effector cells, oxidative stress, and regulation of microbial homeostasis. Finally, the advantages and limitations of natural extraction and artificial synthesis methods were compared, and the application of terpenoids in the food industry were also discussed. This article serves as a useful reference for the development of methods or functional foods based on terpenoids, which could represent a promising avenue for alleviating food allergy.

Effects of intranasal administration with a symbiotic strain of Bacillus velezensis NSV2 on nasal cavity mucosal barrier in lambs.

The nasal mucosa is composed of multiple layers of barrier structures and is the first line of defense against infection by respiratory pathogenic microorganisms. A large number of commensal microorganisms are present in the nasal mucosa that mediate and regulate nasal mucosal barrier function. The objective of this research was to investigate the effects of commensal microorganisms on the nasal mucosal barrier. The results revealed that the strain of Bacillus velezensis (B. velezensis) NSV2 from the nasal cavity has good probiotic abilities to resist Pasteurella multocida, Staphylococcus aureus, Escherichia coli and Salmonella typhimurium. Lambs were subsequently administered intranasally with B. velezensis NSV2 at 3, 12, 21, and 26 days old, respectively. For the microbial barrier, although B. velezensis NSV2 reduces the diversity of nasal microbiota, it significantly increased the relative abundance of beneficial bacteria in the nasal cavity, and reduced the abundance of potential pathogenic bacteria. For the mucus barrier, the number of goblet cells in the nasal mucosa significantly increased after B. velezensis NSV2 treatment. For the immune barrier, B. velezensis NSV2 also significantly increased the number of IgA+ B cells, CD3+ T cells and dendritic cells in the nasal mucosa, as well as the mRNA expression of interleukin (IL) 6, IL11, CCL2, and CCL20 (P < 0.05). The protein level of CCL20 also significantly raised in nasal washings (P < 0.05). Moreover, the heat-inactivated and culture products of B. velezensis NSV2 also drastically induced the expression of CCL20 in nasal mucosa explants (P < 0.05), but lower than that of the live bacteria. This study demonstrated that a symbiotic strain of B. velezensis NSV2 could improve the nasal mucosal barrier, and emphasized the important role of nasal symbiotic microbiota.

The efficacy and active compounds of Chaihuang Qingyi Huoxue granule to Ameliorate intestinal mucosal barrier injury in rats with severe acute pancreatitis by suppressing the HMGB1/TLR4/NF-κB signaling pathway

Intestinal mucosal barrier injury represents a critical complication of severe acute pancreatitis (SAP) without effective treatment. This study investigated the efficacy, underlying mechanism, and responsible active compounds of the traditional Chinese medicinal prescription Chaihuang Qingyi Huoxue granule (CHQY) in treating SAP-induced intestinal mucosal barrier injury. SAP was established in Sprague-Dawley rats via intra-pancreaticobiliary duct infusion of sodium taurocholate, followed by oral CHQY administration (3.15 g/kg every 6 h for 12 and 24 h). Blood and tissues were harvested to assess the severity of pancreatitis, intestinal mucosal barrier integrity, and extent of inflammatory injury. Intestine-absorbing compounds were identified using ultra-high-performance liquid chromatography coupled with high-resolution mass spectrometry (UHPLC-HRMS). Our results showed that CHQY treatment effectively mitigated SAP-induced intestinal mucosal injury, as evidenced by improved intestinal epithelial structure, decreased serum levels of intestinal injury markers (d-lactic acid, diamine oxidase, I-FABP, and Zonulin), restored expression of the tight junction protein ZO-1, and reduced serum endotoxin levels. Furthermore, CHQY administration suppressed the expression of proinflammatory mediator HMGB1, its receptor TLR4, and downstream NF-κB signaling in the intestine, leading to downregulated intestinal IL-1β expression and reduced circulating TNF-α and IL-6. UHPLC-HRMS analysis identified 15 intestine-absorbing compounds in CHQY, of which paeoniflorin sulfite and chrysin-7-O-glucuronide independently inhibited TNF-α-induced tight junction loss in IEC-6 cells and mitigated intestinal mucosal barrier injury in SAP rats through suppressing NF-κB signaling. In summary, CHQY ameliorates SAP-induced intestinal mucosal barrier injury by downregulating the proinflammatory HMGB1/TLR4/NF-κB signaling, with efficacy partially attributed to its active compounds paeoniflorin sulfite and chrysin-7-O-glucuronide.

The Application of Nano Drug Delivery Systems in Female Upper Genital Tract Disorders.

