Relationship between Chemotherapy-Induced Diarrhea and Intestinal Microbiome Composition.

BACKGROUND AND AIM: Fluoropyrimidines (FPs) are key drugs in many chemotherapy regimens; however, recipients are often prone to diarrhea due to gastrointestinal toxicity. Disruption of the intestinal epithelial barrier function by FPs leads to dysbiosis, which may exacerbate intestinal epithelial cell damage as a secondary effect and trigger diarrhea. However, despite studies on chemotherapy-induced changes in the intestinal microbiome of humans, the relationship between dysbiosis and diarrhea is unclear. In this study, we aimed to investigate the relationship between chemotherapy-induced diarrhea and the intestinal microbiome. METHODS: We conducted a single-center prospective observational study. Twenty-three patients who received chemotherapy, including FPs as first-line chemotherapy for colorectal cancer, were included. Stool samples were collected before the start of chemotherapy and after one cycle of treatment to analyze intestinal microbiome composition and perform PICRUSt predictive metagenomic analysis. RESULTS: Gastrointestinal toxicity was observed in 7 of 23 patients (30.4%), diarrhea was observed in 4 (17.4%), and nausea and anorexia were observed in 3 (13.0%). In 19 patients treated with oral FPs, the α diversity of the microbial community decreased significantly following chemotherapy only in the diarrheal group. At the phylum level, the diarrheal group showed a significant decrease in the abundance of Firmicutes and a significant increase in the abundance of Bacteroidetes with chemotherapy (p = 0.013 and 0.011, respectively). In the same groups, at the genus level, Bifidobacterium abundance was significantly decreased (p = 0.019). In contrast, in the non-diarrheal group, Actinobacteria abundance increased significantly with chemotherapy at the phylum level (p = 0.011). Further, Bifidobacterium, Fusicatenibacter, and Dorea abundance significantly increased at the genus level (p = 0.006, 0.019, and 0.011, respectively). The PICRUSt predictive metagenomic analysis revealed that chemotherapy caused significant differences in membrane transport in KEGG pathway level 2 and in 8 KEGG pathway level 3, including transporters and oxidative phosphorylation in the diarrhea group. CONCLUSION: Organic-acid-producing bacteria seem to be involved in diarrhea associated with chemotherapy, including FPs.

Cytomegalovirus infection in ulcerative colitis assessed by quantitative polymerase chain reaction: risk factors and effects of immunosuppressants.

We investigated the risk factors of and appropriate treatment for cytomegalovirus colitis in patients with ulcerative colitis, using quantitative polymerase chain reaction analysis to detect cytomegalovirus in the colonic mucosa. Between February 2013 and January 2017, patients with exacerbated ulcerative colitis who were admitted to our hospital were consecutively enrolled in this retrospective, single-center study. Patients were evaluated for cytomegalovirus using serology (antigenemia) and quantitative polymerase chain reaction analyses of the colonic mucosa, which were sampled during colonoscopy. Of 86 patients, 26 (30.2%) had positive quantitative polymerase chain reaction results for cytomegalovirus; only 4 were also positive for antigenemia. The ages of the cytomegalovirus DNA-positive patients were significantly higher than those of negative patients (p = 0.002). The mean endoscopic score of cytomegalovirus DNA-positive patients was significantly higher than that of cytomegalovirus DNA-negative patients. Treatment with combined immunosuppressants was associated with an increased risk of cytomegalovirus. Fourteen of 15 (93.3%) cytomegalovirus DNA-positive patients who were negative for antigenemia showed a clinical response to treatment with additional oral tacrolimus, without ganciclovir. cytomegalovirus reactivation in active ulcerative colitis is associated with age and combined immunosuppressant therapy. Because additional treatment with tacrolimus was effective, patients who are negative for antigenemia and cytomegalovirus DNA-positive colonic mucosa may recover without antiviral therapy.

Effect of egualen sodium hydrate on small-intestinal mucosal damage induced by low-dose aspirin: a prospective randomized clinical trial.

