An unmet need for pharmacology: Treatments for radiation-induced gastrointestinal mucositis.

Gastrointestinal mucositis (GIM) continues to be a significant issue in the management of abdominal cancer radiation treatments and chemotherapy, causing significant patient discomfort and therapy interruption or even cessation. This review will first focus on radiotherapy induced GIM, providing an understanding of its clinical landscape. Subsequently, the aetiology of GIM will be reviewed, highlighting diverse contributing factors. The cellular and tissue damage and associated molecular responses in GIM will be summarised in the context of the underlying complex biological processes. Finally, available drugs and pharmaceutical therapies will be evaluated, underscoring their insufficiency, and highlighting the need for further research and innovation. This review will emphasize the urgent need for improved pharmacologic therapeutics for GIM, which is a key research priority in oncology.

A preliminary therapeutic study of the effects of molecular hydrogen on intestinal dysbiosis and small intestinal injury in high-fat diet-loaded senescence-accelerated mice.

OBJECTIVES: Aging and excessive fat intake may additively induce dysbiosis of the gut microbiota and intestinal inflammatory damage. Here, we analyzed microbiota dysbiosis and intestinal injury in high-fat diet-loaded senescence-accelerated mice (SAMP8). Additionally, we examined whether treatment with molecular hydrogen could improve the intestinal environment. METHODS: SAMP8 and SAMR1 (control) mice were first fed a normal diet (ND) or high-fat diet (HFD) for 10 wk (n = 10 each group). Subsequently, HFD was supplemented with a placebo jelly or hydrogen-rich jelly (HRJ) for 4 wk. After treatment, isolated small intestinal tissues were used for hematoxylin and eosin staining, immunofluorescence staining, and thiobarbituric acid reactive substances (TBARS) assay. Furthermore, we analyzed alterations in the microbiota composition in cecal feces using 16S rRNA gene analysis for microbiota profiling. Statistical analyses were performed using unpaired Student's t tests or one-way analysis of variance and Tukey's post hoc test for multiple comparisons. RESULT: HFD feeding reduced the expression of caudal-related homeobox transcription factor 2 (CDX2) and 5-bromo-2'-deoxyuridine (BrdU) and enhanced malondialdehyde (MDA) levels in the small intestine of SAMP8. HRJ treatment improved the reduction in CDX2 and BrdU and enhanced MDA levels. We performed a sequence analysis of the gut microbiota at the genus level and identified 283 different bacterial genera from the 30 samples analyzed in the study. Among them, Parvibacter positively correlated with both HFD intake and aging, whereas 10 bacteria, including Anaerofustis, Anaerosporobacter, Butyricicoccus, and Ruminococcus were negatively correlated with both HFD and aging. HRJ treatment increased Lactinobactor and decreased Akkermansia, Gracilibacter, and Marvinbryantia abundance. CONCLUSION: Our findings suggest that treatment with molecular hydrogen may affect microbiota profiling and suppress intestinal injury in HFD-loaded SAMP8.

Endo Belly: What Is It and Why Does It Happen?-A Narrative Review.

Endometriosis is a chronic inflammatory disease where endometrial-like lesions settle outside the uterus, resulting in extensive inflammatory reactions. It is a complex disease that presents with a range of symptoms, with pain and infertility being the most common. Along with severe dysmenorrhea, cyclic and acyclic lower abdominal pain, cyclic dysuria and dyschezia, dyspareunia, and infertility, there are also nonspecific complaints that can cause confusion and make endometriosis the chameleon among gynecological diseases. These symptoms include unspecific intestinal complaints, cyclic diarrhea, but also constipation, nausea, vomiting, and stomach complaints. It appears that in addition to general bowel symptoms, there are also specific symptoms related to endometriosis such as cyclic bloating of the abdomen, known as endo belly. During the second half of the menstrual cycle leading up to menstruation, the abdomen becomes increasingly bloated causing discomfort and pain due to elevated sensitivity of the intestinal wall. Patients with endometriosis exhibit a reduced stretch pain threshold of the intestinal wall. Here, we review the endo belly, for the first time, pathophysiology and the influence of other diseases (such as irritable bowel syndrome-IBS), microbiome, hormonal levels, inflammation, and diet on the presentation of this condition.

In Vitro Evaluation of Probiotic Properties of Two Novel Probiotic Mixtures, Consti-Biome and Sensi-Biome.

