Fish gut-derived probiotic Pediococcus pentosaceus alleviates gossypol-induced intestinal inflammation by inhibiting NLRC3/NF-κB/IL-1ß signal pathway in Nile tilapia.

Cottonseed meal (CSM) and cottonseed protein concentrate (CPC) serve as protein alternatives to fish meal and soybean meal in the feed industry. However, the presence of gossypol residue in CSM and CPC can potentially trigger severe intestinal inflammation, thereby restricting the widespread utilization of these two protein sources. Probiotics are widely used to prevent or alleviate intestinal inflammation, but their efficacy in protecting fish against gossypol-induced enteritis remains uncertain. Here, the protective effect of Pediococcus pentosaceus, a strain isolated from the gut of Nile tilapia (Oreochromis niloticus), was evaluated. Three diets, control diet (CON), gossypol diet (GOS) and GOS supplemented with P. pentosaceus YC diet (GP), were used to feed Nile tilapia for 10 weeks. After the feeding trial, P. pentosaceus YC reduced the activity of myeloperoxidase (MPO) in the proximal intestine (PI) and distal intestine (DI). Following a 7-day exposure to Aeromonas hydrophila, the addition of P. pentosaceus YC was found to increase the survival rate of the fish. P. pentosaceus YC significantly inhibited the oxidative stress caused by gossypol, which was evidenced by lower reactive oxygen species (ROS) and malondialdehyde (MDA), as well as higher activities of glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) in PI and DI. Addition of P. pentosaceus YC significantly inhibited enteritis, with the lower expression of pro-inflammatory cytokines (il-1ß, il-6, il-8) and higher expression of anti-inflammatory cytokines tgf-ß. RNA-seq analysis indicated that P. pentosaceus YC supplementation significantly inhibited nlrc3 and promoted nf-κb expression in PI and DI, and the siRNA interference experiment in vivo demonstrated that intestinal inflammation was mediated by NLRC3/NF-κB/IL-1ß signaling pathway. Fecal bacteria transplantation experiment demonstrated that gut microbiota mediated the protective effect of P. pentosaceus YC. These findings offer valuable insights into the application of P. pentosaceus YC for alleviating gossypol-induced intestinal inflammation in fish.

Multi-omics insights into anti-colitis benefits of the synbiotic and postbiotic derived from wheat bran arabinoxylan and Limosilactobacillus reuteri.

Exploring nutritional therapies that manipulate tryptophan metabolism to activate AhR signaling represents a promising approach for mitigating chronic colitis. Arabinoxylan is a bioactive constituent abundant in wheat bran. Here, we comprehensively investigated anti-colitis potentials of wheat bran arabinoxylan (WBAX), its synbiotic and postbiotic derived from WBAX and Limosilactobacillus reuteri WX-94 (i.e., a probiotic strain exhibiting tryptophan metabolic activity). WBAX fueled L. reuteri and promoted microbial conversion of tryptophan to AhR ligands during in vitro fermentation in the culture medium and in the fecal microbiota from type 2 diabetes. The WBAX postbiotic outperformed WBAX and its synbiotic in augmenting efficacy of tryptophan in restoring DSS-disturbed serum immune markers, colonic tight junction proteins and gene profiles involved in amino acid metabolism and FoxO signaling. The WBAX postbiotic remodeled gut microbiota and superiorly enhanced AhR ligands (i.e., indole metabolites and bile acids), alongside with elevation in colonic AhR and IL-22. Associations between genera and metabolites modified by the postbiotic and colitis in human were verified and strong binding capacities between metabolites and colitis-related targets were demonstrated by molecular docking. Our study advances the novel perspective of WBAX in manipulating tryptophan metabolism and anti-colitis potentials of WBAX postbiotic via promoting gut microbiota-dependent AhR signaling.

The role of intestinal microbiota and metabolites in intestinal inflammation.

