Modeling the cell biology of monogenetic intestinal epithelial disorders.

Monogenetic variants are responsible for a range of congenital human diseases. Variants in genes that are important for intestinal epithelial function cause a group of disorders characterized by severe diarrhea and loss of nutrient absorption called congenital diarrheas and enteropathies (CODEs). CODE-causing genes include nutrient transporters, enzymes, structural proteins, and vesicular trafficking proteins in intestinal epithelial cells. Several severe CODE disorders result from the loss-of-function in key regulators of polarized endocytic trafficking such as the motor protein, Myosin VB (MYO5B), as well as STX3, STXBP2, and UNC45A. Investigations of the cell biology and pathophysiology following loss-of-function in these genes have led to an increased understanding of both homeostatic and pathological vesicular trafficking in intestinal epithelial cells. Modeling different CODEs through investigation of changes in patient tissues, coupled with the development of animal models and patient-derived enteroids, has provided critical insights into the enterocyte differentiation and function. Linking basic knowledge of cell biology with the phenotype of specific patient variants is a key step in developing effective treatments for rare monogenetic diseases. This knowledge can also be applied more broadly to our understanding of common epithelial disorders.

Clinical Implications of Microscopic Colitis Isolated to Polyps.

Microscopic colitis is generally identified on random colon biopsies performed for chronic diarrhea, but rarely incidental polyps have histologic features of microscopic colitis. We compared patients with polypoid microscopic colitis to control patients with conventional polyps to determine the implications of polypoid microscopic colitis.Medical records were searched for patients without prior or concurrent microscopic colitis who were found to have polypoid microscopic colitis. For each patient with polypoid microscopic colitis, one patient with conventional polyps was selected as a control. We reviewed the histologic features of each polypoid microscopic colitis specimen, and evaluated endoscopic and clinical findings for polypoid microscopic colitis patients and controls.Twenty-six patients with polypoid microscopic colitis were identified with histologic features of collagenous colitis in 8 patients (31%) and lymphocytic colitis in 18 patients (69%). Polypoid microscopic colitis was unifocal in 14 patients (54%) and multifocal in 12 patients (46%). Patients with polypoid microscopic colitis were older than control patients (median age = 60 years vs 66 years, P = .04). On follow-up 7 patients with polypoid microscopic colitis (33%) developed chronic diarrhea compared to 3 (12%) controls (P = .16). Of patients with follow-up biopsies, 1 patient with polypoid microscopic colitis (13%) and no control patients developed microscopic colitis (P = 1).Polypoid microscopic colitis may be identified in asymptomatic patients and most patients do not develop chronic diarrhea, but some patients with polypoid microscopic colitis develop diarrhea (33% vs 12% in controls) or conventional microscopic colitis on follow-up. Thus pathologists should distinguish polypoid microscopic colitis from conventional microscopic colitis but may inform clinicians of the uncertain association with chronic diarrhea to guide decisions regarding follow-up.

T-independent B-cell effect of agents associated with swine grower-finisher diarrhea.

Swine dysentery, spirochetal colitis, and salmonellosis are production-limiting enteric diseases of global importance to the swine industry. Despite decades of efforts, mitigation of these diseases still relies on antibiotic therapy. A common knowledge gap among the 3 agents is the early B-cell response to infection in pigs. Thus, this study aimed to characterize the porcine B-cell response to Brachyspira hyodysenteriae, Brachyspira hampsonii (virulent and avirulent strains), Brachyspira pilosicoli, and Salmonella Typhimurium, the agents of the syndromes mentioned above. Immortalized porcine B-cell line derived from a crossbred pig with lymphoma were co-incubated for 8 h with each pathogen, as well as E. coli lipopolysaccharide (LPS) and a sham-inoculum (n = 3/treatment). B-cell viability following treatments was evaluated using trypan blue, and the expression levels of B-cell activation-related genes was profiled using reverse transcription quantitative PCR. Only S. Typhimurium and LPS led to increased B-cell mortality. B. pilosicoli downregulated B-lymphocyte antigen (CD19), spleen associated tyrosine Kinase (syk), tyrosine-protein kinase (lyn), and Tumour Necrosis Factor alpha (TNF-α), and elicited no change in immunoglobulin-associated beta (CD79b) and swine leukocyte antigen class II (SLA-DRA) expression levels, when compared to the sham-inoculated group. In contrast, all other treatments significantly upregulated CD79b and stimulated responses in other B-cell downstream genes. These findings suggest that B. pilosicoli does not elicit an immediate T-independent B-cell response, nor does it trigger antigen-presenting mechanisms. All other agents activated at least one trigger within the T-independent pathways, as well as peptide antigen presenting mechanisms. Future research is warranted to verify these findings in vivo.

