Exercise habits that include exercise partners and irritable bowel syndrome in a young Japanese population: a cross-sectional study.

OBJECTIVE: Evidence regarding the association between exercise habits and irritable bowel syndrome (IBS) remains scarce in a young population. It is also unknown whether the existence of an exercise partner affects this issue. The purpose of this study was to explore the association between exercise habits that include an exercise partner and IBS in a young Japanese population. METHODS: This study enrolled 8923 Japanese university students and examined exercise frequency and intensity, and exercise partners using self-administered questionnaires. IBS and functional dyspepsia were defined according to the Rome III criteria. RESULTS: The prevalence of IBS in this survey was 6.5%. Moderate frequency exercise was inversely related with IBS [adjusted odds ratio (aOR): 0.65 (95% confidence interval, CI: 0.51-0.83), P for trend = 0.005]. Moderate and high exercise intensities were independently and inversely related with IBS, respectively [aORs were moderate: 0.76 (95% CI: 0.61-0.95) and high: 0.62 (95% CI: 0.48-0.78), P for trend = 0.001]. Exercising with a group or with friends instead of alone was independently inversely related with IBS [aOR with groups: 0.53 (95% CI: 0.40-0.70) and with friends: aOR 0.71 (95% CI: 0.54-0.93)]. After excluding subjects with overlapping IBS and functional dyspepsia, an inverse association between high intensity of exercise or exercise in a group and IBS remained significant. CONCLUSION: The frequency and intensity of exercise may be independently inversely related with IBS in a young Japanese population. Also, exercise with others may be important for preventing IBS.

A Network Pharmacology-Based Study on Irritable Bowel Syndrome Prevention and Treatment Utilizing Shenling Baizhu Powder.

METHODS: Metabolomics was used to detect the secondary metabolites in SLBZP; the target protein was acquired by target fishing according to the compound's structure. The SymMap database was used to search herbal medicines for the target protein. The target gene of IBS gave rise to the common gene protein which is the potential target of SLBZP in IBS therapy. The interactions between target proteins were analyzed in a STRING database, the protein relationship network was analyzed using Cytoscape software, and the Kyoto Encyclopedia of Genes and Genomes enrichment analysis of the core target gene group was carried out in a DAVID database in order to construct the "compound-traditional Chinese medicine/molecule-target-pathway" network. Molecular docking was used to verify the core protein and its related small molecular compounds. RESULT: There were 129 types of secondary metabolites in SLBZP. 80 target proteins of these metabolites were potential core targets for IBS treatment including acetylcholinesterase (AChE), arachidonate-5-lipoxygenase (ALOX5), B-cell lymphoma-2 (BCL2), recombinant cyclin D1 (CCND1), and catenin-ß1 (CTNNB1), among others. Results from these targets indicated that the most enriched pathway was the tumor necrosis factor (TNF) signaling pathway (p < 0.001) and that the most abundant pathway was signal transduction. In the network nodes of the TNF signaling pathway, the Chinese medicines with the highest aggregation were Lablab semen album and Glycyrrhizae radix et rhizoma (degree = 11). The small molecules with the highest aggregation were oxypeucedanin and 3,5,6,7,8,3',4'-heptamethoxyflavone (degree = 4). Molecular docking results confirmed that daidzein 7-O-glucoside (daidzin) had the highest degree of binding to TNF proteins in the TNF signaling pathway. CONCLUSION: This study shows that SLBZP can treat IBS by influencing multiple targets and pathways, of which the TNF signaling pathway may be the most significant. This typifies the pharmacological characteristics of traditional Chinese medicine, i.e., multiple targets, numerous pathways, and specific therapeutic effects on diseases. SLBZP can therefore be used as a candidate drug for clinical IBS by intervening in human signal transduction.

Lactobacilli Supplemented with Larch Arabinogalactan and Colostrum Stimulates an Immune Response towards Peripheral NK Activation and Gut Tolerance.

