Fibrosing colonopathy associated with cysteamine bitartrate delayed-release capsules in cystinosis patients.

BACKGROUND: The objective of this report is to identify and characterize cases of fibrosing colonopathy, a rare and underrecognized adverse event, associated with cysteamine delayed-release (DR) in patients with nephropathic cystinosis. METHODS: We searched the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) and the medical literature for postmarketing reports of fibrosing colonopathy associated with cysteamine through August 2, 2023. RESULTS: We identified four cases of fibrosing colonopathy reported with the use of cysteamine DR. The time to onset ranged from 12 to 31 months. In one case, the patient required surgery to have a resection of a section of the strictured colon and a diverting ileostomy. Fibrosing colonopathy was diagnosed by histopathology in two of the cases. CONCLUSIONS: Our case series identified the risk of fibrosing colonopathy in patients taking cysteamine DR and prompted regulatory action by the FDA. As outlined in changes to the U.S. prescribing information for cysteamine DR, healthcare professionals should be aware of the potential risk of fibrosing colonopathy with cysteamine DR, especially as symptoms can be non-specific leading to misdiagnosis or delayed diagnosis. If the diagnosis of fibrosing colonopathy is confirmed, consideration should be given to permanently discontinuing cysteamine DR and switching to cysteamine immediate-release treatment.

Alopecia and colon ulcers following azathioprine use in a patient with myasthenia gravis: A case report.

RATIONALE: Azathioprine is a purine analog (PA) used to treat myasthenia gravis (MG). However, some patients are sensitive to azathioprine and develop severe side effects, such as leukopenia, alopecia, and diarrhea soon after using the medication. Pharmacogenetics plays a crucial role in such intolerance. PATIENT CONCERNS: A 16-year-old woman with MG developed hair loss, pancytopenia, bloody diarrhea, and fever shortly after azathioprine treatment. DIAGNOSIS: Pharmacogenetic analysis revealed compound heterozygosity of the nudix hydrolase 15 (NUDT15) gene, which led to suppressed NUDT15 function. Colonoscopy revealed large ulcers with polypoid lesions in the terminal ileum, cecum, ascending colon, and rectum. These are the characteristics of inflammatory bowel disease (IBD). INTERVENTIONS: Sanger sequencing of NUDT15 gene and colonoscopy for bloody stool evaluation. OUTCOMES: The patient recovered completely from this acute episode after discontinuation of azathioprine treatment. Her hemogram turned back to normal range. There was also no blood in stool during follow-up. LESSONS: Pharmacogenetic effects should be considered when prescribing PA medication. The possibility of secondary or concomitant autoimmune diseases must always be considered in patients with MG.

2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine Induced Colon Injury by Disrupting the Intestinal Bacterial Composition and Lipid Metabolic Pathways in Rats.

2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), one of the most abundant heterocyclic amines, is a common carcinogen produced in thermally processed protein-rich foods. Studies have demonstrated that PhIP could induce colon tumors in rodents, leaving mechanisms uncovered. This study aims to investigate the mechanism of PhIP-induced colon injury in a rat model. The results of 16S rRNA gene sequencing and metabolomics showed that PhIP disrupted intestinal bacterial composition and affected the glycerophospholipid metabolism and linoleic acid metabolism. Simultaneously, the lipid metabolism function in the intestinal flora was inhibited by PhIP. Notably, transcriptomics revealed that PhIP remarkably inhibited the expression of gene sets associated with steroid hormone biosynthesis, fatty acid elongation, fatty acid degradation, and glycerolipid metabolism pathways in the colon. The results provide new perspectives to study the mechanism of PhIP-induced colon injury and theoretical bases for further understanding the toxicity of PhIP.

Toll-like receptor 4 regulates intestinal fibrosis via cytokine expression and epithelial-mesenchymal transition.