Mini-review: Enteric glial cell reactions to inflammation and potential therapeutic implications for GI diseases, motility disorders, and abdominal pain.

Enteric glial cells are emerging as critical players in the regulation of intestinal motility, secretion, epithelial barrier function, and gut homeostasis in health and disease. Enteric glia react to intestinal inflammation by converting to a 'reactive glial phenotype' and enteric gliosis, contributing to neuroinflammation, enteric neuropathy, bowel motor dysfunction and dysmotility, diarrhea or constipation, 'leaky gut', and visceral pain. The focus of the minireview is on the impact of inflammation on enteric glia reactivity in response to diverse insults such as intestinal surgery, ischemia, infections (C. difficile infection, HIV-Tat-induced diarrhea, endotoxemia and paralytic ileus), GI diseases (inflammatory bowel diseases, diverticular disease, necrotizing enterocolitis, colorectal cancer) and functional GI disorders (postoperative ileus, chronic intestinal pseudo-obstruction, constipation, irritable bowel syndrome). Significant progress has been made in recent years on molecular pathogenic mechanisms of glial reactivity and enteric gliosis, resulting in enteric neuropathy, disruption of motility, diarrhea, visceral hypersensitivity and abdominal pain. There is a growing number of glial molecular targets with therapeutic implications that includes receptors for interleukin-1 (IL-1R), purines (P2X2R, A2BR), PPARα, lysophosphatidic acid (LPAR1), Toll-like receptor 4 (TLR4R), estrogen-ß receptor (ERß) adrenergic α-2 (α-2R) and endothelin B (ETBR), connexin-43 / Colony-stimulating factor 1 signaling (Cx43/CSF1) and the S100ß/RAGE signaling pathway. These exciting new developments are the subject of the minireview. Some of the findings in pre-clinical models may be translatable to humans, raising the possibility of designing future clinical trials to test therapeutic application(s). Overall, research on enteric glia has resulted in significant advances in our understanding of GI pathophysiology.

Correlations Between Gastrointestinal Symptoms and Endoscopic-Histologic Disease Activity in Adults with Ulcerative Colitis.

INTRODUCTION: Discordance between gastrointestinal (GI) symptoms and endoscopic inflammation in patients with ulcerative colitis (UC) is known. However, the correlations between symptoms and endoscopic and histologic (endo-histologic) mucosal healing and remains unknown. METHODS: We performed a secondary analysis of prospectively collected clinical, endoscopic, and histologic data on 254 colonoscopies from 179 unique adults at a tertiary referral center from 2014 to 2021. Spearman's rank was used to assess the correlation between patient reported outcomes and objective assessments of disease activity, as measured by validated instruments: Two-item patient-reported outcome measure (PRO-2) for stool frequency and rectal bleeding, the Ulcerative Colitis Endoscopic Index of Severity (UCEIS) for endoscopic inflammation, and the Geboes score for histologic inflammation. The predictive value of objective assessments of inflammation and clinical symptoms was described using sensitivity, specificity, and positive/negative predictive value. RESULTS: One-quarter (28%, 72/254) of cases were in endo-histologic remission; of these, 25% (18/72) report GI symptoms (22% diarrhea; 6% rectal bleeding). Endo-histologically active disease had higher sensitivity (95% rectal bleeding; 87% diarrhea) and negative predictive value (94% rectal bleeding, 78% diarrhea) for clinically active disease compared to active disease on endoscopic (77%) or histologic assessment only (80%). The specificity of endo/histologic inflammation for GI symptoms was < 65%. PRO-2 was positively correlated with endoscopic disease activity (Spearman's rank 0.57, 95% CI 0.54-0.60, p < 0.0001) and histologic disease activity (Spearman's rank 0.49, 0.45-0.53, p < 0.0001). CONCLUSION: One-quarter of patients with ulcerative colitis in endo-histologic (deep) remission have gastrointestinal symptoms, more commonly with diarrhea than rectal bleeding. Endo-histologic inflammation has high sensitivity (≥ 87%) for diarrhea/rectal bleeding.

Dietary Calcium and Risk of Microscopic Colitis.