Changes in the gut microbiome cause recolonization by pathogens and inflammatory responses, leading to the development of intestinal disorders. Probiotics administration has been proposed for many years to reverse the intestinal dysbiosis and to enhance intestinal health. This study aimed to evaluate the inhibitory effects of two newly designed probiotic mixtures, Consti-Biome and Sensi-Biome, on two enteric pathogens Staphylococcus aureus and Escherichia coli that may cause intestinal disorders. Additionally, the study was designed to evaluate whether Consti-Biome and Sensi-Biome could modulate the immune response, produce short-chain fatty acids (SCFAs), and reduce gas production. Consti-Biome and Sensi-Biome showed superior adhesion ratios to HT-29 cells and competitively suppressed pathogen adhesion. Moreover, the probiotic mixtures decreased the levels of pro-inflammatory cytokines, such as tumor necrosis factor-α, interleukin (IL)-6 and IL-1ß. Cell-free supernatants (CFSs) were used to investigate the inhibitory effects of metabolites on growth and biofilms of pathogens. Consti-Biome and Sensi-Biome CFSs exhibited antimicrobial and anti-biofilm activity, where microscopic analysis confirmed an increase in the number of dead cells and the structural disruption of pathogens. Gas chromatographic analysis of the CFSs revealed their ability to produce SCFAs, including acetic, propionic, and butyric acid. SCFA secretion by probiotics may demonstrate their potential activities against pathogens and gut inflammation. In terms of intestinal symptoms regarding abdominal bloating and discomfort, Consti-Biome and Sensi-Biome also inhibited gas production. Thus, these two probiotic mixtures have great potential to be developed as dietary supplements to alleviate the intestinal disorders.

Low fermentable oligosaccharides, disaccharides, monosaccharides, and polyols diet versus traditional dietary advice for functional dyspepsia: a randomized controlled trial.

BACKGROUND AND AIM: Prospective trials evaluating efficacy of specific diet restriction in functional dyspepsia (FD) are scarce. We aimed to assess efficacy of low fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAP) diet in FD, compared with traditional dietary advice (TDA). METHODS: In this prospective, single-blind trial, patients with FD (Rome IV) were randomized into low FODMAP diet (LFD) and TDA groups, for 4 weeks (phase I). In phase II (4-12 weeks), LFD group was advised systematic re-introduction of FODMAPs. Symptom severity and quality of life were assessed using "Short-Form Nepean Dyspepsia Index (SF-NDI)." Primary outcome was symptomatic response (symptom score reduction of ≥ 50%), at 4 weeks. Study was registered with CTRI (2019/06/019852). RESULTS: Of 184 patients screened, 105 were randomized to LFD (n = 54) and TDA (n = 51) groups. At 4 weeks, both groups showed significant reduction in SF-NDI symptom scores compared with baseline, with no significant difference in inter-group response rates [LFD: 66.7% (36/54); TDA: 56.9% (29/51); P = 0.32]. On sub-group analysis, patients with postprandial distress syndrome or bloating had significantly better symptomatic response with LFD (P = 0.04). SF-NDI quality of life scores improved significantly in both groups. On multivariate analysis, factors predicting response to LFD were bloating and male gender. Incidences of adverse events (minor) were similar in both groups. CONCLUSIONS: In patients with FD, LFD and TDA lead to significant symptomatic and quality of life improvement. Patients with postprandial distress syndrome or bloating respond significantly better to LFD. Therefore, dietary advice for FD should be individualized according to FD subtype.

Npr2 mutant mice show vasodilation and undeveloped adipocytes in mesentery.

OBJECTIVE: The biological importance for the signaling of C-type natriuretic peptide (CNP) and natriuretic peptide receptor B (NPR-B) has been recognized. However, the details remain unclear and are debatable. The Npr2 is a gene of NPR-B, and we previously reported a unique phenotype of a spontaneous mutant mouse lacking Npr2 (Npr2slw/slw), such as severe ileus-like disorder with bloodless blood vessels. In this study, we analyzed the bloodless mesenteric vascular morphology of Npr2slw/slw by histological observation to clarify the effects of the CNP/NPR-B signal deficiency. RESULTS: Blood vessels in the mesentery were clearly dilated in the preweaning Npr2slw/slw mice. Additionally, in the Npr2slw/slw mice, the lacteals were partially dilation or randomly direction mucosal epithelial cells in villi, and mesenteric adipocytes were undeveloped. These findings provide important information for understanding the role of CNP/NPR-B signals on intestine with mesentery.

An Observational Real-Life Study with a New Infant Formula in Infants with Functional Gastro-Intestinal Disorders.