With the imbalance of intestinal microbiota, the body will then face an inflammatory response, which has serious implications for human health. Bodily allergies, injury or pathogens infections can trigger or promote inflammation and alter the intestinal environment. Meanwhile, excessive changes in the intestinal environment cause the imbalance of microbial homeostasis, which leads to the proliferation and colonization of opportunistic pathogens, invasion of the body's immune system, and the intensification of inflammation. Some natural compounds and gut microbiota and metabolites can reduce inflammation; however, the details of how they interact with the gut immune system and reduce the gut inflammatory response still need to be fully understood. The review focuses on inflammation and intestinal microbiota imbalance caused by pathogens. The body reacts differently to different types of pathogenic bacteria, and the ingestion of pathogens leads to inflamed gastrointestinal tract disorders or intestinal inflammation. In this paper, unraveling the interactions between the inflammation, pathogenic bacteria, and intestinal microbiota based on inflammation caused by several common pathogens. Finally, we summarize the effects of intestinal metabolites and natural anti-inflammatory substances on inflammation to provide help for related research of intestinal inflammation caused by pathogenic bacteria.

MicroRNA miR-27a-5p reduces intestinal inflammation induced by Clostridioides difficile flagella by regulating the NF-κB signaling pathway.

BACKGROUND: Clostridioides difficile is a major cause of nosocomial post-antibiotic infections, often resulting in severe inflammation and watery diarrhea. Previous studies have highlighted the role of C. difficile flagellin FliC in activating the TLR5 receptor and triggering NF-κB cell signaling, leading to the release of pro-inflammatory cytokines. However, the microRNAs (miRNAs) mediated regulatory mechanisms underlying the FliC-induced inflammatory response remain unclear. METHODS: miRNA expression levels were analyzed in Caco-2 intestinal epithelial cells following FliC stimulation, infection with the epidemic C. difficile R20291 strain, or its unflagellated mutant by RT-qPCR. Chemical inhibitors were used to block NF-κB signaling, and their impact on miR-27a-5p expression was assessed. Knockdown and overexpression experiments with miRNA inhibitor and mimic were conducted to elucidate miR-27a-5p's functional role in FliC-induced inflammatory responses. Additionally, a mouse model of C. difficile infection was treated with miR-27a-5p to evaluate its therapeutic potential in vivo. RESULTS: miR-27a-5p showed significant FliC-dependent overexpression in Caco-2 cells. Inhibition of NF-κB signaling suppressed miR-27a-5p overexpression. Knockdown of miR-27a-5p increased NF-κB activation and TNF-α and IL-8 cytokine production, while its overexpression had the opposite effect. Moreover, miR-27a-5p was overexpressed in the caeca of C. difficile-infected mice, correlating with intestinal IL-8 levels. Treatment of infected mice with miR-27a-5p mimic reduced disease severity and intestinal inflammation. CONCLUSION: miR-27a-5p plays a crucial role in regulating C. difficile-induced inflammation, suggesting its potential as a therapeutic target for controlling severe infection. These findings offer valuable insights into potential therapeutic strategies for managing C. difficile infection and associated inflammatory complications.

Integration of Gut Mycobiota and Oxidative Stress to Decipher the Roles of C-Type Lectin Receptors in Inflammatory Bowel Diseases.

BACKGROUND: Ulcerative colitis (UC) and Crohn's disease (CD) are two subtypes of inflammatory bowel disease (IBD) with rapidly increased incidence worldwide. Although multiple factors contribute to the occurrence and progression of IBD, the role of intestinal fungal species (gut mycobiota) in regulating the severity of these conditions has been increasingly recognized. C-type lectin receptors (CLRs) on hematopoietic cells, including Dectin-1, Dectin-2, Dectin-3, Mincle and DC-SIGN, are a group of pattern recognition receptors (PRRs) that primarily recognize fungi and mediate defense responses, such as oxidative stress. Recent studies have demonstrated the indispensable role of CLRs in protecting the colon from intestinal inflammation and mucosal damage. METHODS AND RESULTS: This review provides a comprehensive overview of the role of CLRs in the pathogenesis of IBD. Given the significant impact of mycobiota and oxidative stress in IBD, this review also discusses recent advancements in understanding how these factors exacerbate or ameliorate IBD. Furthermore, the latest developments in CLR-guided IBD therapy are examined to highlight the modulation of CLRs in fungal recognition and oxidative burst during the IBD process. CONCLUSION: This review emphasizes the importance of CLRs in IBD, offering new perspectives on the etiology and therapeutic approaches for this disease.