Intestinal fibrosis induced by chronic and recurrent colitis, which is exacerbated by bowel stenosis, stricture, and obstruction, is challenging to treat. Toll-like receptor 4 (TLR4) stimulates innate and acquired immunity in response to specific microbial components, but the role of TLR4 in intestinal fibrosis is largely unknown. We investigated its role in intestinal fibrosis using not only a murine fibrosis model but also human myofibroblasts and intestinal epithelial cells. Colon fibrosis was induced in TLR4-deficient (TLR4-/-) mice and its wild-type counterparts with 3% dextran sulfate sodium. Absence of TLR4 gene attenuated chronic inflammation and colonic macrophages infiltration; intestinal fibrosis and collagen deposition were suppressed. Also, the production of tumor necrosis factor-α, interleukin-12p40, and transforming growth factor-ß was reduced in TLR4-deficient peritoneal macrophages. TLR4 was silenced in CCD-18Co cells by small interfering RNA (siRNA), and matrix metalloproteinase-1, tissue inhibitor of metalloproteinase, and collagen α1 expression was evaluated. Role of TLR4 in epithelial-mesenchymal transition (EMT) was evaluated in HCT116 cells. Suppression of TLR4 transcription by siRNAs affected myofibroblasts activity, collagen synthesis, and EMT in the human cancer cell line. Thus, we suggest that TLR4 can be an essential mediator in intestinal chronic inflammation and fibrosis, indicating that TLR4 signaling is a potential therapeutic target for intestinal fibrosis.

Colon perforation in multiple myeloma patients - A complication of high-dose steroid treatment.

Gastrointestinal complications of multiple myeloma (MM) treatment are common and include nausea, constipation, and diarrhea. However, acute gastrointestinal events like perforations are rare. We aimed to describe the characteristics and outcomes of patients with MM that had colonic perforations during their treatment. This is a retrospective study that included patients from all three Mayo Clinic sites who had MM and developed a colonic perforation. All patients were diagnosed with colonic perforations based on CT scans and were surgically treated. Patients diagnosed with AL amyloidosis, a perforated colon complicating neutropenic colitis during ASCT and those with perforation due to colonic cancer were excluded. A high dose of dexamethasone was defined as ≥40 mg dexamethasone once a week. Thirty patients met inclusion criteria. All patients received steroids at doses ≥10 mg once weekly prior to the perforation, while four (11%) were on high-dose dexamethasone without chemotherapy. Fourteen patients were given high doses of dexamethasone. Twenty-five patients required ostomies with all surviving surgery. Twenty-four perforations (80%) were associated with diverticulitis. Treatment with steroids was resumed in 23 patients with no further gastrointestinal complications. The median OS was 20 months following perforation (IQR 8-59). Within the same timeframe 5854 patients were treated at Mayo Clinic for MM, making the risk of bowel perforation 0.5%. Intestinal perforations in MM are rare and, in our series, always occurred with dexamethasone ≥10 mg per week. Urgent surgery is lifesaving and resumption of anti-myeloma treatment appears to be safe.

Essential role of Cav3.2 T-type calcium channels in butyrate-induced colonic pain and nociceptor hypersensitivity in mice.

Given the role of Cav3.2 isoform among T-type Ca2+ channels (T-channels) in somatic and visceral nociceptive processing, we analyzed the contribution of Cav3.2 to butyrate-induced colonic pain and nociceptor hypersensitivity in mice, to evaluate whether Cav3.2 could serve as a target for treatment of visceral pain in irritable bowel syndrome (IBS) patients. Mice of ddY strain, and wild-type and Cav3.2-knockout mice of a C57BL/6J background received intracolonic administration of butyrate twice a day for 3 days. Referred hyperalgesia in the lower abdomen was assessed by von Frey test, and colonic hypersensitivity to distension by a volume load or chemicals was evaluated by counting nociceptive behaviors. Spinal phosphorylated ERK was detected by immunohistochemistry. Cav3.2 knockdown was accomplished by intrathecal injection of antisense oligodeoxynucleotides. Butyrate treatment caused referred hyperalgesia and colonic hypersensitivity to distension in ddY mice, which was abolished by T-channel blockers and/or Cav3.2 knockdown. Butyrate also increased the number of spinal phosphorylated ERK-positive neurons following colonic distension in the anesthetized ddY mice. The butyrate-treated ddY mice also exhibited T-channel-dependent colonic hypersensitivity to intracolonic Na2S, known to enhance Cav3.2 activity, and TRPV1, TRPA1 or proteinase-activated receptor 2 (PAR2) agonists. Wild-type, but not Cav3.2-knockout, mice of a C57BL/6J background, after treated with butyrate, mimicked the T-channel-dependent referred hyperalgesia and colonic hypersensitivity in butyrate-treated ddY mice. Our study provides definitive evidence for an essential role of Cav3.2 in the butyrate-induced colonic pain and nociceptor hypersensitivity, which might serve as a target for treatment of visceral pain in IBS patients.