Low-dose aspirin, which is widely used to reduce the risk of cardio- and cerebrovascular thrombosis, often induces gastroenteropathy by increasing the permeability of the mucosa. However, therapeutic strategies for patients with low-dose aspirin-induced small intestinal injury have not been determined. We evaluated the preventative effect of egualen sodium hydrate, a gastro-protective agent that suppresses indomethacin-induced small-intestinal damage in rats, against small-intestinal mucosal damage induced by low-dose aspirin in healthy adult male volunteers. Participants were randomly allocated to receive aspirin 100 mg/kg daily (control group, n = 10) or aspirin 100 mg/kg plus egualen sodium 30 mg daily (egualen sodium group, n = 10). Small intestinal mucosal injury was evaluated by capsule endoscopy two weeks after initiation of drug administration. Fecal analyses (occult blood test, immunochemical test, transferrin measurement and calprotectin measurement) were carried out before and after treatment. Egualen sodium significantly suppressed the total number of small intestinal injuries detected by capsule endoscopy and the positive ratio for the fecal occult blood test. Daily use of 30 mg of egualen sodium showed a preventative effect on low-dose aspirin-induced small intestinal injury. Since acid suppression therapy was reported to exacerbate NSAIDs-induced enteropathy via dysbiosis, egualen sodium may be useful for patients treated with low-dose aspirin.

Comparing the Effects of Anti-TNF Agent and Ustekinumab on Small Bowel Inflammation in Crohn's Disease: Inverse Probability Weighting With Stabilized Weights of Propensity Scores.

Background: Endoscopic mucosal healing serves as a critical predictor for achieving long-term remission in Crohn's disease treatment. Recent data indicate that the effectiveness of healing varies based on the location of gastrointestinal inflammation. Additionally, reports suggest that antitumor necrosis factor-α (anti-TNF-α) agents exhibit reduced efficacy in treating small intestinal inflammation compared to colorectal inflammation. Conversely, limited research exists regarding the impact of the anti-IL12/23 agent ustekinumab (UST) on small intestinal inflammation. This study aimed to compare the effects of anti-TNF-α agents and UST on small intestinal inflammation using propensity score analysis. Methods: This retrospective observational study involved 70 patients with Crohn's disease who had inflammation in the small intestine and had initiated treatment with either anti-TNF agents or UST between March 2015 and August 2021. Endoscopic findings were evaluated before treatment commencement and at 1-2 years post-treatment initiation. The propensity score was employed to compare the efficacy of TNF agents and UST on small bowel inflammation. Results: Ustekinumab exhibited greater improvement in the small intestinal endoscopy score than anti-TNF-α antibodies according to the propensity score analysis (inverse probability weighting; P = .0448). However, no significant disparity was observed in the overall improvement of endoscopic scores between UST and anti-TNF-α antibodies (P = .5938). Conclusions: This study suggests that UST might be more effective than anti-TNF-α agents in treating small intestinal inflammation in Crohn's disease.

Gut microbiota shifts from onset to remission in immune checkpoint inhibitor-induced enterocolitis: a case report.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are crucial in cancer treatment; however, they carry the risk of immune-related adverse events (irAEs), such as enteritis. CASE PRESENTATION: This study investigated the role of the gut microbiota during the onset and remission of irAE enteritis in a patient with stage IV melanoma undergoing anti-PD-1 and anti-CTLA-4 therapy. Following commencement of ICI treatment, the patient developed severe diarrhea and was diagnosed with grade 3 irAE enteritis. Steroid and probiotic treatments provided swift symptom relief and remission, as confirmed by reduced fecal calprotectin levels and gastrointestinal imaging. Microbiota diversity analysis conducted via 16S rRNA gene sequencing identified a decrease in Streptococcus prevalence with improvement in enteritis symptoms. Conversely, genera Fusobacterium, Faecalibacterium, Bacteroides, Prevotella, and Bifidobacterium showed increased representation after remission. These genera are associated with anti-inflammatory properties and fibrous substrate degradation, aiding gut health. Immunological assessment demonstrated fluctuations in cytokine expression and the modulation of costimulatory molecules, aligning with therapeutic interventions and microbiota alterations. CONCLUSIONS: Our findings indicate a significant correlation between gut microbiota and immune responses in irAE enteritis. This underscores the potential utility of microbiome profiling in predicting irAE occurrence and in providing treatment strategies, thereby promoting a more comprehensive approach to managing the adverse effects of ICIs.