Chicken Meal as a Fishmeal Substitute: Effects on Growth, Antioxidants, and Digestive Enzymes in Lithobates catesbeianus.

In pursuit of sustainable aquaculture, this study was performed to evaluate chicken meal as a substitute for fishmeal in bullfrog diets. Three experimental groups were established: a control group (FM) with 20% fishmeal, a CM50 group with 50% replacement (10% fishmeal), and a CM100 group with 100% replacement (0 fishmeal). Bullfrogs were fed for 56 days. The CM50 group exhibited significant increases in total weight gain and survival rate and a notable decrease in feed coefficient (p < 0.05). However, the CM100 group showed contrary effects. Increasing chicken meal substitution correlated with decreased amino acid content in muscle. Notably, the CM50 group demonstrated enhanced activities of antioxidant enzymes (CAT, T-AOC) and elevated gene expression levels (cat, sod, gst, etc.) in muscle and the intestine (p < 0.05), improved intestinal morphology, enhanced digestive enzyme activities (amylase, lipase), and reduced expression of inflammatory factors (il-1ß, il-8, il-17, etc.). Conversely, the CM100 group's indicators regressed to levels similar to or worse than those of the FM group. Therefore, a 50% substitution of fishmeal with chicken meal effectively promoted bullfrog survival, protected the intestines, and enhanced antioxidant capacity, supporting its potential as a fishmeal alternative. However, the adverse outcomes of the CM100 strategy, including growth retardation and reduced amino acid content in muscle, indicate that complete replacement is unsuitable.

The effect of selenium on the intestinal health of juvenile grass carp based on the ERS-autophagy pathway.

Selenium (Se), a trace element, is vital for the maintenance of cellular redox balance, thyroid hormone metabolism, inflammation, and immunity. Aeromonas hydrophila (A. hydrophila) is a common Gram-negative conditional pathogenic bacterium in fish culture, posing a serious threat to intensive aquaculture. Our study investigated the influence of dietary Se on the intestinal immune function of grass carp (Ctenopharyngodon idella) and the related regulatory mechanisms. The 2160 healthy juvenile grass carp (9.76 ± 0.005 g) were randomly assigned to 6 test groups of 6 replicates each, and fed graded selenomethionine (0.05, 0.20, 0.40, 0.61, 0.77, 0.98 mg Se/kg diet) for 70 days and then injected with A. hydrophila for a 6-day attack test. The results indicated that appropriate Se levels (0.40 mg/kg diet) alleviated intestinal damage caused by A. hydrophila and increased intestinal immune substances C3 and C4 levels as well as the activity of acid phosphatase (ACP) and lysozyme (LZ) (P > 0.05). Appropriate levels of Se (0.40 mg/kg-0.61 mg/kg diet) decreased intestinal pro-inflammatory cytokines (IFN-γ2, IL-6, IL-12p35, IL-17 A F and IL-17D) mRNA levels (P > 0.05) and increased intestinal anti-inflammatory factors (TGF-ß1, IL-4/13A, IL-4/13B, IL-10 and IL-22) mRNA levels (P > 0.05) in juvenile grass carp. Further studies revealed that Se (0.40 mg/kg-0.61 mg/kg diet) inhibited intestinal endoplasmic reticulum stress (ERS)-related signaling pathway. Furthermore, we found that appropriate levels of Se (0.40 mg/kg-0.61 mg/kg diet) inhibited intestinal autophagy in juvenile grass carp, which may be related to ULK1, Beclin 1, ATG5, ATG12, LC3, and P62. In conclusion, appropriate levels of Se can alleviate intestinal inflammation and inhibit ERS and autophagy in juvenile grass carp. A quadratic regression analysis of intestinal ACP and LZ also indicated that the Se requirements of juvenile grass carp were 0.59 and 0.51 mg/kg, respectively.

