Intestinal Diarrhea Research Articles

A Review of the Phytochemistry and Pharmacological Properties of the Genus Arrabidaea.

The genus Arrabidaea, consisting of ~170 species, belongs to the family Bignoniaceae, distributed around the Neotropics and temperate zone. The center of diversity of the family is in Brazil, where 56 genera and about 340 species exist. Most species of the genus Arrabidaea are traditionally utilized as diuretics and antiseptics, as well as for treating intestinal colic, diarrhea, kidney stones, rheumatoid arthritis, wounds, and enterocolitis. The genus is chemically diverse with different substance classes; most of them are triterpenes, phenolic acids, and flavonoids, and they exhibit valuable pharmacological properties, such as antitumor, antioxidant, leishmanicidal, trypanocidal, anti-inflammatory, and healing properties. This review presents information on the chemical constituents isolated from seven Arrabidaea species, and the pharmacological activities of the extracts, fractions and pure substances isolated since 1994, obtained from electronic databases. The various constituents present in the different species of this genus demonstrate a wide pharmacological potential for the development of new therapeutic agents, however its potential has been underestimated.

Astragaloside IV Alleviates Intestinal Barrier Dysfunction via the AKT-GSK3β-β-Catenin Pathway in Peritoneal Dialysis.

Background and aims: Long-term peritoneal dialysis (PD) causes intestinal dysfunction, including constipation, diarrhea, or enteric peritonitis. However, the etiology and pathogenesis of these complications are still unclear and there are no specific drugs available in the clinic. This study aims to determine whether Astragaloside IV (AS IV) has therapeutic value on PD-induced intestinal epithelial barrier dysfunction in vivo and in vitro. Methods: We established two different long-term PD treatment mice models by intraperitoneally injecting 4.25% dextrose-containing peritoneal dialysis fluid (PDF) in uremia mice and normal mice, which were served as controls. In addition, PDF was applied to T84 cells in vitro. The therapeutic effects of AS IV on PD-induced intestinal dysfunction were then examined by histopathological staining, transmission electron microscopy, western blotting, and reverse transcription polymerase chain reaction. The protein levels of protein kinase B (AKT), glycogen synthase kinase 3β (GSK-3β) and β-catenin were examined after administration of AS IV. Results: In the present study, AS IV maintained the intestinal crypt, microvilli and desmosome structures in an orderly arrangement and improved intestinal epithelial permeability with the up-regulation of tight junction proteins in vivo. Furthermore, AS IV protected T84 cells from PD-induced damage by improving cell viability, promoting wound healing, and increasing the expression of tight junction proteins. Additionally, AS IV treatment significantly increased the levels of phosphorylation of AKT, inhibited the activity GSK-3β, and ultimately resulted in the nuclear translocation and accumulation of β-catenin. Conclusion: These findings provide novel insight into the AS IV-mediated protection of the intestinal epithelial barrier from damage via the AKT-GSK3β-β-catenin signal axis during peritoneal dialysis.

Microbiomics Revealed the Disturbance of Intestinal Balance in Rabbits with Diarrhea Caused by Stopping the Use of an Antibiotic Diet.

The harmful effects of diarrhea on the growth performance of rabbits have been well documented, but the details of the potential mechanism of intestinal diarrhea when antibiotics are stopped are still unclear. Here, PacBio sequencing technology was used to sequence the full length 16S rRNA gene of the microbiota of intestinal content samples, in order to characterize the bacterial communities in the small intestine (duodenum and jejunum) and large intestine (colon and cecum) in normal Hyplus rabbits and those with diarrhea. The histopathological examination showed that intestinal necrosis occurred in different degrees in the diarrhea group, and that the mucosal epithelium was shed and necrotic, forming erosion, and the clinical manifestation was necrosis. However, the intestinal tissue structure of the normal group was normal. The results revealed that there were significant differences in bacterial communities and structure between the diarrhea and normal groups of four intestinal segments (p < 0.05). In general, 16 bacterial phyla, 144 bacterial genera and 22 metabolic pathways were identified in the two groups. Tax4Fun functional prediction analysis showed that KEGG related to amino acid metabolism and energy metabolism was enriched in the large intestines of rabbits with diarrhea, whereas lipid metabolism was more abundant in the small intestine of rabbits with diarrhea. In conclusion, the change in the relative abundance of the identified dominant microbiota, which could deplete key anti-inflammatory metabolites and lead to bacterial imbalance and diarrhea, resulted in diarrhea in Hyplus rabbits that stopped using antibiotics.