BACKGROUND: Microscopic colitis (MC) is an increasingly common cause of watery diarrhea particularly in older individuals. The role of diet in MC has received little study. METHODS: We conducted a case-control study at a single institution enrolling patients referred for elective outpatient colonoscopy for diarrhea. Patients were classified as cases with MC or non-MC controls after a review of colon biopsies by 1 research pathologist. Study subjects were interviewed by a trained telephone interviewer using a validated food frequency questionnaire. Adherent microbes were evaluated from colonic biopsies using 16s rRNA sequencing. RESULTS: The study population included 106 cases with MC and 215 controls. Compared with controls, the cases were older, better educated, and more likely to be female. Cases with MC had lower body mass index and were more likely to have lost weight. Subjects in the highest quartile of dietary calcium intake had a lower risk of MC compared with those in the lowest quartile (adjusted odds ratio 0.22, 95% confidence interval 0.07-0.76). The findings were not explained by dairy intake, body mass index, or weight loss. We found that dietary calcium intake had significant associations with the abundance of Actinobacteria and Coriobacteriales in the microbial community of colonic biopsies. DISCUSSION: Compared with patients with diarrhea, cases with MC had a lower intake of dietary calcium. Diet can be associated with alterations in the gut microbiota and with luminal factors that could affect the risk of MC.

Colonic Eosinophilia: Clinicopathologic Study of Paired Right and Left Colon Biopsies from 276 Patients.

OBJECTIVE: This study evaluated differences in eosinophil (Eos) count in the right colon (RC) and left colon (LC) relative to known clinical and pathologic features. METHODS: H&E slides from 276 subjects with biopsies taken from both RC and LC were reviewed. Eos/mm2 were counted in the area with highest concentration then correlated with clinical and pathologic findings for RC and LC. RESULTS: There were higher numbers of Eos/mm2 in RC than in LC (mean 177 vs 122, respectively p<0.0001), and there was significant positive correlation between Eos numbers in the two locations (r=0.57, p<0.001). In RC, the mean Eos/mm2 was 242 with active chronic colitis, 195 with inactive chronic colitis, 160 in microscopic colitis, 144 in quiescent IBD, and 142 with normal histology (p<0.001), and was higher in males (204 vs 164, p=0.022). In LC, mean Eos/mm2 was 186 with active chronic colitis, 168 with inactive chronic colitis, 154 in microscopic colitis, 82 in quiescent IBD, and 84 with normal histology (p<0.001), and was higher in males (154 vs 107, p<0.001). In biopsies with normal histology, RC showed higher mean Eos/mm2 in Asian patients (228 vs 139, p=0.019), and patients with history of UC (205 vs 136, p=0.004), but was not significantly different in patients with or without irritable bowel syndrome with diarrhea (IBS-D) or history of Crohn's disease (CD). In LC the mean Eos/mm2 was higher in males (102 vs 77, p=0.036), and history of CD (117 vs 78, p=0.007), but was not significantly different in patients with or without IBS-D or history of UC. The number of Eos/mm2 was greater in biopsies performed in the summer than during other seasons of the year. CONCLUSION: The mean number of Eos/mm2 in colorectal biopsies varies significantly by location, histopathologic changes, clinical diagnosis, season, gender and ethnicity. Of particular interest is the association between high Eos/mm2 in RC biopsies with otherwise normal histology and clinical history of UC, and in LC biopsies with clinical history of CD. Additional larger and prospective studies that include normal healthy volunteers are needed to establish a reliable cutoff for the histopathologic diagnosis of eosinophilic colitis, taking into consideration the biopsy site within the colon and rectum, as well as patient gender and ethnicity.Presented in part at the annual American College of Gastroenterology meeting, San Antonio, TX October 2019.

CDK4/6 inhibitor modulating active and quiescent intestinal stem cells for prevention of chemotherapy-induced diarrhea.

Chemotherapy-induced diarrhea causes dehydration, debilitation, infection, and even death, but there are currently no Food and Drug Administration (FDA)-approved drugs for treatment of chemotherapy-induced diarrhea. It is generally believed that the timely regulation of intestinal stem cell (ISC) fate may provide a meaningful solution for intestinal injuries. However, the lineage plasticity of ISCs during and after chemotherapy remains poorly understood. Here, we demonstrated that palbociclib, a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, regulated the fate of active or quiescent ISCs, provided multilineage protection from the toxicity of several different chemotherapeutics, and accelerated gastrointestinal epithelium recovery. Consistent with in vivo results, we determined that palbociclib enhanced intestinal organoid and ex vivo tissue survival after chemotherapy. Lineage tracing studies have shown that palbociclib protects active ISCs marked by Lgr5 and Olfm4 during chemotherapy and unexpectedly activates quiescent ISCs marked by Bmi1 to immediately participate in crypt regeneration after chemotherapy. Furthermore, palbociclib does not decrease the efficacy of cytotoxic chemotherapy in tumor grafts. The experimental evidence suggests that the combination of CDK4/6 inhibitors with chemotherapy could reduce damage to the gastrointestinal epithelium in patients. © 2023 The Pathological Society of Great Britain and Ireland.