Neuroendocrine carcinoma of the small intestine diagnosed as a result of paraneoplastic neurological syndrome.

Paraneoplastic neurological syndromes, a diverse group of neurological syndromes, are associated with small cell lung, testicular, ovarian, and breast cancers; however, their association with neuroendocrine carcinoma of the small intestine remains unreported. In this report, we present the case of a 78-year-old man diagnosed with neuroendocrine carcinoma of the small intestine and experienced symptoms such as subacute progressive numbness of the extremities and impaired gait. These symptoms were diagnosed as tumor-associated neurological syndrome. The patient had also undergone pyloric gastrectomy for early-stage gastric cancer several years prior to the appearance of the neurological symptoms. Therefore, we could not determine whether the tumor-related neurologic syndrome was owing to gastric cancer or neuroendocrine carcinoma of the small intestine; however, one of these conditions was the cause of the neuropathy. The gait disturbance and numbness relatively improved after surgery for the neuroendocrine carcinoma of the small intestine, suggesting that the neuroendocrine carcinoma of the small intestine likely caused the paraneoplastic neurological syndrome. Collectively, we present a unique report highlighting the putative relationship between small bowel neuroendocrine carcinoma and tumor-associated neurologic syndromes.

Biomarkers for Monitoring of Changes in Disease Activity in Ulcerative Colitis.

BACKGROUND: In recent years, various biomarkers of ulcerative colitis (UC) have emerged; however, few studies have simultaneously examined the utility of multiple biomarkers for monitoring disease activity. Additionally, serum leucine-rich alpha-2 glycoprotein (LRG), a new biomarker, may show a blunt response to anti-TNF antibody therapy. This prospective study explored effective biomarkers that could monitor disease activity changes in patients with UC. In addition, we examined the effect of anti-TNF antibody therapy on changes in LRG. METHODS: Blood and stool samples were collected twice from patients with UC: at baseline and at least 8 weeks later. Changes in serum LRG, interleukin (IL)-6, prealbumin (pre-Alb), high-sensitivity C-reactive protein (hs-CRP), CRP, and fecal calprotectin (FC) were measured and correlated with changes in disease activity. The relationship between anti-TNF antibody therapy and LRG levels was also examined in patients with the same disease activity. RESULTS: Forty-eight patients with UC (96 samples) were analyzed. ΔLRG and ΔIL-6 correlated strongly with the change in the partial Mayo (pMayo) score between the two time points (ΔpMayo) (r = 0.686, 0.635, respectively). In contrast, FC and IL-6 were particularly accurate predictors of clinical remission, and their area under the curves (AUCs) were significantly higher than that of CRP (AUC: 0.81, 0.76 vs. 0.50; p = 0.001, 0.005). No association was found between the administration of anti-TNF antibody preparations and the LRG values. CONCLUSIONS: Correlations were found between changes in UC disease activity and LRG, IL-6, pre-Alb, hs-CRP, CRP, and FC. LRG reflects disease activity during anti-TNF antibody therapy.

Efficacy of Switching to Adalimumab for Maintenance of Remission Following Induction Therapy with Tacrolimus in Patients with Ulcerative Colitis.