Differences in the Intestinal Microbiome Associated with Diarrhea during Lenvatinib Treatment for Hepatocellular Carcinoma

Introduction: Lenvatinib has been widely used for the treatment of advanced hepatocellular carcinoma (HCC). Some adverse events, including diarrhea, have been reported for lenvatinib. Diarrhea may be associated with the changes in the intestinal microbiome; however, the underlying mechanism has not been elucidated. Aim: In this study, we aimed to investigate the relationship between the intestinal microbiome and diarrhea caused by lenvatinib via analysis of fecal samples collected before treatment. Methods: A total of 21 patients with advanced HCC who were treated with lenvatinib were enrolled. Fecal samples were collected from patients. The patients were divided into diarrhea (n = 8) and nondiarrhea groups (n = 12). We compared the characteristics of patients, incidence of adverse events, composition of the intestinal microbiome, and enrichment of functional pathways between both groups using QIIME2 and PICRUSt2. Results: The median age of the two groups was 73 years. The nondiarrhea group comprised a relatively higher number of male patients than the diarrhea group; however, there were no significant differences in patient characteristics between both groups. The proportion of the microbiome was similar, and alpha and beta diversities were not significantly different between both groups. The relative abundance of order Bacteroidales, including Parabacteroides and Prevotella, was higher in the diarrhea group than in the nondiarrhea group. PICRUSt2 analysis showed some metabolic pathways, including butanoate (butyrate) metabolism, were enriched in the nondiarrhea group when compared with those in the diarrhea group. Conclusion: Differences in the intestinal microbiomes and their functions may influence the incidence of diarrhea during lenvatinib treatment.

Sodium Humate Alleviates Enterotoxigenic Escherichia coli-Induced Intestinal Dysfunction via Alteration of Intestinal Microbiota and Metabolites in Mice.

Enterotoxigenic Escherichia coli (ETEC) can damage intestinal epithelial barrier function and lead to serious intestinal diarrhea in newborns and young animals. Sodium humate (HNa) is natural organic bioactive compound possessing antibacterial, anti-inflammatory, and anti-diarrheal properties. This study investigated the alleviative potential of HNa on the impaired intestinal barrier and intestinal inflammation, and regulatory effects on gut microbiota and metabolites in ETEC K88 infected mice. A total of 30 female mice were randomly assigned into three groups. The mice in the control and ETEC groups were gavaged with 0.2 mL of sterile saline, while the mice in the ETEC + HNa group were gavaged with 0.2 mL of 5% HNa, daily. On day 8, the mice in ETEC and ETEC + HNa group were challenged with ETEC K88. The trial lasted for 12 days. HNa administration elevated ETEC K88-induced body weight loss and ameliorated jejunum and colon pathological injury. HNa also reduced the levels of pro-inflammatory cytokines in the serum, jejunum, and colon. Additionally, HNa reduced intestinal barrier damage by up-regulating the expression of tight junction proteins (TJPs) and mucosal repair factors. 16s rDNA gene sequencing results showed that HNa increased the abundance of beneficial bacteria Lactobacillus, Prevotella_9, and Odoribacter but decreased the abundance of pathogenic bacteria Escherichia and Gastranaerophilales in the feces of mice. Moreover, metabolomic analysis revealed that the concentrations of 15 metabolites, the pathways of protein digestion and absorption, and propanoic acid metabolism were changed by HNa administration. In conclusion, HNa could alleviate ETEC K88-induced intestinal dysfunction through restoring intestinal barrier integrity, modulating gut microbiota, and metabolites.

