Colonic Mucosa Research Articles

MYO5B and the Polygenic Landscape of Very Early-Onset Inflammatory Bowel Disease in an Ethnically Diverse Population.

Genetic discovery in very early-onset inflammatory bowel disease (VEO-IBD) can elucidate not only the origins of VEO-IBD, but also later-onset inflammatory bowel disease. We aimed to investigate the polygenic origins of VEO-IBD in a cohort with a high proportion of Hispanic patients. Patients with VEO-IBD who underwent whole exome sequencing at our center were included. Genes were categorized as genes of interest (GOIs) (129 genes previously described to be associated with VEO-IBD) or non-GOIs. VEO-IBD "susceptibility" single nucleotide variants (SNVs) were identified through enrichment compared with gnomAD (Genome Aggregation Database) and ALFA (Allele Frequency Aggregator) and were scored by Combined Annotation Dependent Depletion for deleteriousness. Gene networks carrying susceptibility SNVs were created. Myosin 5b immunofluorescence was also studied. Fifty-six patients met inclusion criteria, and 32.1% identified as Hispanic. Monogenic disease was infrequent (8.9%). Significant enrichment of GOI susceptibility SNVs was observed, notably in MYO5B, especially in Hispanics. MEFV, TNFAIP3, SH3TC2, and NCF2 were also central participants in the GOI networks. Myosin 5b immunofluorescence in colonic mucosa was significantly reduced in those with MYO5B susceptibility SNVs compared with control subjects. Seven genes (ESRRA, HLA-DQ1, RETSAT, PABPC1, PARP4, CCDC102A, and SUSD2) were central participants in the non-GOI networks. Our results support the polygenic nature of VEO-IBD, in which key participants, like MYO5B, were identified through network analytics. Rare variant load within susceptibility genes may be relevant not only for the genetic origins of inflammatory bowel disease, but also for the age of disease onset. Our findings could guide future work in precision medicine.

The protective effect of dulcitol on lipopolysaccharide-induced intestinal injury in piglets: mechanistic insights

This study investigated the protective effect of dulcitol on LPS-induced intestinal injury in piglets and explored the underlying molecular mechanisms. A total of 108 piglets were divided into three groups: CON, LPS, and DUL. The CON and LPS groups were fed a basal diet, the DUL group was fed a diet supplementation with 500 mg/kg dulcitol. On day 29, 6 piglets in the LPS and DUL groups were injected with 100 μg/kg BW of LPS. At 4 h postchallenge, all pigs were slaughtered, and colonic samples were collected. Results showed that dulcitol supplementation boosted intestinal barrier function in LPS-challenged piglets by enhancing intestinal morphology and integrity, and increasing the gene expression of zonula occludens-1, claudin-1, and occludin in the colonic mucosa (P <0.05). Metabolomics showed DUL supplementation mainly increased (P <0.05) the metabolites related to steroid and vitamin metabolism (Cholesterol and Vitamin C). Proteomics showed that dulcitol supplementation altered the protein expression involved in maintaining barrier integrity (FN1, CADM1, and PARD3), inhibiting inflammatory response (SLP1, SFN, and IRF3), and apoptosis (including FAS, ING1, BTK, MTHFR, NOX, and P53BP2) in LPS-challenged piglets (P <0.05). Additionally, dulcitol addition also suppressed the TLR4/NF-κB signaling pathway and apoptosis in mRNA and protein levels. Dulcitol increased the abundance of short-chain fatty acid-producing bacteria (Lactobacillus, Blautia, and Faecalibacterium) at the genus level, but decreased the relative abundance of Proteobacteria at the phylum level and Pseudomonas and Delftia at the genus level in piglets (P<.05). In conclusion, these results suggested that the addition of dulcitol alleviated LPS-induced intestinal barrier injury in piglets, probably by maintaining its integrity, inhibiting the TLR4/NF-κB signaling pathways and apoptosis, and modulating the gut microbiota. Therefore, dulcitol can be considered a potential dietary additive for improving intestinal health in pig models.

Risks and benefits of anti-TNF therapy for ulcerative colitis in a patient with autoimmune hepatitis-related cirrhosis: Case report.

Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) characterized by continuous inflammation of the colonic mucosa. Autoimmune hepatitis (AIH) is a chronic liver disease characterized by hypergammaglobulinemia, circulating autoantibodies, interface hepatitis, and favorable response to immunosuppression. An association between IBD and AIH is uncommon, and experts have suggested that in patients with overlapping IBD and AIH, the anti-tumor necrosis factor agents can be used. Therefore, this study reports a rare case of a patient with liver cirrhosis due to AIH and UC refractory to conventional treatment and discusses the risks and benefits of using anti-tumor necrosis factor in both conditions. A 28-year-old female presented with symptoms of diarrhea, abdominal pain, asthenia, and inappetence, accompanied by abdominal collateral circulation, anemia, alteration of liver enzymes, and elevation of C-reactive protein levels. The patient underwent a liver biopsy, which was consistent with liver cirrhosis due to AIH. Colonoscopy showed an inflammatory process throughout the colon, compatible with moderately active UC. The patient received mesalazine, azathioprine, and corticotherapy, with no control of the inflammatory process. Faced with refractoriness to drug treatment and side effects of corticosteroids with an increased risk of severe infection due to cirrhosis, we opted to use infliximab for the treatment of UC. The patient presented with a clinical response and infliximab therapy was maintained. Eight months after starting infliximab therapy, the patient developed pneumonia with complications from disseminated intravascular coagulation and died. AIH is a rare cause of elevated transaminase levels in patients with UC. The best treatment to control the 2 conditions should be evaluated with vigilance for the side effects of medications, mainly infections, especially in patients with cirrhosis.

The Interplay among Wnt/β-catenin Family Members in Colorectal Adenomas and Surrounding Tissues.

The colorectal adenoma undergoes neoplastic progression via the normal epithelium-adenoma-adenocarcinoma sequence as reported in the Vogelgram. The hazard of developing a tumor is deeply associated with the number and size of adenomas and their subtype. Adenomatous polyps are histologically categorized as follows: approximately 80-90% are tubular, 5-15% are villous, and 5-10% are tubular/villous. Given the higher risk of a malignant transformation observed in tubular/villous adenomas, patients diagnosed with adenomatous polyposis are at an improved risk of developing CRC. The Wnt/β-catenin pathway plays a key role in the onset of colorectal adenoma; in particular, intestinal cells first acquire loss-of-function mutations in the APC gene that induce the formation of adenomas. Wnt/β-catenin pathway APC, Wnt3a, Wnt5a, LEF1, and BCL9 genes and protein expression analyses were conducted by qRT-PCR and western blot in 68 colonic samples (polyps and adjacent mucosa) from 41 patients, of which 17 were affected by FAP. Ten normal colonic mucosal samples were collected from 10 healthy donors. In this study, both the APC gene and protein were less expressed in the colon tumor compared to the adjacent colonic mucosa. Conversely, the activated β-catenin was more expressed in polyps than in the adjacent mucosa. All results confirmed the literature data on carcinomas. A statistically significant correlation between Wnt3a and BCL9 both in polyps and in the adjacent mucosa underlines that the canonical Wnt pathway is activated in early colon carcinogenesis and that the adjacent mucosa is already altered. This is the first study analyzing the difference in expression of the Wnt/β-catenin pathway in human colorectal adenomas. Understanding the progression from adenomas to colorectal carcinomas is essential for the development of new therapeutic strategies and improving clinical outcomes with the use of APC and β-catenin as biomarkers.