The prevalence of female reproductive system disorders is increasing, especially among women of reproductive age, significantly impacting their quality of life and overall health. Managing these diseases effectively is challenging due to the complex nature of the female reproductive system, characterized by dynamic physiological environments and intricate anatomical structures. Innovative drug delivery approaches are necessary to facilitate the precise regulation and manipulation of biological tissues. Nanotechnology is increasingly considered to manage reproductive system disorders, for example, nanomaterial imaging allows for early detection and enhances diagnostic precision to determine disease severity and progression. Additionally, nano drug delivery systems are gaining attention for their ability to target the reproductive system successfully, thereby increasing therapeutic efficacy and decreasing side effects. This comprehensive review outlines the anatomy of the female upper genital tract by highlighting the complex mucosal barriers and their impact on systemic and local drug delivery. Advances in nano drug delivery are described for their sustainable therapeutic action and increased biocompatibility to highlight the potential of nano drug delivery strategies in managing female upper genital tract disorders.

Sanguinarine chloride hydrate mitigates colitis symptoms in mice through the regulation of the intestinal microbiome and metabolism of short-chain fatty acids

Sanguinarine constitutes the main components of Macleaya cordata, and exhibits diverse biological and pharmacological activities. This study investigated the effects of sanguinarine chloride hydrate (SGCH) on dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) mice. Five groups were designed to investigate the effects of SGCH on the pathological symptoms, the mRNA expression levels of inflammatory cytokines, colonic mucosal barrier damage, microbiota composition, and SCFAs metabolism in UC mice. The administration of SGCH in DSS-induced UC mice resulted in the amelioration of pathological symptoms, as evidenced by an increase in body weight, a decrease in disease activity index score, elongation of colon length, reduction in spleen index, and improvement in colon injury. SGCH can regulate the expression of inflammatory cytokines (IL-6, TNF-α, IL-1β and IL-10) and tight junction proteins (ZO-1 and Occludin) associated with UC. SGCH exhibited a significant decrease in NF-κB P65 mRNA expression levels, accompanied by a significantly reduced protein level of NF-κB P-P65/P65. Further studies revealed SGCH effectively reversed the decrease in intestinal microbiota diversity induced by UC, thereby promoting the growth of beneficial bacteria such as Akkermansia, Alistipes, and norank_o_Clostridia_UCG-014. Correlation analysis demonstrated a positive association between butanoic acid, propanoic acid, isobutyric acid, isovaleric acid, valeric acid, hexanoic acid with Colidextribacter, while Coriobacteriaceae_UCG-002 exhibited a negative correlation with butanoic acid, acetic acid and propanoic acid. In conclusion, the administration of SGCH can ameliorate clinical symptoms in UC mice, regulate the expression of inflammatory cytokines and tight junction proteins, modulate intestinal microbiota metabolism and SCFAs production.

Genetic landscape of congenital pouch colon: systematic review and functional enrichment study.

Despite extensive clinical documentation, few studies have explored the genetic basis of congenital pouch colon (CPC) which is crucial for early detection, personalized treatment, and genetic counselling. To compile the information on the genetic basis of CPC and the functional enrichment of underlying molecular pathways. The review was conducted in accordance with PRISMA guidelines. The implicated genes were investigated for underlying molecular pathways. A network was subsequently created on String-database followed by gene-ontology analysis. The study included 20 CPC cases and 52 controls (across 4 studies). Numerous variants, including 24 missense SNPs, 63 frameshift variants, and stop-gain/stop-loss mutations in 11 genes were identified. Notable genetic markers included MUC5B, FRG1, and TAF1B, with potential roles in mucosal barrier functions, colonic muscular development, and ribosomal RNA transcription, respectively. Copy number variants and lnc-EPB41-1-1 were also implicated. Genetic hotspots were identified on chromosomes 11, 17 and 16. RGPD2 and RGPD4, contributing to GTPase activator activity and known to be associated with bowel/colon, were differentially expressed. Pathway analysis highlighted Wnt and HOX pathways, with JAG1 and MLL relevant to CPC pathogenesis. The study integrates genetic evidence and pathway analysis, shedding light on the complex genetic architecture of CPC. While the importance of genetic markers in the etiopathogenesis of CPC is underscored, the need for validating the findings on larger cohorts, diverse populations and through functional studies is suggested.