Major Constituents From Brucea javanica and Their Pharmacological Actions.

Brucea javanica (Ya-dan-zi in Chinese) is a well-known Chinese herbal medicine, which is traditionally used in Chinese medicine for the treatment of intestinal inflammation, diarrhea, malaria, and cancer. The formulation of the oil (Brucea javanica oil) has been widely used to treat various types of cancer. It has also been found that B. javanica is rich in chemical constituents, including quassinoids, triterpenes, alkaloids and flavonoids. Pharmacological studies have revealed that chemical compounds derived from B. javanica exhibit multiple bioactivities, such as anti-cancer, anti-bacterial, anti-diabetic, and others. This review provides a comprehensive summary on the pharmacological properties of the main chemical constituents presented in B. javanica and their underlying molecular mechanisms. Moreover, the review will also provide scientific references for further research and development of B. javanica and its chemical constituents into novel pharmaceutical products for disease management.

Subtilase cytotoxin from Shiga-toxigenic Escherichia coli impairs the inflammasome and exacerbates enteropathogenic bacterial infection

SummarySubtilase cytotoxin (SubAB) is an AB5 toxin mainly produced by the locus of enterocyte effacement-negative Shiga-toxigenic Escherichia coli (STEC) strain such as O113:H21, yet the contribution of SubAB to STEC infectious disease is unclear. We found that SubAB reduced activation of the STEC O113:H21 infection-induced non-canonical NLRP3 inflammasome and interleukin (IL)-1β and IL-18 production in murine macrophages. Downstream of lipopolysaccharide signaling, SubAB suppressed caspase-11 expression by inhibiting interferon-β/STAT1 signaling, followed by disrupting formation of the NLRP3/caspase-1 assembly. These inhibitions were regulated by PERK/IRE1α-dependent endoplasmic reticulum (ER) stress signaling initiated by cleavage of the host ER chaperone BiP by SubAB. Our murine model of SubAB-producing Citrobacter rodentium demonstrated that SubAB promoted C. rodentium proliferation and worsened symptoms such as intestinal hyperplasia and diarrhea. These findings highlight the inhibitory effect of SubAB on the NLRP3 inflammasome via ER stress, which may be associated with STEC survival and infectious disease pathogenicity in hosts.

SAHA Alleviates Diarrhea-Predominant Irritable Bowel Syndrome Through Regulation of the p-STAT3/SERT/5-HT Signaling Pathway.

ObjectiveIrritable bowel syndrome (IBS) is characterized by abdominal pain, bloating, and stool irregularity. However, its pathophysiological mechanisms, which trigger intestinal motility disorders and diarrhea leading to diarrhea-predominant IBS (D-IBS), remain largely unknown.MethodsIn the present study, we established a D-IBS rat model by mother–infant separation combined with restraint stress. Then we exposed the modelled rats to suberoylanilide hydroxamic acid (SAHA) treatment, followed by determination of their visceral sensitivity. Toluidine blue staining served to reveal the effects of SAHA treatment on mast cells of D-IBS model rats. Then we measured the expression of serotonin (5-hydroxytryptamine; 5-HT) and its receptors by ELISA.ResultsConstruction of short hairpin RNA (sh)-serotonin transporter (SERT) lentivirus vectors verified the regulation of the 5-HT signaling pathway by phosphorylated (p)-STAT/SERT. SAHA treatment of D-IBS model rats reduced the fecal water content, electromyography integral change rate, abdominal withdrawal reflex score, and number of mast cells, as well as the expression of 5-HT type 3A (5-HT3AR), 3B receptor (5-HT3BR), and 4 receptor (5-HT4R) receptors. The treatment also elevated the expression of signal transducer and activator for transcription 3 (STAT3) and SERT. Activation of p-STAT3 may reverse the inhibitory effect of SAHA on the elevated visceral sensitivity of D-IBS model rats. Moreover, SAHA promoted the transcription of SERT through repression of the p-STAT3/5-HT signaling, thereby inhibiting the visceral sensitivity of D-IBS model rats.ConclusionThis study highlights that SAHA treatment can alleviate D-IBS through regulation of the p-STAT3/SERT/5-HT signaling pathway.