Dietary Milk Phospholipids Increase Body Fat and Modulate Gut Permeability, Systemic Inflammation, and Lipid Metabolism in Mice

The study aimed at how dietary milk polar lipids affect gut permeability, systemic inflammation, and lipid metabolism during diet-induced obesity (DIO). C57BL/6J mice (n = 6x3) were fed diets with 34% fat as energy for 15 weeks: (1) modified AIN-93G diet (CO); (2) CO with milk gangliosides (GG); (3) CO with milk phospholipids (MPL). Gut permeability was assessed by FITC-dextran and sugar absorption tests. Intestinal tight junction proteins were evaluated by Western blot. Plasma cytokines were measured by immunoassay. Body composition was assessed by magnetic resonance imaging. Tissue lipid profiles were obtained by thin layer chromatography. Hepatic expression of genes associated with lipid metabolism was assessed by RT-qPCR. MPL increased the efficiency of converting food into body fat and facilitated body fat accumulation compared with CO. MPL and GG did not affect fasting glucose or HOMA-IR during DIO. MPL increased while GG decreased plasma TG compared with CO. MPL decreased phospholipids subclasses in the muscle while increased those in the liver compared with CO. GG and MPL had little effect on hepatic expression of genes associated with lipid metabolism. Compared with CO, MPL decreased polar lipids content in colon mucosa. Small intestinal permeability decreased while colon permeability increased and then recovered during the feeding period. High-fat feeding increased plasma endotoxin after DIO but did not affect plasma cytokines. MPL and GG did not affect plasma endotoxin, adipokines and inflammatory cytokines. After the establishment of obesity, MPL increased gut permeability to large molecules but decreased intestinal absorption of small molecules while GG tended to have the opposite effects. MPL and GG decreased mannitol and sucralose excretions, which peaked at d 45 in the CO group. MPL decreased occludin in jejunum mucosa compared with CO. GG and MPL did not affect zonula occludens-1 in gut mucosa. In conclusion, during DIO, milk GG decreased gut permeability, and had little effect on systemic inflammation and lipid metabolism; MPL facilitated body fat accumulation, decreased gut permeability, did not affect systemic inflammation.

Determining the expression of vitamin D receptor, regulator of iron metabolism hepcidin and cathelicidin antimicrobial peptide genes for development of future diagnostic and therapeutic options in patients with inflammatory bowel disease.

Patients with inflammatory bowel diseases (IBD) frequently experience malnutrition and develop nutrients deficiencies such as vitamin D or iron. Collectively, 39 patients were recruited to the study - 32 with IBD and 7 patients constituting the control group (CG). Quantitative real-time polymerase chain reaction was used to assess the expression of vitamin D receptor (VDR), hepcidin (HAMP) and cathelicidin antimicrobial peptide (CAMP) in colon mucosa. The mean expression of VDR and CAMP was higher in patients with ulcerative colitis than other groups (VDR vs. CG, p<0.05). However, the mean HAMP expression reached higher values in CG than in groups with IBD. Further research to understand the relationship between the VDR, HAMP and CAMP may constitute the way for development of future diagnostic and therapeutic options in patients with IBD.

Decreased Serum Tryptophan and Severe Ulcerative Damage of Colon Mucosa Identify Inflammatory Bowel Disease Patients With High Risk of Cytomegalovirus Colitis.

Patients with inflammatory bowel disease (IBD) are predisposed to the reactivation of viral infections such as cytomegalovirus (CMV). Clinical discrimination of disease flares and colonic CMV reactivation is difficult in patients with established diagnosis of IBD, and there are no reliable noninvasive diagnostic tools yet. Furthermore, the influence of novel therapeutics including biologicals and Janus kinase inhibitors on the risk of CMV colitis is unclear. The goal of this study was to identify risk factors and clinical determinants of CMV colitis that could serve as minimally invasive markers both for active CMV colitis and relapse. To this end, a retrospective analysis of 376 patients with suspected or confirmed CMV colitis 2016-2023 was performed. Previous administration of systemic steroids increased the odds of CMV colitis to OR 4.6. Biologicals did not change the incidence of CMV colitis but decreased the OR of a relapse to 0.13. Clinical parameters such as severely bloody diarrhea, intense microscopic ulcerative damage, and decreased serum tryptophan correlated with detection of CMV. Importantly, persistent decrease of tryptophan was observed in patients with CMV relapse. Furthermore, tryptophan degradation through the kynurenine pathway was increased in CMV-positive patients. Taken together, we identify decreased serum tryptophan as a novel potential minimally invasive marker to aid identification of IBD patients with active CMV colitis and at high risk for relapse.