A systematic review of preclinical studies targeted toward the management of co-existing functional gastrointestinal disorders, stress, and gut dysbiosis.

Modern dietary habits and stressed lifestyle have escalated the tendency to develop functional gastrointestinal disorders (FGIDs) through alteration in the gut-brain-microbiome axis. Clinical practices use symptomatic treatments, neglect root causes, and prolong distress in patients. The past decade has seen the evolution of various interventions to attenuate FGIDs. But clinical translation of such studies is very rare mostly due to lack of awareness. The aim of this review is to meticulously integrate different studies and bridge this knowledge gap. Literature between 2013 and 2023 was retrieved from PubMed, ProQuest, and Web of Science. The data was extracted based on the PRISMA guidelines and using the SYRCLE's risk of bias and the Cochrane Risk of Bias tools, quality assessment was performed. The review has highlighted molecular insights into the coexistence of FGIDs, stress, and gut dysbiosis. Furthermore, novel interventions focusing on diet, probiotics, herbal formulations, and phytoconstituents were explored which mostly had a multitargeted approach for the management of the diseases. Scientific literature implied positive interactions between the interventions and the gut microbiome by increasing the relative abundance of beneficial bacteria and reducing stress-related hormones. Moreover, the interventions reduced intestinal inflammation and regulated the expression of epithelial tight junction proteins in different in vivo models. This systematic review delves deep into the preclinical interventions to manage coexisting FGIDs, stress, and gut dysbiosis. However, in most of the discussed studies, long-term risks and toxicity profile of the interventions are lacking. So, it is necessary to highlight them for improved clinical outcomes.

Alterations in tryptophan metabolism and de novo NAD+ biosynthesis within the microbiota-gut-brain axis in chronic intestinal inflammation.

Background: Inflammatory bowel disease is an incurable and idiopathic disease characterized by recurrent gastrointestinal tract inflammation. Tryptophan metabolism in mammalian cells and some gut microbes comprise intricate chemical networks facilitated by catalytic enzymes that affect the downstream metabolic pathways of de novo nicotinamide adenine dinucleotide (NAD+) synthesis. It is hypothesized that a correlation exists between tryptophan de novo NAD+ synthesis and chronic intestinal inflammation. Methods: Transcriptome analysis was performed using high-throughput sequencing of mRNA extracted from the distal colon and brain tissue of Winnie mice with spontaneous chronic colitis and C57BL/6 littermates. Metabolites were assessed using ultra-fast liquid chromatography to determine differences in concentrations of tryptophan metabolites. To evaluate the relative abundance of gut microbial genera involved in tryptophan and nicotinamide metabolism, we performed 16S rRNA gene amplicon sequencing of fecal samples from C57BL/6 and Winnie mice. Results: Tryptophan and nicotinamide metabolism-associated gene expression was altered in distal colons and brains of Winnie mice with chronic intestinal inflammation. Changes in these metabolic pathways were reflected by increases in colon tryptophan metabolites and decreases in brain tryptophan metabolites in Winnie mice. Furthermore, dysbiosis of gut microbiota involved in tryptophan and nicotinamide metabolism was evident in fecal samples from Winnie mice. Our findings shed light on the physiological alterations in tryptophan metabolism, specifically, its diversion from the serotonergic pathway toward the kynurenine pathway and consequential effects on de novo NAD+ synthesis in chronic intestinal inflammation. Conclusion: The results of this study reveal differential expression of tryptophan and nicotinamide metabolism-associated genes in the distal colon and brain in Winnie mice with chronic intestinal inflammation. These data provide evidence supporting the role of tryptophan metabolism and de novo NAD+ synthesis in IBD pathophysiology.