Intestinal secretory mechanisms and diarrhea.

One of the primary functions of the intestinal epithelium is to transport fluid and electrolytes to and from the luminal contents. Under normal circumstances, absorptive and secretory processes are tightly regulated such that absorption predominates, thereby enabling conservation of the large volumes of water that pass through the intestine each day. However, in conditions of secretory diarrhea, this balance becomes dysregulated, so that fluid secretion, driven primarily by Cl- secretion, overwhelms absorptive capacity, leading to increased loss of water in the stool. Secretory diarrheas are common and include those induced by pathogenic bacteria and viruses, allergens, and disruptions to bile acid homeostasis, or as a side effect of many drugs. Here, we review the cellular and molecular mechanisms by which Cl- and fluid secretion in the intestine are regulated, how these mechanisms become dysregulated in conditions of secretory diarrhea, currently available and emerging therapeutic approaches, and how new strategies to exploit intestinal secretory mechanisms are successfully being used in the treatment of constipation.

Could paraprobiotics be a safer alternative to probiotics for managing cancer chemotherapy-induced gastrointestinal toxicities?

Clinical oncology has shown outstanding progress improving patient survival due to the incorporation of new drugs. However, treatment success may be reduced by the emergency of dose-limiting side effects, such as intestinal mucositis and diarrhea. Mucositis and diarrhea management is symptomatic, and there is no preventive therapy. Bacterial and fungal-based compounds have been suggested as an alternative for preventing the development of diarrhea in cancer patients. Using probiotics is safe and effective in immunocompetent individuals, but concerns remain during immunosuppressive conditions. Paraprobiotics, formulations composed of non-viable microorganisms, have been proposed to overcome such limitation. The present literature review discusses current evidence regarding the possible use of paraprobiotics as an alternative to probiotics to prevent gastrointestinal toxicity of cancer chemotherapy.

Visible intestinal peristalsis and chronic diarrhea due to a rare lymphoproliferative disease.

We present the case of a 45-year-old man with watery diarrhea for 2 years, leading to marked weight loss (52 kg). On admission, the patient presented with pallor, dehydration and cachexia. Abdominal examination revealed increased bowel sounds, painful and visible intestinal peristalsis, suggesting intestinal obstruction. There was no response to a gluten-free diet and nutritional support. Finally, the patient developed pulmonary infection, septic shock and died 3 months after admission. The diagnosis of CD4+/CD8+ indolent T-cell lymphoma of the GI tract was made post-mortem.

Antimicrobials added to the feed of weaned piglets at two ages improves the molecular expression of intestinal barrier proteins

Context Weaning is the most critical period during a pig’s life, because it is a challenge with the change of environment, and the digestive system is not adapted to a solid diet at the time of weaning, favouring the appearance of intestinal disorders, infections and diarrhoea. Aims To quantify the gene abundance of intestinal barrier tight junction proteins in pigs fed diets added with antimicrobials and weaned at two ages. Methods A total of 150 pigs weaned at two ages (21 and 28 days) were distributed into groups: Control Diet 1 (D1-Ctrl) without antimicrobial; Diet 2 (D2-Ant): Ctrl with an antibiotic (bacitracin zinc); Diet 3 (D3-Prob): Ctrl with Bacillus subtilis PB6 (PTA-6737); Diet 4 (D4-OEO): Ctrl with oregano essential oil (OEO; Lippia origanoides); Diet 5 (D5-OA): Ctrl with a mixture of organic acids. On post-weaning Days 1, 15 and 30, pigs were euthanised, and a portion of the jejunum was removed to assess the gene abundance of the intestinal tight junction proteins (occludin-OCLN, zonula occludens-ZO-1 and claudins-CLAU) that were measured by qPCR. Key results The pigs fed the diet with the addition of D3-Prob and D4-OEO showed a higher abundance (P &lt; 0.05) of intestinal barrier tight junction protein genes (CLAU-1, CLAU-4, OCLN, ZO-1) compared with the other diets. This abundance was observed in both piglets weaned early, at 21 days, and later at 28 days of age, where, in addition, a statistically significant difference between weaning ages (P &lt; 0.05) was evidenced in favour of later weaning. Conclusions The addition of probiotics in the growth phase, together with weaning at 28 days of age, have a favourable impact on the intestinal digestive function of pigs, being able to influence morphometric and productive parameters, and serve as a basis for the analysis of molecular research related to intestinal health. Implications This research provides a basis for the use of natural nutritional alternatives, such as probiotic bacteria, as alternatives to growth-promoting antibiotics in the feed of growing pigs; in addition to encouraging a better adaptation of the piglet to the post-weaning phase, through late weaning.