Antioxidant Activities and Laxative Effect of Bioactive Compounds from Cynara cardunculus var. sylvestris

The present study aims to investigate the antioxidant and anti-constipation activities of the derived phenolic extracts in ribs wild cardoon (Cynara sylvestris). Analysed extracts (acetone, methanol and aqueous) exhibited high level of phenolic compounds and excellent antioxidant activities with significant IC50 values (p ≤0.05), as assessed by the DPPH radical-scavenging activity (0.84±0.08 - 2.44±0.007 μg/mL), ABTS cationic radical test (0.96 ±0.01- 136.67±6.75 μg/mL) and β-carotene bleaching assay (2.09±0.02-51.12±1.32 μg/mL). Also, higher levels of insoluble dietary fibers were found (56.18 ± 0.91% DW of neutral detergent fiber). The in vivo investigation was performed on Wistar rats to explore the ability of C. sylvestris aqueous extract (CSAE) in the enhancement of the gastrointestinal transit and the treatment of induced constipation by Loperamide (commercialized as Idium). A significant increase of 15, 24.5 and 32.4% in gastrointestinal motility was recordedwhen doses of CSAE increased (75, 150 and 300 mg/kg b.w, respectively). Food intake, water consumption, number and weight of stools were also increased in a dose-dependent manner, compared to the positive control (untreated). Moreover, CSAE provided significantly (p ≤0.05) and dose-dependently protection against oxidative stress by preserving normal antioxidant enzymes activities (SOD and GPx) in intestinal and colonic mucosa, and resorted hepatic enzymes (AST and ALT) and renal (urea and creatinine) levels to normal values. These results can be explained by the abundance of phenolic compounds and insoluble fibers in this plant. Therefore, its use can be encouraged in alimentary and pharmaceutical applications as antioxidant and laxative food supplements.

Effect of probiotics on hematology and histopathology of organs associated with immune system in male and female Wistar rats

In the present study, potential probiotics were isolated from dairy products and characterized on a molecular basis. Male and female (16 + 16, n = 4) Wistar rats were randomly assigned to 5 groups to revise the effects of isolated potential probiotics on the gut immune system: 0-day, negative control, positive control (commercial product Lactobacillus acidophilus-14), laboratory isolated strains Pro-3 (Weissella confusa MZ735961), and Pro-4 (Lactiplantibacillus plantarum MZ727611). Aspartate-aminotransferase, Interleukin-6, bilirubin, and Alanine-transaminase values in both genders were expected but AST and creatinine values had a minor increase in the female group compared to the male probiotic-treated group. Cellular blood count level of mean corpuscular hemoglobin in male groups showed no considerable differences (p = 0.95), while there were decreased differences (p = 0.00) in female groups. The level of mean corpuscular hemoglobin concentration (MCHC) showed distinct variations (p = 0.02) in male groups, while these values were insignificant changes (p > 0.05) among female groups. No damage to the liver, thymus, or colon was ascertained based on morphological findings. The colon wall thickness, external muscle, crypt depth, and mucosa were significantly (p = 0.03) improved in rats given potential probiotics. In conclusion, probiotic supplementation stimulates the immune system. It may protect the intestinal mucosa by strengthening the gut’s immune system and promoting intestinal efficiency (nutrient absorption and number of goblet cells). L. plantarum can therefore offer a reliable, affordable, and safe treatment for functional gastrointestinal illnesses.

Dietary Nitrosamines from Processed Meat Intake as Drivers of the Fecal Excretion of Nitrosocompounds.

Diet is one of the main exogenous sources of potentially carcinogenic nitrosamines (NAs) along with tobacco and cosmetics. Several factors can affect endogenous N-nitroso compounds (NOCs) formation and therefore the potential damage of the intestinal mucosa at initial colorectal cancer stages. To address this issue, 49 volunteers were recruited and classified according to histopathological analyses. Lifestyle and dietary information were registered after colonoscopy. The mutagenicity of fecal supernatants was assayed by a modified Ames test. Fecal heme-derived NOCs and total NOC concentrations were determined by selective denitrosation and chemiluminescence-based detection. Results revealed processed meats as the main source of dietary nitrites and NAs, identifying some of them as predictors of the fecal concentration of heme-derived and total NOCs. Furthermore, increased fecal NOC concentrations were found as the severity of colonic mucosal damage increased from the control to the adenocarcinoma group, these concentrations being strongly correlated with the intake of the NAs N-nitrosodimethylamine, N-nitrosopiperidine, and N-nitrosopyrrolidine. Higher fecal NOC concentrations were also noted in higher fecal mutagenicity samples. These results could contribute to a better understanding of the importance of modulating dietary derived xenobiotics as related with their impact on the intestinal environment and colonic mucosa damage.