Functional gastro-intestinal disorders (FGIDs) impair the quality of life of many infants and their families. A formula with partial whey hydrolysate, starch, high magnesium content, prebiotic fructo-oligosaccharide and galacto-oligosaccharide and the probiotic Lactobacillus reuteri DSM 17938 was given during two weeks to 196 infants with at least two FGIDs. The efficacy was evaluated with the Cow Milk-associated Symptom Score (CoMiSS®) and quality of life with the QUALIN score. The formula was shown to decrease FGIDs within three days (decrease of CoMiSS -1.29 (3.15) (mean (SD), p < 0.0001) followed by an improvement of quality of life after seven days (increase QUALIN +1.4 (7.8); p: 0.008). Constipation decreased from 18.8% to 6.5% within three days. In combination with reassurance and guidance, the nutritional intervention was shown to be effective in infants with FGIDS in real-life circumstances.

Immune checkpoint inhibitor-induced enteritis assessed using capsule endoscopy.

We performed capsule endoscopy for a patient with immune checkpoint inhibitor-induced enteritis and found multiple erosions or small ulcers in the small intestine. No reports demonstrated the effectiveness of capsule endoscopy for immune checkpoint inhibitor-induced gastrointestinal adverse events, and our case suggests that capsule endoscopy may be useful to evaluate immune checkpoint inhibitor-induced enteritis.

Deficiency in the anti-apoptotic protein DJ-1 promotes intestinal epithelial cell apoptosis and aggravates inflammatory bowel disease via p53.

Parkinson disease autosomal recessive, early onset 7 (PARK7 or DJ-1) is involved in multiple physiological processes and exerts anti-apoptotic effects on multiple cell types. Increased intestinal epithelial cell (IEC) apoptosis and excessive activation of the p53 signaling pathway is a hallmark of inflammatory bowel disease (IBD), which includes ulcerative colitis (UC) and Crohn's disease (CD). However, whether DJ-1 plays a role in colitis is unclear. To determine whether DJ-1 deficiency is involved in the p53 activation that results in IEC apoptosis in colitis, here we performed immunostaining, real-time PCR, and immunoblotting analyses to assess DJ-1 expression in human UC and CD samples. In the inflamed intestines of individuals with IBD, DJ-1 expression was decreased and negatively correlated with p53 expression. DJ-1 deficiency significantly aggravated colitis, evidenced by increased intestinal inflammation and exacerbated IEC apoptosis. Moreover, DJ-1 directly interacted with p53, and reduced DJ-1 levels increased p53 levels both in vivo and in vitro and were associated with decreased p53 degradation via the lysosomal pathway. We also induced experimental colitis with dextran sulfate sodium in mice and found that compared with DJ-1-/- mice, DJ-1-/-p53-/- mice have reduced apoptosis and inflammation and increased epithelial barrier integrity. Furthermore, pharmacological inhibition of p53 relieved inflammation in the DJ-1-/- mice. In conclusion, reduced DJ-1 expression promotes inflammation and IEC apoptosis via p53 in colitis, suggesting that the modulation of DJ-1 expression may be a potential therapeutic strategy for managing colitis.

Fecal Calprotectin: A Comparison of Two Commercial Enzymoimmunoassays and Study of Fecal Extract Stability at Room Temperature.

BACKGROUND: The aims of the study were: 1) to compare the fecal calprotectin (fCal) assay results with Calprolab™ ELISA (HRP) (Calpro AS) versus our routine method, Elia™ fluoroenzymoimmunoassay (Thermo Fisher), and 2) to determine whether the fCal assay results do not vary following storage of the extract at room temperature for 4 days with the Calpro AS buffer, this being the estimated shipment time from the home of the patient, and an aspect little studied to date. METHODS: The fCal was determined in 198 patients divided into three groups: inflammatory bowel disease (IBD), organic intestinal disease, and functional intestinal disorders. Fecal extraction was carried out using the Roche Diagnostics kit with the corresponding specific buffers. RESULTS: The fCal assay with the Thermo Fisher method was found to be more sensitive but less specific than with the Calpro AS technique. The positive predictive value was low (just over 50%), though the negative predictive value was high (over 90%) with both methods. The likelihood ratios revealed small but occasionally important pre- versus post-test differences. When we compared the two methods, the Spearman correlation coefficient (ρ) was 0.819 (95% CI: 0.768 - 0.860) (P < 0.0001), reflecting a positive correlation. Similarly, when stratifying the fCal results into < 50 µg/g, 50 - 100 µg/g and > 100 µg/g, the resulting Cohen's kappa coefficient was 0.7766 (95% CI: 0.7025 - 0.8507), reflecting a substantial agreement between both methods. The stability of fCal was high in fecal extracts with the Calpro AS extraction buffer at room temperature for 4 days, which yielded a Spearman correlation coefficient of 0.951 (95% CI: 0.933 - 0.965), when the results were compared to those of the recent extracts (P < 0.0001). CONCLUSIONS: A positive correlation was observed between the two methods. In view of the high negative predictive value obtained with fCal, the presence of organic disease is highly unlikely in the presence of a normal concentration of this marker. We also confirmed the excellent stability of fCal in fecal extracts with the Calpro AS extraction buffer stored at room temperature. Thus, and for the sake of convenience and hygiene, it would be ideal for the patient to perform the extraction at home.