Probiotics possibly affect local and systemic immune reactions and maintain the intestinal immune homeostasis in healthy individuals and patients with diseases such as irritable bowel syndrome (IBS). In this single-center, blinded trial, we enrolled 40 individuals (20 patients with IBS and 20 healthy individuals) whose blood and fecal samples were collected before and after a 21-day administration of a product comprising Lactobacillus spp., larch arabinogalactan, and colostrum. The percentage of HLA-DR+ natural killer (NK) cells was higher in healthy individuals (p = 0.03) than in patients with IBS after product supplementation. In the fecal samples of patients with IBS, we observed a decline in IL-6, IFN-γ, TNF-α, and secretory IgA levels and, simultaneously, an increase in IL-10 and IL-17A levels after supplementation, although non-significant, whereas, in healthy individuals, we observed a significant decline in IL-6 and IFN-γ levels after supplementation (p < 0.001). Nevertheless, we observed a clinical improvement of symptoms in 65-75% of patients with IBS and the complete resolution of the initial symptoms in five of the 20 patients. We also observed a possible prophylactic effect by the inducing system antiviral impact accompanied by a trend for local immune tolerance in the gut in healthy individuals, where it is the desirable state.

The multicomponent medication Spascupreel attenuates stress-induced gut dysfunction in rats.

BACKGROUND: Irritable bowel syndrome (IBS) is a common disorder worldwide. It is characterized by abdominal pain/discomfort and changes in bowel habits. Due to the multifactorial pathophysiology and the heterogeneity of IBS patients, appropriate treatment of IBS is still a challenge. Spascupreel (SP-11), as a multicomponent medication, has the potential to modulate multiple pathophysiological pathways simultaneously. Therefore, the objective of the current study was to investigate the effects of oral SP-11 treatment on stress-induced changes of peripheral and central functions in a rat model mimicking human IBS. METHODS: Naïve Wistar rats were treated with SP-11 (0.9 tab/kg) or NaCl 0.9% by oral gavage for 4 days before 2-hour partial restraint stress (PRS) procedure. Twenty minutes after PRS, central and peripheral stress-induced changes affecting IBS were assessed. These include the hypothalamic-pituitary-adrenal (HPA) axis response through plasma ACTH and corticosterone measurements, visceral pain in response to colorectal distension, gut permeability, colonic mast cell number, and sensitization as well as gut transit time. RESULTS: Treatment with SP-11 reduced the HPA axis activation in response to PRS. At the gut level, a reduction in colonic hypersensitivity to colorectal distension, a normalization of gut transit time acceleration, a reduced mast cell sensitization, and a trend toward reduced gut hyperpermeability were observed. CONCLUSIONS: These data suggest that stress-induced IBS signs can be reduced using SP-11 in rats. The observed effects and the good tolerability of the drug make SP-11 an innovative candidate in the management of IBS.

'Rapid transit' constipation in children: a possible genesis for irritable bowel syndrome.

Children with chronic idiopathic constipation (CIC) often end up at the surgeon when medical treatments have failed. This opinion piece discusses a recently described pattern of CIC called 'Rapid transit constipation (RTC)' first identified in 2011 as part of surgical workup. RTC was identified using a nuclear medicine gastrointestinal transit study (NMGIT or nuclear transit study) to determine the site of slowing within the bowel and to inform surgical treatment. Unexpectedly, we found that RTC occured in 29% of 1000 transit studies in a retrospective audit. Irritable bowel syndrome (IBS) occurs in 7-21% of the population, with a higher prevalence in young children and with constipation type dominating in the young. While 60% improve with time, 40% continue with symptoms. First-line therapy for IBS in adults is a diet low in fermentable oligosaccharides, disaccharides, monosaccharides and polyols which reduces symptoms in > 70% of patients. In children with functional gastrointestinal disorders, fructose intolerance occurs in 35-55%. Reducing fructose produced significant improvement in 77-82% of intolerant patients. In children with RTC and a positive breath test upon fructose challenge, we found that exclusion of fructose significantly improved constipation, abdominal pain, stool consistency and decreased laxative use. We hypothesise that positive breath tests and improvement of pain and bowel frequency with sugar exclusion diets in RTC suggest these children have IBS-C. These observations raise the possibility that many children with CIC could be treated by reducing fructose early in their diet and this might prevent the development of IBS in later life.

Natural polyphenols for the prevention of irritable bowel syndrome: molecular mechanisms and targets; a comprehensive review.