Exploring the anti-inflammatory effects of postbiotic proteins from Lactobacillus delbrueckii CIDCA 133 on inflammatory bowel disease model

Lactobacillus delbrueckii CIDCA 133 is a promising health-promoting bacterium shown to alleviate intestinal inflammation. However, the specific bacterial components responsible for these effects remain largely unknown. Here, we demonstrated that consuming extractable proteins from the CIDCA 133 strain effectively relieved acute ulcerative colitis in mice. This postbiotic protein fraction reduced the disease activity index and prevented colon shortening in mice. Furthermore, histological analysis revealed colitis prevention with reduced inflammatory cell infiltration into the colon mucosa. Postbiotic consumption also induced an immunomodulatory profile in colitic mice, as evidenced by both mRNA transcript levels (Tlr2, Nfkb1, Nlpr3, Tnf, and Il6) and cytokines concentration (IL1β, TGFβ, and IL10). Additionally, it enhanced the levels of secretory IgA, upregulated the transcript levels of tight junction proteins (Hp and F11r), and improved paracellular intestinal permeability. More interestingly, the consumption of postbiotic proteins modulated the gut microbiota (Bacteroides, Arkkemansia, Dorea, and Oscillospira). Pearson correlation analysis indicated that IL10 and IL1β levels were positively associated with Bacteroides and Arkkemansia_Lactobacillus abundance. Our study reveals that CIDCA 133-derived proteins possess anti-inflammatory properties in colonic inflammation.

Enzyme/ROS dual-sensitive nanoplatform with on-demand Celastrol release capacity for enhanced ulcerative colitis therapy by ROS scavenging, microbiota rebalancing, inflammation alleviating

BackgroundThe oral administration of drugs for treating ulcerative colitis (UC) is hindered by several factors, including inadequate gastrointestinal stability, insufficient accumulation in colonic lesions, and uncontrolled drug release.MethodsA multiple sensitive nano-delivery system comprising β-cyclodextrin (CD) and 4-(hydroxymethyl)phenylboronic acid (PAPE) with enzyme/reactive oxygen species (ROS) sensitivity was developed to load celastrol (Cel) as a comprehensive treatment for UC.ResultsOwing to the positive charge in the site of inflamed colonic mucosa, the negatively charged nanomedicine (Cel/NPs) could efficiently accumulate. Expectedly, Cel/NPs showed excellent localization ability to colon in vitro and in vivo tests. The elevated concentration of ROS and intestinal enzymes in the colon microenvironment quickly break the CD, resulting in Cel release partially to rebalance microbiota and recover the intestinal barrier. The accompanying cellular internalization of residual Cel/NPs, along with the high concentration of cellular ROS to trigger Cel burst release, could decrease the expression of inflammatory cytokines, inhibit colonic cell apoptosis, promote the macrophage polarization, scavenge ROS, and regulate the TLR4/NF-κB signaling pathway, which certified that Cel/NPs possessed a notably anti-UC therapy outcome.ConclusionsWe provide a promising strategy for addressing UC symptoms via an enzyme/ROS-sensitive oral platform capable of releasing drugs on demand.Graphical

Prokineticin-2 Is Highly Expressed in Colonic Mucosa of Early Parkinson's Disease Patients.