Carvone Attenuates Irinotecan-Induced Intestinal Mucositis and Diarrhea in Mice

Intestinal mucositis is referring to inflammatory or ulcerative lesions of the oral or gastrointestinal tract; one of the main reasons is treatment with cancer chemotherapy. The prodrug Irinotecan is converted by carboxylesterase to the active metabolite SN-38, conjugated by UGT enzyme to SN-38G and then deconjugated by ?-glucoronidase produced by intestinal bacterial flora to produce SN-38. Irinotecan induces intestinal mucositis and diarrhea due to increased concentration of its active metabolite (SN-38).To evaluate the protective effect of carvone, I.P injection of (75mg/kg/day) of irinotecan for 4 days to induce intestinal mucositis, carvone administered to mice orally for 6 days starting from day 1. Results showed that carvone (50mg/Kg and 100mg/Kg) significantly and by dose-dependent manner attenuated body weight loss (-9.39±1.56 vs. -23.21±1.65 %), diarrhea scores (0.50±0.244 vs. 2.67±0.211) and serum TNF-? level (1361.44±55.075 vs. 3402.12±321.56 ng/ml) compared to experimental model group. In conclusion, carvone exerted a dose dependent anti-inflammatory and protective effect by attenuation irinotecan-induced intestinal mucositis.

Oral administration of cystine and theanine attenuates 5-fluorouracil-induced intestinal mucositis and diarrhea by suppressing both glutathione level decrease and ROS production in the small intestine of mucositis mouse model

BackgroundChemotherapy is frequently used in cancer treatment; however, it may cause adverse events, which must be managed. Reactive oxygen species (ROS) have been reported to be involved in the induction of intestinal mucositis and diarrhea, which are common side effects of treatment with fluoropyrimidine 5-fluorouracil (5-FU). Our previous studies have shown that oral administration of cystine and theanine (CT) increases glutathione (GSH) production in vivo. In the present study, we hypothesized that CT might inhibit oxidative stress, including the overproduction of ROS, and attenuate 5-FU-induced mucositis and diarrhea.MethodsWe investigated the inhibitory effect of CT administration on mucositis and diarrhea, as well as its mechanism, using a mouse model of 5-FU-induced intestinal mucositis.ResultsCT administration suppressed 5-FU-induced diarrhea and weight loss in the studied mice. After 5-FU administration, the GSH level and the GSH/GSSG ratio in the small intestine mucosal tissue decreased compared to normal control group; but CT administration improved the GSH/GSSG ratio to normal control levels. 5-FU induced ROS production in the basal region of the crypt of the small intestine mucosal tissue, which was inhibited by CT. CT did not affect the antitumor effect of 5-FU.ConclusionsCT administration suppressed intestinal mucositis and diarrhea in a mouse model. This finding might be associated with the antioxidant characteristics of CT, including the improved rate of GSH redox and the reduced rate of ROS production in the small intestine mucosal tissue. CT might be a suitable candidate for the treatment of gastrointestinal mucositis associated with chemotherapy.

Inhibitory Activity of 4-O-Benzoyl-3'-O-(OMethylsinapoyl) Sucrose from Polygala tenuifolia on Escherichia coliβ-Glucuronidase.