Effects of Sphingolipid Fractions from Golden Oyster Mushroom (Pleurotus citrinopileatus) on Apoptosis Induced by Inflammatory Stress in an Intestinal Tract in vitro Model.

Previously, we reported that the polar lipid fraction from the golden oyster mushroom, Pleurotus citrinopileatus, suppresses colon injuries which result from apoptosis induced by inflammatory stresses in vivo and in vitro (Yamashita et al., J. Oleo Sci., 69, 751-757 (2020)). Here, we investigated the use of lipid classes in mushroom polar lipid fraction in alleviating colon injury using differentiated Caco-2 cells as an intestinal tract model. The mushroom polar lipid fraction was separated into four fractions using silica thin layer chromatography. Each mushroom polar lipid fraction suppressed lipopolysaccharide (LPS)-induced decreases in the viability of intestinal cells, and the effects of sphingolipid fractions were significantly stronger than those of fraction that did not contain sphingolipids. Addition of sphingolipid fractions suppressed the expression of apoptosis-related proteins (e.g., death receptors and caspases) in the LPS-treated cells. Mushroom polar lipids, especially sphingolipids suppress intestinal apoptosis induced by inflammatory stress, and highly polar sphingolipids may exert stronger suppressive effects.

Spontaneous intramural hematoma of the alimentary canal.

Spontaneous intramural hematoma of the alimentary canal has rarely been reported. We present two cases in which anticoagulation therapy brings spontaneous intramural hematoma of the alimentary canal. In one case, the lesion was located in the ileum, and the other was located in the ascending colon and distal ileum. Both patients were cured through conservative treatment. We suggest that increased attention should be paid if a patient has acute abdominal pain with a history of oral anticoagulant therapy, and the diagnosis of spontaneous intermural hematoma should be considered.

Isoorientin attenuates benzo[a]pyrene-induced colonic injury and gut microbiota disorders in mice.

Benzo[a]pyrene (BaP, most toxic polycyclic aromatic hydrocarbon) is a global food-borne pollutant, and is associated with many diseases and gut microbiota disorders. The present study was designed to investigate the protective effects of isoorientin (ISO), a flavonoid compound in the human diet, on BaP-induced colonic damage and gut microbial disorders in mice. ISO was administered orally to mice at doses of 20 mg/kg body weight before BaP challenge (oral administration, 50 mg/kg body weight). The results revealed that ISO suppressed the BaP-induced reduction of body weight in mice, and it also prevented colonic damage, as evidenced by the increase in colon total superoxide dismutase (T-SOD) and glutathione peroxidase (GSH-Px) activities, and the decrease in colon malonaldehyde (MDA) and hydrogen peroxide (H2O2) levels, compared to BaP-treated mice. Meanwhile, we used 16S rRNA gene sequencing to investigate the impact of BaP with or without ISO on the colon contents associated bacteria in mice. ISO could relieve the BaP-induced change in the abundance of gut microbiota, especially the genera of Feacalibaculum, Lactobacillus, Acinetobacter, Desulfovibrio and Alistipes. And ISO ameliorated BaP-induced microbiota metabolic disturbance, especially the metabolic pathways of LPS and sulphur compounds. In conclusion, our findings indicated that ISO could be of significant advantage in suppressing the colonic injury and the gut microbiota disorder induced by BaP.