Irritable bowel syndrome (IBS) is a well diagnosed disease, thoroughly attributed to series of symptoms criteria that embrace a broad range of abdominal complainers. Such criteria help to diagnosis the disease and can guide controlled clinical trials to seek new therapeutic agents. Accordingly, a verity of mechanisms and pathophysiological conditions including inflammation, oxidative stress, lipid peroxidation and different life styles are involved in IBS. Predictably, diverse therapeutic approaches are available and prescribed by clinicians due to major manifestations (i.e., diarrhea-predominance, constipation-predominance, abdominal pain and visceral hypersensitivity), psychological disturbances, and patient preferences between herbal treatments versus pharmacological therapies, dietary or microbiological approaches. Herein, we gathered the latest scientific data between 1973 and 2019 from databases such as PubMed, Google Scholar, Scopus and Cochrane library on relevant studies concerning beneficial effects of herbal treatments for IBS, in particular polyphenols. This is concluded that polyphenols might be applicable for preventing IBS and improving the IBS symptoms, mainly through suppressing the inflammatory signaling pathways, which nowadays are known as novel platform for the IBS management. Graphical abstract.

Repeated transcutaneous electrical nerve stimulation of nonspecific acupoints of the upper body attenuates stress-induced visceral hypersensitivity in rats.

Irritable bowel syndrome (IBS) is a common stress-related gastrointestinal disorder and visceral hypersensitivity (VH) is characteristically found in IBS patients. Transcutaneous electrical nerve stimulation (TENS) applied to certain acupoints has been shown to benefit IBS patients. Here, we investigated whether nonspecific acupoint is involved in the efficacy of TENS treatment for IBS. Twenty-five male rats were randomly assigned to four experimental groups and one sham-control group. The four experimental groups were defined as TENS-RR, TENS-RL, TENS-LR, and TENS-LL based on the location of the two TENS patches [right (R) or left (L)]. The former and latter letter pairs indicate that the patch locations were the upper chest and upper back, respectively. The heterotypic intermittent stress (HIS) protocol was performed for 16 days. VH was assessed by electromyography to evaluate response to rectal distention (RD). Modulated medium-frequency TENS, sweep range 1-10 Hz, amplitude slightly above the supra motor threshold, was applied 30 min per day followed by RD every second day for the final 7 days of the 16-day HIS period. VH was induced after the rats had been subjected to HIS for 10 days. A significant reduction of VH was observed only in the TENS-LL group compared with that in the sham-control group. These data suggest that repeated TENS treatment can alleviate stress-induced VH in rats. Further, whether TENS patches are attached to the left or right side of the body, which are nonspecific acupoints for gastrointestinal functions, may be an important factor in the treatment of stress-associated gastrointestinal symptoms.

Berberine improves intestinal epithelial tight junctions by upregulating A20 expression in IBS-D mice.

To investigate effects of berberine exerts on A20 expression and regulation of intestinal epithelial tight junctions via the TNF-α-NF-κB-MLCK pathway in Diarrhea-Predominant Irritable Bowel Syndrome (IBS-D). C57BL/6 wild type (WT) and A20 IEC-KO mice (48 each) were randomly divided into normal control (NC), model control (MC), rifaximin and berberine groups (12 mice per group). An experimental model of IBS-D was established using 4% acetic acid and evaluated by haematoxylin-eosin (HE) staining. rifaximin and berberine mice were treated with rifaximin and berberine, respectively. Intestinal epithelial space of WT berberine mice improved more than A20 IEC-KO berberine mice compared to MC mice. WT berberine mice exhibited greater expression of A20 compared with MC mice(P < 0.01). TNF-α, NF-kB p65, MLCK, MLC, TRAF6 and RIP1 levels in A20 IEC-KO and WT berberine mice were all decreased compared to MC mice(P all<0.05). NF-κB p65, MLCK and TRAF6 levels were increased in A20 IEC-KO berberine mice as compared to WT berberine mice (P all<0.05). Intestinal epithelial levels of occludin, claudin-1, ZO-1 and F-actin increased in all berberine mice (P all<0.01-0.05), while occludin, claudin-1, and ZO-1 levels were lower in A20 IEC-KO berberine mice(P < 0.05). Berberine downregulates abnormal activation of the TNF-α-NF-κB-MLCK pathway by upregulating expression of A20 in a mouse model of IBS-D, thereby protecting intestinal epithelial tight junctions and repairing the damage IBS-D causes to the intestinal epithelial barrier.

[Probiotic using as a part of complex therapy of disbiotic violations at some intestinal diseases].