Rice Water-Fried Atractylodis Rhizoma Relieves Spleen Deficiency Diarrhea by Regulating the Intestinal Microbiome.

Background: Spleen deficiency diarrhea (SDD) is a common Traditional Chinese Medicine (TCM) gastrointestinal condition, the causes of which include dysfunction of the intestinal barrier and microbiota. Rice water-fried Atractylodis Rhizoma (RAR) is a commonly used drug to treat this condition, but its mechanism remains unclear. This study explored the related mechanisms of ethanolic extract of rice water-fried Atractylodis Rhizoma (EAR) in the treatment of SDD by examining changes in the intestinal microbiota. Method: Wistar rats were randomly divided into 4 groups including the control, model, EAR low, and high-dose groups, 6 rats in each group. All rats, except the control group, were induced to develop SDD by a bitter-cold purgation method with rhubarb. The therapeutic effect of EAR on SDD was evaluated by pathological sections, inflammatory indicators (TNF-α, IL-1ß, and IL-10), gastrointestinal-related indicators (GAS, DAO, D-lactate, VIP, and SIgA), and intestinal flora (bacteria and fungi) analysis. Results: The results showed that the developed SDD rat model (model group) showed weight loss, decreased food intake, and increased fecal moisture content. Compared with those of the control group, the levels of TNF-α, IL-1ß, DAO, D-lactate, and VIP in the model group were significantly increased, but the levels of IL-10, GAS and SIgA were significantly decreased (p < 0.05). However, the indicators were significantly improved after EAR treatment, indicating that EAR maintained the balance of pro- and anti-inflammatory cytokines and reduced gastric emptying, thereby protecting intestinal barrier function, alleviating intestinal mucosal injury, and relieving SDD by regulating the release of neurotransmitters. EAR was also shown to prevent infection by promoting the accumulation of noninflammatory immunoglobulin SIgA and improving intestinal mucosal immunity to inhibit the adhesion of bacteria, viruses, and other pathogens. Intestinal microbiome analysis showed that the intestinal bacteria and fungi of SDD model rats changed greatly compared with the control group, resulting in intestinal microecological imbalance. The reversal in the composition of the flora after EAR treatment was mainly characterized by a large enrichment of beneficial bacteria represented by Lactobacillus and a decrease in the abundance of potentially pathogenic fungi represented by Aspergillus. Thus, it was speculated that EAR primarily functions to alleviate SDD by increasing the abundance of beneficial bacteria and reducing the abundance of potentially pathogenic fungi. Conclusion: The strong therapeutic effect of EAR on SDD suggests that it is a promising treatment for this condition.

Langerhans Cell Histiocytosis in a Pediatric Patient with Simultaneous Gastrointestinal and Skin Involvement: A Case Report and Literature Review.

Background: Langerhans cell histiocytosis (LCH) has heterogeneous presentations involving single or multiple systems, but simultaneous isolated skin and gastrointestinal involvement is not common. Case report: A female infant with intermittent bloody diarrhea was unresponsive for treatment of food allergy. Histology of gastric and colonic tissues demonstrated Langerhan's cell histiocytosis. The infant also had red rashes that were histologically proven Langerhan's cell histiocytosis. Chemotherapy utilized vincristine, cytarabine and prednisone. The bloody diarrhea and rash completely resolved with no recurrence in the 11 months of follow-up. Conclusion: Langerhan cell histiocytosis may present with simultaneous gastrointestinal and skin involvement.

Fisetin Treats Kidney Oxidative Stress, Inflammation, and Apoptosis in Rat Diarrhea.