BACKGROUND: Tacrolimus (TAC) effectively induces remission in refractory ulcerative colitis (UC). However, TAC therapy usually lasts for 3 months. Although azathioprine (AZA) is often used in maintenance therapy, the relapse rate remains high. Herein, we evaluated the efficacy of adalimumab (ADA) for remission maintenance in patients with UC after induction therapy with TAC. METHODS: We prospectively enrolled patients with moderate-to-severe UC who achieved clinical remission after 3 months of TAC therapy with endoscopic non-mucosal healing (Cohort A). After TAC discontinuation, the remission maintenance rate up to 1 year after starting ADA therapy was examined. We retrospectively enrolled patients with UC treated with TAC (Cohort B). Among patients in clinical remission after TAC treatment for 3 months, those who received AZA as remission maintenance therapy after TAC discontinuation constituted the AZA group. Patients in Cohort A who received ADA and AZA as remission maintenance therapy after TAC discontinuation constituted the ADA + AZA group. We compared the remission maintenance rates in the AZA and ADA + AZA groups for up to 5 years after TAC discontinuation. RESULTS: In Cohort A, of the 46 patients with UC treated with TAC, 17 were eligible for analysis after receiving ADA as remission maintenance therapy. A notable 88.2% (15/17) were still in remission 1 year after starting ADA. The ADA + AZA group (n = 16) exhibited a significantly higher relapse-free rate than the AZA group (n = 26) (p < 0.05; log-rank test). CONCLUSION: switching to ADA for remission maintenance in patients with refractory UC who achieved clinical remission with TAC is clinically useful.

Serum IL-13 Predicts Response to Golimumab in Bio-Naïve Ulcerative Colitis.

A certain number of patients with ulcerative colitis (UC) are refractory to anti-TNF-α antibodies; biomarkers are thus needed to predict treatment efficacy. This study aimed to evaluate whether serum biomarkers that were reported to be associated with UC or anti-TNF-α antibody could predict the response to golimumab, a human anti-TNF-α monoclonal antibody, in bio-naïve patients with UC. We prospectively enrolled 23 consecutive patients with UC who were treated with golimumab. Serum samples were collected before the first golimumab dose. Eleven molecules were measured by electrochemiluminescence (ECL) or enzyme-linked immunosorbent assay (ELISA) and their association with efficacy after 10 weeks of golimumab treatment. Among the serum biomarkers, IL-13 levels were significantly higher in the non-remission group than in the remission group (p = 0.014). IL-15 levels were significantly lower in the non-response group than in the response group (p = 0.04). For clinical remission at week 10, the IL-13 0.20 concentration of pg/mL was associated with a sensitivity and specificity of 82.4% and 83.3%, respectively. Serum IL-13 may be a biomarker to predict golimumab efficacy in biologic-naïve patients with UC, and thus may help to tailor personalized treatment strategies.

The Differential Diagnosis of Colorectal Polyps Using Colon Capsule Endoscopy.

Objective Although colorectal polyps (CPs) can be observed with colon capsule endoscopy (CCE), it is difficult to determine the type of polyp using CCE. The objective of this study was to differentiate adenomatous polyps (APs) from hyperplastic polyps (HPs) with CCE. Methods In this single-center retrospective study, an analysis was conducted on the same CPs with both CCE and colonoscopy (CS) and histopathologically diagnosed as AP or HP. The color difference (ΔE) between the polyp surface and the surrounding mucosa was calculated using the CIE1976 L*a*b* color space method on white light (WL), flexible spectral imaging color enhancement (FICE), and blue mode (BM) CP images. We investigated the ability of the ratio of the color differences (ΔE') to differentiate between APs and HPs. Results The size of all 51 polyps (34 APs, 17 HPs) was 7.5±4.6 mm with CCE and 7.3±4.2 mm with CS, and this difference was not significant (p=0.28). The FICEΔE' of APs was 3.3±1.8, which was significantly higher than the FICEΔE' of HPs (1.3±0.6; p<0.001). A receiver operating characteristic analysis showed that FICEΔE' was useful for differentiating between APs and HPs, with an area under the curve of 0.928 (95% confidence interval, 0.843-1). The sensitivity was 91.2%, and the specificity was 88.2% with a cut-off value of 1.758. Conclusion Using FICE on CCE images of CPs and applying the CIELAB color space method, we were able to differentiate between APs and HPs with high accuracy. This method has the potential to reduce unnecessary CS procedures.