Diseases of intestines are among the most widespread in this connection their effective prevention and treatment represents a priority problem of practical health care. Nowadays the set of the indisputable evidence that the microbiota of intestines played a key role in pathogenesis of many diseases has been obtained. Aim - the analysis of the available data on a role of microflora and efficiency of probiotic cultures for treatment of irritable bowel syndrome, the necrotic enterocolitis, Krone's disease. Based on the data, which is available in literature, the main aspects of biological properties of probiotic bacteria, first in the context of their regulating influence on inflammatory immune reaction have been discussed. The question of strain-specific effect of probiotics has been considered. The basic provisions concerning change of a fecal microbiota, prospect and difficulty of realization of this technique have been presented in the article. Conclusion. Despite of wide use of pro- and prebiotics in clinic for treatment of diseases of digestive tract, a large number of the questions connected with selection of concrete strains for each patient, a dosage and duration of therapy for achievement of steady remission still remains.

Exit Gluten-Free and Enter Low FODMAPs: A Novel Dietary Strategy to Reduce Gastrointestinal Symptoms in Athletes.

Exercise-associated physiological disturbances alter gastrointestinal function and integrity. These alterations may increase susceptibility to dietary triggers, namely gluten and a family of short-chain carbohydrates known as FODMAPs (fermentable oligo-, di-, monosaccharides and polyols). A recent surge in the popularity of gluten-free diets (GFDs) among athletes without celiac disease has been exacerbated by unsubstantiated commercial health claims and high-profile athletes citing this diet to be the secret to their success. Up to 41% of athletes at least partially adhere to a GFD diet, with the belief that gluten avoidance improves exercise performance and parameters influencing performance, particularly gastrointestinal symptoms (GIS). In contrast to these beliefs, seminal work investigating the effects of a GFD in athletes without celiac disease has demonstrated no beneficial effect of a GFD versus a gluten-containing diet on performance, gastrointestinal health, inflammation, or perceptual wellbeing. Interestingly, the subsequent reduction in FODMAPs concurrent with the elimination of gluten-containing grains may actually be the factors affecting GIS improvement, not gluten. Pre-existent in the gastrointestinal tract or ingested during exercise, the osmotic and gas-producing effects of variably absorbed FODMAPs may trigger or increase the magnitude of exercise-associated GIS. Research using FODMAP reduction to address gastrointestinal issues in clinically healthy athletes is emerging as a promising strategy to reduce exercise-associated GIS. Applied research and practitioners merging clinical and sports nutrition methods will be essential for the effective use of a low FODMAP approach to tackle the multifactorial nature of gastrointestinal disturbances in athletes.

Kluyveromyces marxianus yeast enables the production of low FODMAP whole wheat breads.

There is evidence that a diet low in Fermentable Oligo-, Di-, Monosaccharides And Polyols (FODMAPs) alleviates symptoms in approx. 70% of the patients suffering from irritable bowel syndrome. Through fructans, wheat containing products are a major source of FODMAPs in the western diet. Although fructans are partially degraded during dough fermentation by Saccharomyces cerevisiae invertase, wheat bread contains notable fructan levels. In this study, it was shown that Kluyveromyces marxianus strain CBS6014 can degrade more than 90% of the fructans initially present in wheat whole meal during bread making, which can be attributed to its high inulinase activity. As K. marxianus CBS6014 was not able to consume maltose during fermentation, alternative sugars (sucrose) or glucose releasing enzymes (amyloglucosidase) had to be included in the bread making recipe to ensure sufficient production of CO2 and high bread quality. Five volatile flavor compounds were produced in significantly different levels when K. marxianus CBS6014 was used as starter culture compared with the conventional S. cerevisiae bakery strain. These differences were, however, not detected when sensory analysis of the crumb was performed. This study demonstrates the potential of inulinase-producing K. marxianus strains for the production of (whole meal) breads low in FODMAPs.

Evaluation of FODMAP Carbohydrates Content in Selected Foods in the United States.

We analyzed the fermentable oligosaccharide, disaccharide, monosaccharide, and polyols (FODMAP) content of several foods potentially low in FODMAP which are commonly consumed by children. We determined that several processed foods (eg, gluten-free baked products) had unlabeled FODMAP content. Determining FODMAP content within foods distributed in the US may support educational and dietary interventions.

Does a low FODMAPs diet reduce symptoms of functional abdominal pain disorders? A systematic review in adult and paediatric population, on behalf of Italian Society of Pediatrics.