BACKGROUND: Diarrhea is the increase in the excretion of human water; meanwhile, fisetin, a bioactive flavonol molecule, is widely used in the treatment/prevention of gastrointestinal disorders. The purpose of this study is to investigate the anti-diarrheal activity of fisetin by restoring kidney function, antioxidant activity, inflammatory markers, Na+/K+-ATPase level, apoptosis, and protein content in diarrheal rats. METHODS: A total of 36 male rats were distributed into two groups (18 rats/group): normal and diarrheal. The normal group was further divided into three subgroups (6 rats/subgroup): Control, fisetin, and desmopressin drug subgroups, consisting of normal rats orally treated once a day for 4 weeks with 1 mL distilled water, 50 mg/kg fisetin, and 1 mg/kg desmopressin drug, respectively. A lactose diet containing 35% lactose was fed to the normal rats for a month. The diarrheal rats were also divided into three subgroups (6 rats/subgroup): diarrheal rats, diarrheal rats + fisetin, and diarrheal rats + desmopressin drug groups, whereby the diarrheal rats were orally treated once a day for 4 weeks with 1 mL distilled water, 50 mg/kg fisetin, and 1 mg/kg desmopressin drug, respectively. RESULTS: Fisetin significantly decreased serum urea (41.20 ± 2.6-29.74 ± 2.65), creatinine (1.43 ± 0.05-0.79 ± 0.06), and urinary volume (1.30 ± 0.41-0.98 ± 0.20), while significantly increasing kidney weight (0.48 ± 0.03-0.67 ± 0.07), sodium, potassium, and chloride balance in both serum and urine. Fisetin significantly increased the antioxidant activity (superoxide dismutase (1170 ± 40-3230 ± 50), glutathione peroxidase (365 ± 18-775 ± 16), catalase (0.09 ± 0.03-0.14 ± 0.06), and nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) oxidase activity (8.6 ± 1.31-10.5 ± 1.25), while significantly decreasing malondialdehyde (19.38 ± 0.54-9.54 ± 0.83), conjugated dienes (1.86 ± 0.24-1.64 ± 0.19), and oxidative index (0.62 ± 0.04-0.54 ± 0.05)), alongside the inflammatory markers (tumor necrosis factor-α (65.2 ± 2.59-45.3 ± 2.64), interleukin-1ß, interleukin-6 (107 ± 4.5-56.1 ± 7.2), and interleukin-10) in the diarrheal rats to values approaching the control values. Fisetin also restored the Na+/K+-ATPase level, apoptosis, protein content, and kidney architecture in diarrheal rats to be near the control group. CONCLUSIONS: Fisetin treated diarrhea in rats by restoring kidney function, antioxidant activity, inflammatory markers, apoptosis, proteome content, and histology.

Clinical benefits of oral capecitabine over intravenous 5-fluorouracyl regimen in case of neoadjuvant chemoradiotherapy followed by surgery for locally advanced rectal cancer.

Background: During the last decade, one of the most important treatment options for locally advanced, potencially resectable rectal tumours was neoadjuvant chemoradiotherapy (CRT) followed by surgery. Methods: Effects of the neoadjuvant treatment on surgical outcomes were retrospectively analysed in 185 patients with stage T2-T4 and N0-2, resectable rectal tumour among two patient groups defined by radiosensitizer agents. Group 1 (n = 94) involved radiotherapy (RT) with 50.4 Gy total dose (25 × 1.8 Gy + 3 × 1.8 Gy tumour bed boost), and intravenous 5-fluorouracil (5-FU) (350 mg/m2) with leucovorin (20 mg/m2) on the 1-5 and 21-25 days, while Group 2 (n = 91) RT and orally administrated capecitabine (daily 2 × 825 mg/m2) on RT days. Surgery was carried out after 8-10 weeks. Side effects, perioperative complications, type of surgery, number of removed regional lymph nodes, resection margins and tumour regression grade (TRG) were analysed. Results: More favourable side effects were observed in Group 2. Despite the same rate of diarrhoea (Group 1 vs. Group 2: 54.3% vs. 56.0%), Grade 2-3 diarrhoea ratio was lower (p = 0.0352) after capecitabine (Group 2). Weight loss occurred in 17.0% and 2.2% (p = 0.00067), while nausea and vomiting was described in 38.3% and 15.4% (p = 0.00045) with 5-FU treatment and capecitabine respectively. Anaemia was observed in 33.0% and 22.0% (p = 0.0941). Complete tumour regression occurred in 25.3% after oral- and 13.8% after intravenous treatment (p = 0.049). Ratio of sphincter preservation was higher with laparoscopy than open surgery (72.3% vs. 39.7%) (p = 0.00001). Conclusion: The study confirms advantages of neoadjuvant chemoradiotherapy with oral capecitabine for rectal tumours, such as more favourable side effect profile and overall clinical outcome, with increased rate of complete tumour regression.

Microbial Associations With Microscopic Colitis.