Bacterial β-glucuronidase in the intestine is involved in the conversion of 7-ethyl-10- hydroxycamptochecin glucuronide (derived from irinotecan) to 7-ethyl-10-hydroxycamptothecin, which causes intestinal bleeding and diarrhea (side effects of anti-cancer drugs). Twelve compounds (1-12) from Polygala tenuifolia were evaluated in terms of β-glucuronidase inhibition in vitro. 4-O-Benzoyl-3'-O-(O-methylsinapoyl) sucrose (C3) was highly inhibitory at low concentrations. C3 (an uncompetitive inhibitor) exhibited a ki value of 13.4 μM; inhibitory activity increased as the substrate concentration rose. Molecular simulation revealed that C3 bound principally to the Gln158-Tyr160 enzyme loop. Thus, C3 will serve as a lead compound for development of new β- glucuronidase inhibitors.

Subtilase Cytotoxin from Shiga-Toxigenic Escherichia Coli Impairs the Inflammasome and Exacerbates Enteropathogenic Bacterial Infection

Subtilase cytotoxin (SubAB) is an AB5 toxin mainly produced by the locus of enterocyte effacement-negative Shiga-toxigenic Escherichia coli (STEC) strain such as O113:H21, yet the contribution of SubAB to STEC infectious disease is unclear. We found that SubAB reduced activation of the STEC O113:H21 infection-induced non-canonical NLRP3 inflammasome and interleukin (IL)-1β and IL-18 production in murine macrophages. Downstream of lipopolysaccharide signaling, SubAB suppressed caspase-11 expression by inhibiting interferon-β/STAT1 signaling, followed by disrupting formation of the NLRP3/caspase-1 assembly. These inhibitions were regulated by PERK/IRE1α-dependent endoplasmic reticulum (ER) stress signaling initiated by cleavage of the host ER chaperone BiP by SubAB. Our murine model of SubAB-producing Citrobacter rodentium demonstrated that SubAB promoted C. rodentium proliferation and worsened symptoms such as intestinal hyperplasia and diarrhea. These findings highlight the inhibitory effect of SubAB on the NLRP3 inflammasome via ER stress, which may be associated with STEC survival and infectious disease pathogenicity in hosts.

Selected Species of the Genus Phellinus - Chemical Composition, Biological Activity, and Medicinal Applications.

This study presents the current knowledge on chemical composition, biological activity, and possible medicinal applications of Phellinus igniarius, Phellinus pini, Phellinus pomaceus, and Phellinus robustus. These inedible arboreal species are phytopathogens that cause the enzymatic decomposition of wood. These species belong to the medicinal mushrooms and have been known for centuries in the traditional medicine of the Far East. They have been used as an effective remedy for stomach and intestinal ailments, diarrhea, and hemorrhages. Mycochemical studies have proved the presence of polysaccharides, phenolic compounds, and terpenoids. These compounds show biological activities such as anticancer, antioxidant, antiangiogenic, and antiviral. Research studies conducted using modern analytical methods have advanced the knowledge on the potential therapeutic use of compounds isolated not only from the fruiting bodies but also from biomass obtained with in vitro biotechnological methods.

Celiac Disease Prevalence in Patients with Chronic Noninflammatory Diarrhea in 2017

Introduction: Celiac disease is an autoimmune disorder. Eating gluten, which is part of the cereals, can lead to intestinal mucosal injury and diarrhea. Although celiac disease is more common today with non-digestive symptoms, we sometimes encounter cases of chronic non-inflammatory diarrhea, which is one of the clinical manifestations of celiac disease. This study was performed to evaluate the prevalence of celiac disease in patients with chronic non-inflammatory diarrhea. Because diarrhea in celiac disease has distinct and efficient treatment we decided to do this study to evaluate the prevalence of celiac disease in patients with chronic non-inflammatory diarrhea. Methods: This was a descriptive cross sectional study on 200 patients with chronic non-inflammatory diarrhea in Yazd in 2017. Stool exam and tissue transglutaminase Antibody (TTG Ab) was done for the patients; upper endoscopy and duodenum biopsy was done for the patients with high serum TTG Ab. Findings analyzed in SPSS.ver.17 statistical software. Chi-Square, t-test and Fisher Exact tests were used for statistical analysis. P-value less than 0.05 was considered significant. Results: Two hundred patients, including 93 (46.5%) men and 107 women (53.5%) participated in this study. The average age was 34.32 ± 17.84 years. Among these cases, 31 patients (15.5%) had celiac disease. Among cases of celiac (16.1%), 15 (16.1%) were male and 16 (15%) were female. The relative frequency of celiac disease was the same in both sexes and in all age groups. Conclusion: Significant portion of patients (15.5%) with chronic non-inflammatory diarrhea has celiac disease.