Innovative Disease Model: Zebrafish as an In Vivo Platform for Intestinal Disorder and Tumors.

Colorectal cancer (CRC) is one of the world's most common cancers and is the second leading cause of cancer deaths, causing more than 50,000 estimated deaths each year. Several risk factors are highly associated with CRC, including being overweight, eating a diet high in red meat and over-processed meat, having a history of inflammatory bowel disease, and smoking. Previous zebrafish studies have demonstrated that multiple oncogenes and tumor suppressor genes can be regulated through genetic or epigenetic alterations. Zebrafish research has also revealed that the activation of carcinogenesis-associated signal pathways plays an important role in CRC. The biology of cancer, intestinal disorders caused by carcinogens, and the morphological patterns of tumors have been found to be highly similar between zebrafish and humans. Therefore, the zebrafish has become an important animal model for translational medical research. Several zebrafish models have been developed to elucidate the characteristics of gastrointestinal diseases. This review article focuses on zebrafish models that have been used to study human intestinal disorders and tumors, including models involving mutant and transgenic fish. We also report on xenograft models and chemically-induced enterocolitis. This review demonstrates that excellent zebrafish models can provide novel insights into the pathogenesis of gastrointestinal diseases and help facilitate the evaluation of novel anti-tumor drugs.

18F-FDG PET imaging for identifying the dynamics of intestinal disease caused by SFTSV infection in a mouse model.

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging disease that causes fever, enteritis, thrombocytopenia, and leucopenia and can be fatal in up to 30% of cases. However, the mechanism of severe disease is not fully understood. Molecular imaging approaches, such as positron-emission tomography (PET), are functional in vivo imaging techniques that provide real-time dynamics of disease progression, assessments of pharmacokinetics, and diagnoses for disease progression. Molecular imaging also potentially provides useful approaches to explore the pathogenesis of viral infections. Thus, the purpose of this study was to image the pathological features of SFTSV infection in vivo by PET imaging. In a mouse model, we showed that 18F-FDG accumulations clearly identified the intestinal tract site as a pathological site. We also demonstrated that 18F-FDG PET imaging can assess disease progression and response to antiserum therapy within the same individual. This is the first report demonstrating a molecular imaging strategy for SFTSV infection. Our results provide potentially useful information for preclinical studies such as the elucidation of the mechanism of SFTSV infection in vivo and the assessment of drugs for SFTS treatment.

Role of innate immunity and altered intestinal motility in LPS- and MnCl2-induced intestinal intussusception in mice.

Intestinal intussusception (ISS) commonly causes intestinal obstruction in children. One mechanism that has been proposed to cause ISS is inflammation-induced alteration of intestinal motility. We investigated whether innate inflammatory factors or altered motility is required for induction of ISS by LPS. We compared rates of ISS among BALB/c and C57BL/6 mice, mice lacking lymphocytes or depleted of phagocytes, or mice with defects in the Toll-like receptor 4 (TLR4) signaling pathway following administration of LPS or the Ca(2+) analog MnCl2. At 6 or 2 h after administration of LPS or MnCl2, respectively, mice underwent image analysis to assess intestinal contraction rate or laparotomy to identify ISS. LPS-induced ISS (LPS-ISS) was observed in BALB/c mice, but not in C57BL/6 mice or any BALB/c mice with disruptions of TLR4 signaling. LPS-induced serum TNF-α, IL-6, and nitric oxide (NO) and intestinal NO levels were similar in BALB/c and C57BL/6 mice. The rate of LPS-ISS was significantly reduced in phagocyte-depleted, but not lymphocyte-deficient, mice. Intestinal contraction rates were reduced in LPS-ISS-susceptible BALB/c mice, but not in LPS-ISS-resistant C57BL/6 or TLR4 mutant mice, suggesting a role for reduced intestinal contraction rate in LPS-ISS susceptibility. This was tested with MnCl2, a Ca(2+) antagonist that reduced intestinal contraction rates and induced ISS, irrespective of mouse strain. Therefore, LPS-ISS is initiated by innate immune signaling that requires TLR4 and phagocytes but may be independent of TNF-α, IL-6, and NO levels. Furthermore, alteration of intestinal motility, specifically, reduced intestinal contraction rate, is a key factor in the development of ISS.