Synbiotics containing sea buckthorn polysaccharides ameliorate DSS-induced colitis in mice via regulating Th17/Treg homeostasis through intestinal microbiota and their production of BA metabolites and SCFAs.

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

Impact of Microbiota and Metabolites on Intestinal Integrity and Inflammation in Severe Obesity.

Obesity is a multifactorial disease associated with low-grade inflammation. The gut is thought to be involved in obesity-related inflammation, as it is continuously exposed to antigens from food, microbiota and metabolites. However, the exact underlying mechanisms are still unknown. Therefore, we examined the relation between gut pathology, microbiota, its metabolites and cytokines in adults with severe obesity. Individuals eligible for bariatric surgery were included. Fecal and plasma samples were collected at surgery timepoint, to assess microbiota and metabolite composition. Jejunal biopsies were collected during surgery and stained for cytotoxic T cells, macrophages, mast cells and tight junction component zonula occludens-1. Based on these stainings, the cohort was divided into four groups: high versus low intestinal inflammation and high versus low intestinal integrity. We found no significant differences in microbiota diversity between groups, nor for individual bacterial species. No significant differences in metabolites were observed between the intestinal inflammatory groups. However, some metabolites and cytokines differed between the intestinal integrity groups. Higher plasma levels of interleukin-8 and tauro-chenodeoxycholic acid were found, whereas isovaleric acid and acetic acid were lower in the high intestinal integrity group. As the results were very subtle, we suggest that our cohort shows very early and minor intestinal pathology.

Intestinal epithelial Cldn-7 regulates intestinal inflammation by altering the gut microbiota.

BACKGROUND AND AIM: Tight junctions maintain gut homeostasis by forming a physical barrier that protects the gut from invasion by microbiota. Cldn-7 is an important component involved in this protection, but the relationship between Cldn-7, intestinal inflammation, and gut microbiota has not been clarified. Here, we hypothesize that Cldn-7 depletion affects intestinal inflammation by altering the gut microbiota. METHODS: Based on the induced intestinal condition of Cldn-7 knockout mice (Cldn7fl/fl;villin-CreaERT2), we established the intestinal flora depletion model and colitis model by antibiotic drinking and feeding with dextran sodium sulfate (DSS). The environment of Cldn-7 gene deletion mice was changed by co-housing experiment. AB-PAS staining and Muc2 were used to detect the effect of co-housing and Cldn-7 deficiency on the mucus layer after flora depletion. qRT-PCR was used to detect the expression of intestinal inflammatory factors and AMPs in mice. Feces were collected and proportions of microbiota were analyzed by 16 S rRNA amplicon sequencing. RESULTS: Mice in the co-housing experiment had altered intestinal microbiota, including diversity, composition, and functional prediction, compared to controls. Intestinal inflammation was restored to some extent following altered intestinal microbiota. The intestinal inflammation caused by Cldn-7 deficiency and susceptibility to DSS could be reduced after antibiotic administration compared to controls, in terms of phenotype, pathological changes, inflammatory factors, mucus barrier, and expression of AMPs. CONCLUSIONS: In analyses of intestinal tissues, colitis induction, and gut microbiota in mice with intestinal disruption of Cldn-7, we found this protein to prevent intestinal inflammation by regulating the gut microbiota. Cldn-7might therefore be an important mediator of host-microbiome interactions. Our research has revealed that Cldn-7 plays an indispensable role in maintaining intestinal homeostasis by regulating the gut microbiota and impacting intestinal inflammation. These findings provide new insights into the pathogenesis of ulcerative colitis.