Elevated levels of prokineticin-2 (PK2), regarded as a protein involved in modulating immune/inflammatory responses, have been detected in the substantia nigra, serum, and olfactory neurons of Parkinson's disease (PD) patients. Of note, emerging evidence suggests that gut alterations, including dysbiosis and enteric inflammation, play a role in PD via the gut-brain axis. Our goal was to investigate the expression of PK2 in colonic biopsies of PD patients. Mucosal biopsies from the descending colon were obtained in 11 PD patients and five asymptomatic subjects. Biopsy samples were processed for PK2 immunofluorescence and western blot. We revealed an increased PK2 expression in colonic mucosa from PD patients in the early stages compared to controls. In addition, we found that PK2 was expressed by activated enteric glial cells and macrophages. PK2 is highly expressed within neurogenic/inflammatory cells of colonic mucosa from early PD patients, suggesting a potential role of PK2 in gut inflammation, especially in the early stages of PD. © 2024 International Parkinson and Movement Disorder Society.

Comparative Analysis of Endoscopic Treatment of Superficial Polypoid and Non-Polypoid Neopologists of the Colon Mucosa

Comparative Analysis of Endoscopic Treatment of Superficial Polypoid and Non-Polypoid Neopologists of the Colon Mucosa

An artificial intelligence-assisted system versus white light endoscopy alone for adenoma detection in individuals with Lynch syndrome (TIMELY): an international, multicentre, randomised controlled trial

Computer-aided detection (CADe) systems for colonoscopy have been shown to increase small polyp detection during colonoscopy in the general population. People with Lynch syndrome represent an ideal target population for CADe-assisted colonoscopy because adenomas, the primary cancer precursor lesions, are characterised by their small size and higher likelihood of showing advanced histology. We aimed to evaluate the performance of CADe-assisted colonoscopy in detecting adenomas in individuals with Lynch syndrome. TIMELY was an international, multicentre, parallel, randomised controlled trial done in 11 academic centres and six community centres in Belgium, Germany, Italy, and Spain. We enrolled individuals aged 18 years or older with pathogenic or likely pathogenic MLH1, MSH2, MSH6, or EPCAM variants. Participants were consecutively randomly assigned (1:1) to either CADe (GI Genius) assisted white light endoscopy (WLE) or WLE alone. A centre-stratified randomisation sequence was generated through a computer-generated system with a separate randomisation list for each centre according to block-permuted randomisation (block size 26 patients per centre). Allocation was automatically provided by the online AEG-REDCap database. Participants were masked to the random assignment but endoscopists were not. The primary outcome was the mean number of adenomas per colonoscopy, calculated by dividing the total number of adenomas detected by the total number of colonoscopies and assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT04909671. Between Sept 13, 2021, and April 6, 2023, 456 participants were screened for eligibility, 430 of whom were randomly assigned to receive CADe-assisted colonoscopy (n=214) or WLE (n=216). 256 (60%) participants were female and 174 (40%) were male. In the intention-to-treat analysis, the mean number of adenomas per colonoscopy was 0·64 (SD 1·57) in the CADe group and 0·64 (1·17) in the WLE group (adjusted rate ratio 1·03 [95% CI 0·72-1·47); p=0·87). No adverse events were reported during the trial. In this multicentre international trial, CADe did not improve the detection of adenomas in individuals with Lynch syndrome. High-quality procedures and thorough inspection and exposure of the colonic mucosa remain the cornerstone in surveillance of Lynch syndrome. Spanish Gastroenterology Association, Spanish Society of Digestive Endoscopy, European Society of Gastrointestinal Endoscopy, Societat Catalana de Digestologia, Instituto Carlos III, Beca de la Marato de TV3 2020. Co-funded by the European Union.

Adhesion of Bacteroides vulgatus and Fusobacterium varium to the Colonic Mucosa of Healthy Beagles.