Evaluation of the impact of linked color imaging for improving the visibility of colonic polyp.

Linked color imaging (LCI) is a novel endoscopic system used to increase color contrast. As LCI does not decrease luminal brightness, it may improve the detection of colonic neoplasms. However, the extent to which LCI improves the visibility of colonic polyps has not yet been determined. Between December 2016 and May 2017, patients who received total colonoscopy were consecutively recruited into this retrospective, single-center study. For each polyp identified, images obtained from white light (WL) imaging, blue laser imaging (BLI), and LCI of the same lesion and its surrounding mucosa were evaluated. The color differences (ΔE) between each lesion and its surrounding mucosa in non-magnified images were computed quantitatively using the CIELAB color space, which defines color perception according to colorimetric values, and compared among WL, BLI, LCI, and chromoendoscopy. The ΔE between the vessel and non-vessel areas in magnified images was also assessed. Of the 64 patients who were incorporated into this study, non-magnified and magnified (×80) images from 113 and 95 polyps, respectively, were assessed. The ΔE was intensified by LCI and chromoendoscopy compared with WL and BLI. The ΔE of neoplastic lesions was also intensified by LCI. In magnified images, BLI and LCI significantly increased the ΔE between the vessel and non-vessel areas compared with WL. Luminal brightness, indicated by L*, was not impaired by LCI; however, was reduced by BLI compared with WL and LCI. These results suggest that LCI enhanced the detection of colonic neoplasms without impairing luminal brightness. We propose the routine use of LCI for colonic polyp detection and BLI for magnifying observations of colonic polyps detected by LCI.

Massive Bleeding from a Small Intestinal Submucosal Tumor-like Arterial Malformation: An Unclassifiable Vascular Lesion Revealed by a Detailed Pathological Evaluation.

A 53-year-old woman presented with repeated copious bloody stool. Small bowel capsule endoscopy revealed a submucosal tumor (SMT)-like lesion, with erosion of the surface, in the first third of the small bowel. Balloon-assisted small intestinal endoscopy also revealed a pulsatile SMT-like lesion with an exposed vessel on the surface. This unknown lesion was surgically resected. The histopathological findings of the resected SMT-like lesion showed a dilated artery with thrombosis blockage and recanalization. Since this case could not be classified as any of the small intestinal vascular lesion patterns endoscopically, its classification will require the accumulation of further cases.

Autophagy deficiency exacerbates colitis through excessive oxidative stress and MAPK signaling pathway activation.

BACKGROUND AND AIM: Autophagy is an essential process involved in the pathogenesis of inflammatory bowel disease (IBD). Although there are many data showing the roles of autophagy in intestinal epithelial cells (IECs), the mechanisms involved remain to be fully elucidated. We investigated the influence of autophagy in IECs on gastrointestinal tract inflammation. METHODS: Mice with conditional knockout of Atg5 in IECs (Atg5flox/flox/villin-Cre mice) were subjected to dextran sulfate sodium (DSS)-induced colitis and analyzed for colitis susceptibility. Additionally, we used Atg5-silenced rat IECs (IEC6shAtg5 cells) for in vitro assays. RESULTS: Sensitivity to DSS markedly increased in Atg5flox/flox/villin-Cre mice compared to that in wild-type mice. In IEC6shAtg5 cells, apoptosis was enhanced, and cell viability significantly decreased compared to IEC-6 cells. The expression of proinflammatory cytokines increased upon suppression of autophagy. Furthermore, silencing of Atg5 was associated with inflammation of IECs, activation of the mitogen-activated protein kinase (MAPK) signaling pathway by the intracellular reactive oxygen species accumulation, and NF-κB p65 phosphorylation. CONCLUSIONS: Autophagy in IECs plays an essential role in the maintenance of intestinal homeostasis, and autophagy deficiency triggers inflammation. Development of methods targeting autophagy might be beneficial in the treatment of IBD.