CRIg+ macrophages deficiency enhanced inflammation damage in IBD due to gut extracellular vesicles containing microbial DNA.

Gut microbiota-derived extracellular vesicles (mEVs) are reported to regulate inflammatory response by delivering bacterial products into host cells. The complement receptor of the immunoglobulin superfamily macrophages (CRIg+ Mφ) could clear invading bacteria and their derivatives. Here, we investigate the role of CRIg+ Mφ and the mechanism by which mEVs regulate intestinal inflammation. We found that it is exacerbated in IBD patients and colitis mice by mEVs' leakage from disturbed gut microbiota, enriching microbial DNA in the intestinal mucosa. CRIg+ Mφ significantly decrease in IBD patients, allowing the spread of mEVs into the mucosa. The microbial DNA within mEVs is the key trigger for inflammation and barrier function damage. The cGAS/STING pathway is crucial in mEVs-mediated inflammatory injury. Blocking cGAS/STING signaling effectively alleviates inflammation caused by mEVs leakage and CRIg+ Mφ deficiency. Microbial DNA-containing mEVs, along with CRIg+ Mφ deficiency, stimulate inflammation in IBD, with the cGAS/STING pathway playing a crucial role.

Characterization of idiopathic chronic diarrhea and associated intestinal inflammation and preliminary observations of effects of vagal nerve stimulation in a non-human primate.

BACKGROUND: Diarrhea is commonly associated with irritable bowel syndrome, inflammatory bowel disease, microscopic colitis, and other gastrointestinal dysfunctions. Spontaneously occurring idiopathic chronic diarrhea is frequent in rhesus macaques, but has not been used as a model for the investigation of diarrhea or its treatment. We characterized this condition and present preliminary data demonstrating that left vagal nerve stimulation provides relief. METHODS: Stool consistency scores were followed for up to 12 years. Inflammation was assessed by plasma C-reactive protein, [18F]fluorodeoxyglucose (FDG) uptake, measured by positron emission tomography (PET), multiplex T cell localization, endoscopy and histology. The vagus was stimulated for 9 weeks in conscious macaques, using fully implanted electrodes, under wireless control. KEY RESULTS: Macaques exhibited recurrent periods of diarrhea for up to 12 years, and signs of inflammation: elevated plasma C-reactive protein, increased bowel FDG uptake and increased mucosal T helper1 T-cells. The colon and distal ileum were endoscopically normal, and histology revealed mild colonic inflammation. Application of vagal nerve stimulation to conscious macaques (10 Hz, 30 s every 3 h; 24 h a day for 9 weeks) significantly reduced severity of diarrhea and also reduced inflammation, as measured by FDG uptake and C-reactive protein. CONCLUSIONS AND INFERENCES: These macaques exhibit spontaneously occurring diarrhea with intestinal inflammation that can be reduced by VNS. The data demonstrate the utility of this naturally occurring primate model to study the physiology and treatments for chronic diarrhea and the neural control circuits influencing diarrhea and inflammation that are not accessible in human subjects.

Effects of Chinese Gallotannins on Antioxidant Function, Intestinal Health, and Gut Flora in Broilers Challenged with Escherichia coli Lipopolysaccharide.

This experiment was conducted to study the protective effects of dietary Chinese gallotannins (CGT) supplementation against Escherichia coli lipopolysaccharide (LPS)-induced intestinal injury in broilers. Four hundred and fifty healthy Arbor Acres broilers (one-day-old) were randomly divided into three groups: (1) basal diet (CON group), (2) basal diet with LPS challenge (LPS group), and (3) basal diet supplemented with 300 mg/kg CGT as well as LPS challenge (LPS+CGT group). The experiment lasted for 21 days. Intraperitoneal LPS injections were administered to broilers in the LPS group and the LPS+CGT group on days 17, 19, and 21 of the trial, whereas the CON group received an intraperitoneal injection of 0.9% physiological saline. Blood and intestinal mucosa samples were collected 3 h after the LPS challenge. The results showed that LPS administration induced intestinal inflammation and apoptosis and damaged small intestinal morphology and structure in broilers. However, dietary supplementation with CGT alleviated the deleterious effects on intestinal morphology and barrier integrity caused by the LPS challenge, while also reducing intestinal apoptosis and inflammation, enhancing intestinal antioxidant capacity, and increasing cecal microbial alpha diversity in the LPS-challenged broilers. Therefore, our findings demonstrated that a 300 mg/kg CGT addition could improve intestinal morphology and gut barrier structure, as well as maintaining bacterial homeostasis, in broilers exposed to LPS. This might partially be attributed to the reduced cell apoptosis, decreased inflammatory response, and enhanced antioxidant capacity in the small intestinal mucosa.