Lycopene alleviates chemotherapy-induced mucositis via enhancing intestinal barrier function and attenuating TLR4/MyD88/NF-κB signaling cascade

5-Fluorouracil (5-FU) is one of the most common chemotherapeutic agents used in treating solid tumors. Lycopene is a natural exogenous carotenoid with antioxidant, anti-inflammatory, immunomodulatory, and anticancer activity. Intestinal mucositis is a commonly encountered complication for chemotherapy. However, effective or preventive treatment for this common complication is still need to be elucidated. The current study aimed to appraise the effect of lycopene on 5-FU-induced intestinal mucositis (FUIIM). Twenty-eight male rats were divided randomly and equally into four groups: control, lycopene, FUIIM, and 5-FU + lycopene groups. Parameters for mucosal barrier integrity, redox and inflammatory status, and apoptosis were immunoassayed in addition to histological assessment. Decreased body weight, significantly impaired redox status, increased caspase 3 level, toll-like receptor (TLR) 4 level, myd88 and NF-κB expression. However, decreased Bcl-2, and Ki-67 expression were detected in 5-FUIIM group. Furthermore, impairment in intestinal barrier integrity, represented by decreased Occludin and claudin1 levels with impaired histological features and ultrastructural features, were also detected. Meanwhile, lycopene co-administration protected against weight loss, heightened oxidative stress, apoptosis, inflammation, disturbed intestinal barrier integrity, and impaired histological and ultrastructure features. In conclusion, lycopene significantly improved intestinal mucositis, barrier integrity and gut toxicity induced by 5-FU in rats.

The therapeutic efficacy of adipose mesenchymal stem cell-derived microvesicles versus infliximab in a dextran sodium sulfate induced ulcerative colitis rat model

ABSTRACT Ulcerative colitis (UC) is a chronic relapsing intestinal inflammation that is becoming of increasing incidence worldwide and has insufficient treatment. Therefore, finding effective therapies remains a priority. A dextran sodium sulfate colitis model was established to elucidate colonic layers alterations and compare adipose mesenchymal stem cell-derived microvesicles (MSC-MVs) versus infliximab (IFX) efficacy through biochemical, light, and electron microscope studies. Fifty-four rats were allocated to 4 groups: Control (Con), UC, UC+IFX, and UC+MSC-MVs groups. End body weights (BW) and serum malondialdehyde (MDA) levels were recorded. Colitis severity was estimated by disease activity index (DAI). Colonic specimens were processed to evaluate the histological structure, collagen content, surface mucous and goblet cells, CD44, TNF-α, and GFAP immune expression. Morphometric and statistical analyses were performed. The UC group revealed congested, stenosed colons, a significant decline in end BW, and a significant increase in serum MDA and DAI. Furthermore, disturbed histoarchitecture, inflammatory infiltration, depletion of surface mucous and goblet cells, increased collagen, and TNF-α expression and decreased GFAP expression were observed. Alterations were partially attenuated by IFX therapy, whereas MSC-MVs significantly improved all parameters. In conclusion, MSC-MVs were a superior therapeutic option, via attenuating oxidative stress and inflammatory infiltration, in addition to restoring intestinal epithelial integrity and mucosal barrier.

Protective Role of Indole-3-Acetic Acid Against Salmonella Typhimurium: Inflammation Moderation and Intestinal Microbiota Restoration.

Indole-3-acetic acid (IAA), a metabolite derived from microbial tryptophan metabolism, plays a crucial role in regulating intestinal homeostasis. However, the influence and potential applications of IAA in the context of animal pathogen infections remain underexplored. This study investigates the prophylactic effects of IAA pretreatment against Salmonella typhimurium (ST) SL1344 infection, focusing on its ability to attenuate inflammatory responses, enhance intestinal barrier integrity, inhibit bacterial colonization, and restore colonic microbiota dysbiosis. The results demonstrated that IAA ameliorated the clinical symptoms in mice, as evidenced by reduced weight loss and histopathological damage. Furthermore, IAA inhibited the inflammatory response by downregulating the gene expression of pro-inflammatory cytokines IL-17A, TNF-α, IL-1β, and IL-6 in colon, ileum, and liver. IAA also preserved the integrity of the intestinal mucosal barrier and promoted the expression of tight junction proteins. Additionally, 16S rRNA gene sequencing revealed significant alterations in intestinal microbiota structure induced by ST infection following IAA treatment. Notable changes in β diversity and species richness were characterized by the enrichment of beneficial bacteria including Bacteroideaceae, Spirillaceae, and Bacillus. The proliferation of Salmonella enterica subspecies enterica serovar Typhi was significantly inhibited, thereby enhancing the intestinal health of the host. In summary, the oral administration of IAA contributes to the alleviation of inflammation, restoration of the intestinal barrier, and correction of colonic microbiota disturbance in mice challenged with ST.