The relative abundances of Bacteroidetes and Fusobacteria phyla have been reported to be decreased in dogs with chronic enteropathies. In colitis, obligate anaerobes (e.g., Bacteroides and Fusobacterium) are likely to vanish in response to the heightened oxidative stress in the colon's inflammatory environment. The ability to adhere to the colonic mucosa is viewed as an essential step for obligate anaerobic bacteria to colonize and subsequently interact with the host's epithelium and immune system. The reintroduction of a balanced community of obligate anaerobic bacteria using probiotics can restore the microbial function in the intestine. We found no studies on dogs regarding the adhesion properties of Bacteriodes vulgatus and Fusobacterium varium on paraffin-embedded canine colonic mucosa. Thus, the objective of this study is to investigate the adhesion capacities of these two bacterial species to paraffin-embedded colonic mucosa from healthy dogs. Additionally, we investigated their hydrophobicity properties to determine whether differences in adhesion capability can be explained by this factor. The results of our study showed that B. vulgatus adhered significantly lower than F. varium to the canine colonic mucosa (p = 0.002); however, B. vulgatus showed higher hydrophobicity (46.1%) than F. varium (12.6%). In conclusion, both bacteria have potential as probiotics, but further studies will be required to determine the efficacy and safety of the strains to be used, which strains to use, and the reasons other than hydrophobicity for attachment.

Unveiling the molecular mechanisms of Dendrobium officinale polysaccharides on intestinal immunity: An integrated study of network pharmacology, molecular dynamics and in vivo experiments

Intestinal immunity plays a pivotal role in overall immunological defenses, constructing mechanisms against pathogens while maintaining balance with commensal microbial communities. Existing therapeutic interventions may lead to drug resistance and potential toxicity when immune capacity is compromised. Dendrobium officinale, a traditional Chinese medicine, contains components identified to bolster immunity. Employing network pharmacology strategies, this study identified constituents of Dendrobium officinale and their action targets in the TCMSP and Swiss Target Prediction databases, and compared them with intestinal immunity-related targets. Protein-protein interaction networks revealed the core targets of Dendrobium officinale polysaccharides, encompassing key pathways such as cell proliferation, inflammatory response, and immune reactions, particularly in association with the Toll-like receptor 4. Molecular docking and molecular dynamics simulation further confirmed the high affinity and stability between Dendrobium officinale polysaccharides and Toll-like receptor 4. In vivo experiments demonstrated that Dendrobium officinale polysaccharides modulates the expression of Toll-like receptor 4 and its downstream key proteins in the colonic mucosa of mice. Consequently, these findings suggest that Dendrobium officinale polysaccharides may serve as a potential modulator for intestinal immune functions, with its mechanism potentially related to the Toll-like receptor 4.

Underlying Mechanism of Fluoride Inhibits Colonic Gland Cells Proliferation by Inducing an Inflammation Response.

The integrity of colonic gland cells is a prerequisite for normal colonic function and maintenance. To evaluate the underlying injury mechanisms in colonic gland cells induced by excessive fluoride (F), forty-eight female Kunming mice were randomly allocated into four groups and treated with different concentrations of NaF (0, 25, 50, and 100 mg F-/L) for 70 days. As a result, the integrity of the colonic mucosa and the cell layer was seriously damaged after F treatment, as manifested by atrophy of the colonic glands, colonic cell surface collapse, breakage of microvilli, and mitochondrial vacuolization. Alcian blue and periodic acid Schiff staining revealed that F decreased the number of goblet cells and glycoprotein secretion. Furthermore, F increased the protein expression of TLR4, NF-κB, and ERK1/2 and decreased IL-6, interfered with NF-κB signaling, following induced colonic gland cells inflammation. The accumulation of F inhibited proliferation via the JAK/STAT signaling pathway, as characterized by decreased mRNA and protein expression of JAK, STAT3, STAT5, PCNA, and Ki67 in colon tissue. Additionally, the expression of CDK4 was up-regulated by increased F concentration. In conclusion, excessive F triggered colonic inflammation and inhibited colonic gland cell proliferation via regulation of the NF-κB and JAK/STAT signaling pathways, leading to histopathology and barrier damage in the colon. The results explain the damaging effect of the F-induced inflammatory response on the colon from the perspective of cell proliferation and provide a new idea for explaining the potential mechanism of F-induced intestinal damage.