Gastrointestinal problems in a valproic acid-induced rat model of autism: From maternal intestinal health to offspring intestinal function.

BACKGROUND: Autism spectrum disorder (ASD) is a developmental disorder characterized by social deficits and repetitive behavior. Gastrointestinal (GI) problems, such as constipation, diarrhea, and inflammatory bowel disease, commonly occur in patients with ASD. Previously, GI problems of ASD patients were attributed to intestinal inflammation and vertical mother-to-infant microbiome transmission. AIM: To explore whether GI problems in ASD are related to maternal intestinal inflammation and gut microbiota abnormalities. METHODS: An ASD rat model was developed using valproic acid (VPA). Enzyme-linked immunosorbent assay and fecal 16S rRNA sequencing were used to test GI changes. RESULTS: VPA exposure during pregnancy led to pathological maternal intestinal changes, resulting in alterations in maternal gut microbiota. Additionally, the levels of inflammatory factors also increased. Moreover, prenatal exposure to VPA resulted in impaired duodenal motility in the offspring as well as increased levels of inflammatory factors. CONCLUSION: GI problems in ASD may be associated with maternal intestinal inflammation and microbiota abnormality. Future research is required to find more evidence on the etiology and treatment of GI problems in ASD.

A Case of Osseous Metaplasia in a Juvenile Rectal Polyp.

Rectal mucosal prolapse is uncommon in children. While most patients present with rectal bleeding and constipation, the occurrence of osseous metaplasia within the prolapsed mucosa is extremely rare. Overlapping clinical, gross, and histological features between rectal mucosal prolapse polyps and malignancy pose a challenge for diagnoses. We describe a case of a 16-year-old male who had a rectal mucosal prolapsed polyp with osseous metaplasia. He initially presented due to periumbilical pain with a sore throat and fever. Incidentally, during the workup of his periumbilical pain, he was found to have a soft tissue mass in his rectum on a CT scan, with a biopsy confirming the diagnosis. The case was complicated by the development of sepsis. The patient was treated with empiric antibiotics and was discharged without further complications.

Seliciclib alleviates ulcerative colitis by inhibiting ferroptosis and improving intestinal inflammation.

BACKGROUND: Ulcerative colitis (UC) is a chronic, recurrent, non-specific inflammatory disease, and the pathogenesis of the disease remains unclear. Ferroptosis is a form of programmed cell death characterized by the accumulation of iron-dependent lipid peroxides, which are simultaneously closely related to reactive oxygen species (ROS). Although seliciclib is highly effective against immune inflammation, its mechanism on colitis is unclear. This study demonstrated that seliciclib administration partially inhibited ferroptosis, alleviating symptoms and inflammation in experimental colitis. METHODS: The mouse UC model was induced by 3.0 % dextran sodium sulfate (DSS) for 7 days and treated with seliciclib (10 mg/kg) for 5 days. In the in vitro model, LPS (100 µg/mL) was used for induction and seliciclib (10 µM) was applied for 2 h. Meanwhile, appropriate histopathology, inflammatory response, oxidative stress, and ferroptosis regulators were measured. RESULTS: This study primarily investigated the role of seliciclib in regulating ferroptosis in UC. Bioinformatics analysis indicated that Dual oxidase 2 (DUOX2) may serve a role involved in the ferroptosis of UC. The experimental findings demonstrated that seliciclib alleviates symptoms and inflammation in DSS-induced UC mice and partially mitigates the occurrence of ferroptosis both in vivo and in vitro, possibly through the modulation of DUOX2. CONCLUSIONS: Ferroptosis is strongly associated with the development of colitis, and seliciclib plays an essential role in ferroptosis and inflammation in UC. The suppression of ferroptosis in the intestinal epithelium could be a therapeutic approach for UC.