INTRODUCTION: Microscopic colitis is a relatively common cause of chronic diarrhea and may be linked to luminal factors. Given the essential role of the microbiome in human gut health, analysis of microbiome changes associated with microscopic colitis could provide insights into the development of the disease. METHODS: We enrolled patients who underwent colonoscopy for diarrhea. An experienced pathologist classified patients as having microscopic colitis (n = 52) or controls (n = 153). Research biopsies were taken from the ascending (ASC) and descending (DES) colon, and the microbiome was characterized with Illumina sequencing. We analyzed the associations between microscopic colitis and microbiome with a series of increasingly complex models adjusted for a range of demographic and health factors. RESULTS: We found that alpha diversity was significantly lower in cases with microscopic colitis compared with that in controls in the DES colon microbiome. In the DES colon, a series of models that adjusted for an increasing number of covariates found taxa significantly associated with microscopic colitis, including Proteobacteria that was enriched in cases and Collinsella that was enriched in controls. While the alpha diversity and taxa were not significantly associated with microscopic colitis in the ASC colon microbiome, the inference P values based on ASC and DES microbiomes were highly correlated. DISCUSSION: Our study demonstrates an altered microbiome in cases with microscopic colitis compared with that in controls. Because both the cases and controls experienced diarrhea, we have identified candidate taxa that could be mechanistically responsible for the development of microscopic colitis independent of changes to the microbial community caused by diarrhea.

Wumei pills attenuates 5-fluorouracil-induced intestinal mucositis through Toll-like receptor 4/myeloid differentiation factor 88/nuclear factor-κB pathway and microbiota regulation.

BACKGROUND: Radiotherapy and chemotherapy can kill tumor cells and improve the survival rate of cancer patients. However, they can also damage normal cells and cause serious intestinal toxicity, leading to gastrointestinal mucositis[1]. Traditional Chinese medicine is effective in improving the side effects of chemotherapy. Wumei pills (WMP) was originally documented in the Treatise on Exogenous Febrile Diseases. It has a significant effect on chronic diarrhea and other gastrointestinal diseases, but it is not clear whether it affects chemotherapy-induced intestinal mucositis (CIM). AIM: To explore the potential mechanism of WMP in the treatment of CIM through experimental research. METHODS: We used an intraperitoneal injection of 5-fluorouracil (5-Fu) to establish a CIM mouse model and an oral gavage of WMP decoction (11325 and 22650 mg/kg) to evaluate the efficacy of WMP in CIM. We evaluated the effect of WMP on CIM by observing the general conditions of the mice (body weight, food intake, spleen weight, diarrhea score, and hematoxylin and eosin stained tissues). The expression of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), IL-1ß, and myeloperoxidase (MPO), as well as the Toll-like receptor 4/myeloid differentiation factor 88/nuclear factor-κB (TLR4/MyD88/NF-κB) signaling pathway proteins and tight junction proteins (zonula occludens-1, claudin-1, E-cadherin, and mucin-2) was determined. Furthermore, intestinal permeability, intestinal flora, and the levels of short-chain fatty acids (SCFA) were also assessed. RESULTS: WMP effectively improved the body weight, spleen weight, food intake, diarrhea score, and inflammatory status of the mice with intestinal mucositis, which preliminarily confirmed the efficacy of WMP in CIM. Further experiments showed that in addition to reducing the levels of TNF-α, IL-1ß, IL-6, and MPO and inhibiting the expression of the TLR4/MyD88/NF-κB pathway proteins, WMP also repaired the integrity of the mucosal barrier of mice, regulated the intestinal flora, and increased the levels of SCFA (such as butyric acid). CONCLUSION: WMP can play a therapeutic role in CIM by alleviating inflammation, restoring the mucosal barrier, and regulating gut microbiota.

Efficacy, safety and unmet needs of evolving medical treatments for carcinoid syndrome.

This review reports on the currently available medical treatment options for the control of symptoms due to carcinoid syndrome in patients with neuroendocrine tumors. The efficacy and adverse events (AEs) of approved drugs such as somatostatin analogues (SSA), telotristat ethyl (TE) and interferon-alpha, are reviewed. Somatostatin analogues remain the standard treatment of carcinoid syndrome based on the high expression of somatostatin receptors and the resulting inhibition of secretion of bioactive compounds; their use is associated with relatively mild AEs, involving mainly the gastrointestinal system, and being usually transient. Although dose escalation of SSA remains an unapproved option, it is clinically implemented to alleviate symptoms in refractory carcinoid syndrome and supported by the most recent guidelines. The side effects associated with the increased dose are in general mild and consistent with standard dose of SSA. Telotristat ethyl, an oral inhibitor of tryptophan hydroxylase, the rate-limiting enzyme in serotonin biosynthesis, represents a rather novel innovative treatment option in patients with carcinoid syndrome suffering from diarrhea and complements the standard therapy of SSA. Given the low toxicity profile, TE may be considered an early add-on treatment to SSA in patients with uncontrolled carcinoid syndrome. However, further prolonged follow-up of patients treated with TE may be needed to exclude potential AEs, such as liver toxicity or depressed mood, in patients with long-term treatment. Interferon alpha is a cytokine with direct inhibitory effect on hormone secretion and tumor cell proliferation and an approved therapy in carcinoid syndrome but is associated with significant AEs in the majority of the patients requiring frequently dose reduction. The finding of a more favorable tolerability of pegylated interferon needs to be confirmed in a prospective study.