S100B Inhibition Attenuates Intestinal Damage and Diarrhea Severity During Clostridioides difficile Infection by Modulating Inflammatory Response

The involvement of the enteric nervous system, which is a source of S100B, in Clostridioides difficile (C. difficile) infection (CDI) is poorly understood although intestinal motility dysfunctions are known to occur following infection. Here, we investigated the role of S100B in CDI and examined the S100B signaling pathways activated in C. difficile toxin A (TcdA)- and B (TcdB)-induced enteric glial cell (EGC) inflammatory response. The expression of S100B was measured in colon tissues and fecal samples of patients with and without CDI, as well as in colon tissues from C. difficile-infected mice. To investigate the role of S100B signaling in IL-6 expression induced by TcdA and TcdB, rat EGCs were used. Increased S100B was found in colonic biopsies from patients with CDI and colon tissues from C. difficile-infected mice. Patients with CDI-promoted diarrhea exhibited higher levels of fecal S100B compared to non-CDI cases. Inhibition of S100B by pentamidine reduced the synthesis of IL-1β, IL-18, IL-6, GMCSF, TNF-α, IL-17, IL-23, and IL-2 and downregulated a variety of NFκB-related genes, increased the transcription (SOCS2 and Bcl-2) of protective mediators, reduced neutrophil recruitment, and ameliorated intestinal damage and diarrhea severity in mice. In EGCs, TcdA and TcdB upregulated S100B-mediated IL-6 expression via activation of RAGE/PI3K/NFκB. Thus, CDI appears to upregulate colonic S100B signaling in EGCs, which in turn augment inflammatory response. Inhibition of S100B activity attenuates the intestinal injury and diarrhea caused by C. difficile toxins. Our findings provide new insight into the role of S100B in CDI pathogenesis and opens novel avenues for therapeutic interventions.

Protective and Anti-Inflammatory Effects of Protegrin-1 on Citrobacter rodentium Intestinal Infection in Mice.

Infectious intestinal colitis, manifesting as intestinal inflammation, diarrhea, and epithelial barrier disruption, affects millions of humans worldwide and, without effective treatment, can result in death. In addition to this, the significant rise in antibiotic-resistant bacteria poses an urgent need for alternative anti-infection therapies for the treatment of intestinal disorders. Antimicrobial peptides (AMPs) are potential therapies that have broad-spectrum antimicrobial activity due to their (1) unique mode of action, (2) broad-spectrum antimicrobial activity, and (3) protective role in GI tract maintenance. Protegrin-1 (PG-1) is an AMP of pig origin that was previously shown to reduce the pathological effects of chemically induced digestive tract inflammation (colitis) and to modulate immune responses and tissue repair. This study aimed to extend these findings by investigating the protective effects of PG-1 on pathogen-induced colitis in an infection study over a 10-day experimental period. The oral administration of PG-1 reduced Citrobacter rodentium intestinal infection in mice as evidenced by reduced histopathologic change in the colon, prevention of body weight loss, milder clinical signs of disease, and more effective clearance of bacterial infection relative to challenged phosphate-buffered saline (PBS)-treated mice. Additionally, PG-1 treatment altered the expression of various inflammatory mediators during infection, which may act to resolve inflammation and re-establish intestinal homeostasis. PG-1 administered in its mature form was more effective relative to the pro-form (ProPG-1). To our knowledge, this is the first study demonstrating the protective effects of PG-1 on infectious colitis.