Cynaroside ameliorates methotrexate-induced enteritis in rats through inhibiting NLRP3 inflammasome activation.

Introduction: Cynaroside exhibits various biological properties, including anti-inflammatory, antiviral, antitumor, and cardioprotective effects. However, its involvement in methotrexate (MTX)-induced intestinal inflammation remains inadequately understood. Thus, we investigated the impact of cynaroside on MTX-induced intestinal inflammation and its potential mechanisms. Methods: To assess the protective potential of cynaroside against intestinal inflammation, Sprague-Dawley rats were subjected to a regimen of 7 mg/kg MTX for 3 days, followed by treatment with cynaroside at varying doses (10, 20, or 40 mg/kg). Histopathological evaluations were conducted alongside measurements of inflammatory mediators to elucidate the involvement of the NLRP3 inflammasome in alleviating intestinal inflammation. Results: Administration of 7 mg/kg MTX resulted in decreased daily food intake, increased weight loss, and elevated disease activity index in rats. Conversely, treatment with cynaroside at 20 or 40 mg/kg ameliorated the reductions in body weight and daily food intake and suppressed the MTX-induced elevation in the disease activity index. Notably, cynaroside administration at 20 or 40 mg/kg attenuated inflammatory cell infiltration, augmented goblet cell numbers and lowered serum levels of tumor necrosis factor-α, interleukin (IL)-1ß, and IL-18, as well as the CD68-positive cell rate in the intestines of MTX-induced rats. Furthermore, cynaroside downregulated the expression levels of NLRP3, cleaved caspase 1, and cleaved IL-1ß in MTX-induced rats. Discussion: Collectively, our findings indicated that cymaroside alleviates intestinal inflammatory injury by inhibiting the activation of NLRP3 inflammasome in MTX-induced rats.

Intestinal Epithelial Creatine Transporter SLC6A8 Dysregulation in Inflammation and in Response to Adherent Invasive E. coli Infection.

Creatine transporter (CrT1) mediates cellular uptake of creatine (Cr), a nutrient pivotal in maintaining energy homeostasis in various tissues including intestinal epithelial cells (IECs). The impact of CrT1 deficiency on the pathogenesis of various psychiatric and neurological disorders has been extensively investigated. However, there are no studies on its regulation in IECs in health and disease. Current studies have determined differential expression of CrT1 along the length of the mammalian intestine and its dysregulation in inflammatory bowel disease (IBD)-associated inflammation and Adherent Invasive E. coli (AIEC) infection. CrT1 mRNA and protein levels in normal intestines and their alterations in inflammation and following AIEC infection were determined in vitro in model IECs (Caco-2/IEC-6) and in vivo in SAMP1/YitFc mice, a model of spontaneous ileitis resembling human IBD. CrT1 is differentially expressed in different regions of mammalian intestines with its highest expression in jejunum. In vitro, CrT1 function (Na+-dependent 14C-Cr uptake), expression and promoter activity significantly decreased following TNFα/IL1ß treatments and AIEC infection. SAMP1 mice and ileal organoids generated from SAMP1 mice also showed decreased CrT1 mRNA and protein compared to AKR controls. Our studies suggest that Cr deficiency in IECs secondary to CrT1 dysregulation could be a key factor contributing to IBD pathogenesis.