LncRNA ALDB-898 modulates intestinal epithelial cell damage caused by Clostridium perfringens type C in piglet by regulating ssc-miR-122-5p/OCLN signaling.

Diarrhea of piglets caused by Clostridium perfringens type C (C. perfringens type C) infection is a global problem afflicting piglet production. Long noncoding RNA (LncRNA) and microRNA (miRNA) have emerged as critical regulators of this pathological process, but the underlying molecular mechanisms remain unclear. In this study, we first observed the expression changes of ALDBSSCG0000000898 (ALDB-898) and ssc-miR-122-5p in infected ileum tissue of piglets with C. perfringens type C, and then used C. perfringens beta2 toxin (CPB2) to induce intestinal porcine epithelial cells (IPEC-J2) to construct an injury model. Cytometry kit 8 (CCK-8), lactate dehydrogenase (LDH), real-time quantitative polymerase chain reaction (RT-qPCR), Western blot, flow cytometry and fluorescein isothiocyanate-dextran 4 (FITC-Dextran 4) flux assays were performed to study the effect of ALDB-898 and ssc-miR-122-5p in apoptosis, inflammation and intestinal barrier damage and inflammatory in IPEC-J2 cells induced by CPB2. In addition, dual-luciferase reporter gene analysis was performed to confirm the relationship between ssc-miR-122-5p and ALDB-898 or ssc-miR-122-5p and occludin (OCLN), respectively. There were lower expression levels of ALDB-898 and OCLN and higher expression levels of ssc-miR-122-5p in diarrhea piglets caused by Clostridium perfringens type C. ALDB-898 and OCLN were significantly decreased and ssc-miR-122-5p was increased in IPEC-J2 after exposure to the CPB2 in a dose- and time-dependent manner. ALDB-898 overexpression mitigated CPB2-induced cell injury by promoting viability, restraining apoptosis, cytotoxicity, and inflammatory response, as well as weakening the destruction of the intestinal barrier. Further mechanisms disclosed that ALDB-898 functioned as a competing endogenous RNA (ceRNA) via binding to ssc-miR-122-5p, and OCLN was a target of ssc-miR-122-5p. Importantly, the ssc-miR-122-5p mimic led to abolishing the protective function of ALDB-898 on CPB2-induced IPEC-J2 cell damage, and the addition of OCLN reversed the negative impact of ssc-miR-122-5p, thereby restoring the protection of ALDB-898. Our data showed that ALDB-898 could enhance the expression of OCLN through competitive binding ssc-miR-122-5p to suppress CPB2-induced damage. The ALDB-898/ssc-miR-122-5p/OCLN signaling may be a candidate therapeutic pathway for diarrhea of piglets.

Efficacy and Side Effects of Irinotecan Combined with Nedaplatin versus Paclitaxel Combined with Cisplatin in Neoadjuvant Chemotherapy for Locally Advanced Cervical Cancer and Tumor Marker Analysis: Based on a Retrospective Analysis.

Objective: A case-control study was adopted to investigate the efficacy and side effects of irinotecan combined with nedaplatin (NP) versus paclitaxel combined with cisplatin for locally advanced cervical cancer (CC) neoadjuvant chemotherapy (NACT) and to analyze the changes in tumor marker levels. Methods: A total of 96 patients with locally advanced CC who were treated from October 2019 to October 2021 were enrolled in our hospital as the research subjects, and their clinical data were collected for retrospective analysis and grouped according to their treatment regimens. Among them, 53 patients received paclitaxel combined with cisplatin as the control group, and the other 43 patients received irinotecan combined with NP as the observation group. The clinical effectiveness of neoadjuvant chemotherapy and alterations in tumor markers (CEA, AFP, CA125, and SCCA) were compared between the two groups. The incidence of common chemotherapy side effects was observed and compared between the two groups, including nausea and vomiting, abdominal pain and diarrhea, liver function impairment, bone marrow suppression, transient hyperglycemia, rash, ECG abnormalities, peripheral neurotoxicity, and muscle aches and pains. Results: The clinical efficiency of neoadjuvant chemotherapy was 97.67% in the observation group and 81.13% in the control group, with no statistically significant difference between the groups (P > 0.05). There was no significant difference in CEA, AFP, and CA125 between the two groups before and after chemotherapy, but the decrease of SCCA before and after chemotherapy was statistically significant. There was no significant difference in the incidence of liver function damage, myelosuppression, abnormal ECG, and rash between the two groups (P > 0.05). There are statistically significant differences in the incidence of nausea and vomiting, transient hyperglycemia, peripheral neurotoxicity, and muscle aches between the observation and control groups (P < 0.05). The incidence of nausea and vomiting, transient hyperglycemia, peripheral neurotoxicity, and muscle aches was higher in the control group than in the observation group, with statistically significant differences (P < 0.05). The difference in the incidence of diarrhea and abdominal pain between the observation group and the control group was statistically significant (P < 0.05), and the incidence of diarrhea and abdominal pain in the observation group was higher than that in the control group. Conclusion: Irinotecan in combination with nedaplatin can be an effective neoadjuvant chemotherapy regimen for advanced localized cervical cancer, particularly in patients with combined diabetes.