Combined gut microbiome and metabolomics to reveal the mechanism of proanthocyanidins from the roots of Ephedra sinica Stapf on the treatment of ulcerative colitis

Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD) that primarily affects mucosa and submucosa of colon and rectum. Although the exact etiology of UC remains elusive, increasing evidence has demonstrated that the gut microbiome and its interaction with host metabolism plays an important role in UC development. The objective of this study was to investigate the therapeutic potential and mechanism of dimeric proanthocyanidins (PAC) enriched from ethyl acetate extract of Ephedra roots on UC from the perspective of gut microbiota and metabolic regulation. In this study, a bio-guided strategy integrating LC-MS analysis, DMAC assay, antioxidant screening, and antiinflammation activity screening was used to enrich dimeric PAC from Ephedra roots, then untargeted metabolomics combined with gut microbiota analysis was performed to investigate the therapeutic mechanism of PRE on UC. This is the first study that combines a bio-guided strategy to enrich dimeric PAC from Ephedra roots and a comprehensive analysis of their effects on gut microbiota and host metabolism. Oral administration of PRE was found to significantly relieve dextran sodium sulfate (DSS)-induced ulcerative colitis symptoms in mice, characterized by the reduced disease activity index (DAI), increased colon length and improved colon pathological damage, together with the down-regulation of colonic inflammatory and oxidative stress levels. In addition, 16 S rRNA sequencing combined with untargeted metabolomics was conducted to reveal the effects of PRE on gut microbiota composition and serum metabolites. PRE improved gut microbiota dysbiosis through increasing the relative abundance of beneficial bacteria Lachnospiraceae_NK4A136_group and decreasing the level of potentially pathogenic bacteria such as Escherichia-Shigella. Serum metabolomics showed that the disturbed tryptophan and glycerophospholipid metabolism in UC mice was restored after PRE treatment. Collectively, PRE was proved to be a promising anti-UC candidate, which deserves further investigation in future research.

Effects of different ratios of soluble to insoluble dietary fiber on growth performance and intestinal health of piglets

This study investigated the impact of different ratios of soluble to insoluble dietary fiber (SDF:IDF) formulations by sugar beet pulp (SBP) supplementation on piglet growth performance, nutrient digestibility, immune function, intestinal morphology, intestinal microbiota and intestinal health. A total of 60 crossbred piglets (Duroc × [Landrace × Yorkshire]) at 40 d old with body weight of 10.0 ± 0.3 kg were randomly assigned to 5 treatments with 6 replicates per treatment and 2 piglets per replicate in a 21-d trial. The dietary treatments included a corn-soybean meal diet (0% SBP supplementation; CON), and diets supplemented with 2%, 4%, 6%, and 8% SBP, representing different SDF:IDF ratios at 10.16%, 13.53%, 16.79%, 19.86%, and 24.81%, respectively. The results indicated that the 8% SBP treatment had a negative effect on feed-to-gain ratio (linear, P = 0.009) compared with the CON treatment (P = 0.021). The apparent total tract digestibility (ATTD) of crude protein was lower in treatments supplemented with SBP (P = 0.002) and showed a linear decrease (P = 0.001), while the ATTD of IDF showed a linear increase (P = 0.037) in four SBP treatments compared to the CON treatment. The 4% SBP treatment increased serum concentrations of triglyceride (quadratic, P = 0.019) and K (linear, P < 0.0037), and decreased alanine transaminase concentration (quadratic, P = 0.015) compared with the CON treatment. The concentrations of Cit, Cys, Ile, Leu, Orn, Arg, taurine, urea, 1-methylhistidine, α-aminoadipic acid, α-aminobutyric acid and cystathionine in the 4% SBP treatment were highest among all treatments (P < 0.05). The serum concentrations of interleukin-6, interleukin-8, interleukin-10, transforming growth factor-β, and tumor necrosis factor-α in the 6% SBP treatment were higher than those in the CON treatment (P < 0.05), which also increased mucin-2 and G protein-coupled receptor 41 mRNA expression (P < 0.05) in colonic mucosa compared with the CON treatment and improved the intestinal barrier function. Diets containing more than 19.86% SDF:IDF could impair the intestinal health in piglets when SBP was used as the SDF source. Supplementing nursery piglet diets with 16.79% to 19.86% SDF:IDF is recommended for improving intestinal barrier function, increasing short-chain fatty acids concentrations, and improving intestinal microbiota composition.