Protective effect of polysaccharides isolated from the seeds of Cuscuta chinensis Lam. on 5-fluorouracil-induced intestinal mucositis in mice.

PURPOSE: To evaluate the protective effect of Cuscuta chinensis Lam. polysaccharides (PCCL) on 5-fluorouracil-(5-FU)-induced intestinal mucositis (IM) in mice. METHODS: PCCL was orally administered at a dose of 20 mg·kg-1 for 7 days and its protective effect on 5-FU-induced IM (5-FU, 50 mg·kg-1 for 5 days) was evaluated by monitoring changes in body weight, degree of diarrhea, levels of tissue inflammatory factors (tumor necrosis factor α, interleukin 6, and interleukin 1ß levels), apoptosis rates, and the expression levels of caspase-3, Bax and Bcl-2. RESULTS: The severity of mucosal injury (as reflected by body weight changes, degree of diarrhea, height of villi, and damage to crypts) was significantly attenuated by PCCL administration. PCCL also reduced the levels of tissue inflammatory factors, the apoptosis rate, and the expression of caspase-3 and Bax, and increased Bcl-2 expression. CONCLUSIONS: PCCL administration may be significantly protective against 5-FU-induced IM by inhibiting apoptosis and regulating the abnormal inflammation associated with it.

A case of cerebrotendinous xanthomatosis with brain and spinal involvement without tendon xanthomas: Identification of a novel mutation of the CYP27A1 gene.

Cerebrotendinous xanthomatosis (CTX) is a rare inherited disorder of the alternative pathway of bile acid biosynthesis, due to mutation(s) of the gene CYP27A1, leading to sterol 27-hydroxylase deficiency. The latter results in a systematic deposition of cholestanol and cholesterol to the central nervous system and tendons, premature cataract, as well as the manifestation of systematic symptoms, such as chronic diarrhea, osteoporosis, and premature atherosclerosis. Due to its marked clinical heterogeneity, prompt diagnosis of this disorder is challenging. We present a case of a 38-year-old male with gait difficulty, a progressive deterioration in ambulation, several episodes of vertigo and episodic diarrhea. Clinical history revealed neonatal jaundice, juvenile bilateral cataracts, borderline intellectual capacity, hypothyroidism, testicular cancer. Magnetic resonance imaging demonstrated increased T2-weighted signal in internal capsules, midbrain, cerebellum, and spinal cord. Electrodiagnostic study showed mixed polyneuropathy. Genetic analysis revealed a novel, biallelic, most likely pathogenic mutation, in gene CYP2A1 (c.1410_1411del). Plasma sterol profiling confirmed the diagnosis of CTX. Our patient was treated with chenodeoxycholic acid and one year later, he shows a progressive improvement of gait, normalization of plasma sterol biochemistry and electrophysiological parameters. This case highlights the importance of maintaining a high index of suspicion as the key to an early diagnosis of CTX, taking into consideration its clinical variability and, if promptly identified, the good response to treatment.

Microvillous inclusion disease as a cause of severe congenital diarrhea in a newborn.

Microvillous inclusion disease (MVID), also known as congenital microvillus atrophy remains an important differential diagnosis of intractable secretory diarrhea in neonatal period. The condition is inherited as an autosomal recessive disorder with no sex predilection and more commonly reported in those tribes with consanguineous marriages. The pathognomonic electron microscopic findings includes villous atrophy with the formation of intracellular microvillous inclusions. Definite treatment includes either isolated small bowel or combined small bowel and liver transplantation. Herein, we are describing a case of intractable diarrhea in a preterm neonate with MVID phenotype presented on second day of life with intractable diarrhea. The diagnosis was established by classical electron microscopic findings in the intestinal biopsy sample.