BACKGROUND: Despite the rising of the Functional Gastrointestinal Disorders (FGIDs)' incidence in the last years, the etio-pathogenesis of FGIDs remains unclear. The diet seems to play an important role in these disorders. Indeed, at least two thirds of adult patients with Irritable Bowel Syndrome (IBS) and of children with FGIDs perceive their GI symptoms to be food-related. In particular, in the last years, more interest has been focused in the low Fermentable Oligosaccharides, Disaccharides, Monosaccharides, and Polyol (FODMAPs) diet. AIMS: To provide a systematic review on the efficacy of a low FODMAPs diet in reducing symptoms associated with functional abdominal pain disorders. METHODS: Cochrane Library, MEDLINE (via Pubmed), and EMBASE databases from inception to June 2017 were searched. We included randomized controlled trials (RCTs), prospective and retrospective studies, systematic reviews and meta-analyses, reporting the efficacy of the FODMAPs diet intervention in FGIDs patients. RESULTS: Nineteen studies were eligible. A FODMAPs-restricted diet is beneficial in 12/13 intervention trials. The low FODMAPs diet improves overall GI symptoms, especially abdominal pain and bloating. In children, only one study reported positive results of a low FODMAPs diet. No effect was found for the lactose free diet whilst fructose-restricted diet was effective in 3/4 studies. The duration of the intervention was very different among the studies, ranging from 2 days to 16 months, and from 3 and 9 weeks for the RCTs. The majority of the trials presented differences in symptoms scoring scales, diet, food diaries, and food frequencies questionnaire. CONCLUSIONS: The FODMAPs-restricted diet may be an effective dietary intervention for reducing IBS symptoms in adults. In children, there are promising data, although only one randomized double-blind study exists and further data are needed to better clarify the role of FODMAPs and fructose-restricted diet in IBS. The current evidence does not support the use of a lactose-restricted diet in children with FGIDs.

Guidance on the use of probiotics in clinical practice in children with selected clinical conditions and in specific vulnerable groups.

AIM: The use of probiotics has been covered by many guidelines, position papers and evidence-based recommendations, but few have referred to specific patient groups or clinical indications. This review summarises recommendations and scientifically credited guidelines on the use of probiotics for children with selected clinical conditions and provides practice points. METHODS: An expert panel was convened by the European Paediatric Association in June 2017 to define the relevant clinical questions for using probiotics in paediatric health care and review and summarise the guidelines, recommendations, position papers and high-quality evidence. RESULTS: The panel found that specific probiotic strains were effective in preventing antibiotic-associated and nosocomial diarrhoea, treating acute gastroenteritis and treating infantile colic in breastfed infants. However, special caution is indicated for premature infants, immunocompromised and critically ill patients and those with central venous catheters, cardiac valvular disease and short-gut syndrome. This review discusses the safety of using probiotics in selected groups of paediatric patients and the quality of the available products providing practice points based on proved findings. CONCLUSION: Efficacy of probiotics is strain specific. Their benefits are currently scientifically proven for their use in selected clinical conditions in children and not recommended for certain patient groups.

Putative mechanisms of kiwifruit on maintenance of normal gastrointestinal function.

Kiwifruits are recognized as providing relief from constipation and symptoms of constipation-predominant irritable bowel syndrome (IBS-C). However, the underlying mechanisms, specifically in regards to gastrointestinal transit time and motility, are still not completely understood. This review provides an overview on the physiological and pathophysiological processes underlying constipation and IBS-C, the composition of kiwifruit, and recent advances in the research of kiwifruit and abdominal comfort. In addition, gaps in the research are highlighted and scientific studies of other foods with known effects on the gastrointestinal tract are consulted to find likely mechanisms of action. While the effects of kiwifruit fiber are well documented, observed increases in gastrointestinal motility caused by kiwifruit are not fully characterized. There are a number of identified mechanisms that may be activated by kiwifruit compounds, such as the induction of motility via protease-activated signaling, modulation of microflora, changes in colonic methane status, bile flux, or mediation of inflammatory processes.

A Novel Prebiotic Blend Product Prevents Irritable Bowel Syndrome in Mice by Improving Gut Microbiota and Modulating Immune Response.

Irritable bowel syndrome (IBS) is the most common functional gastrointestinal disorder yet it still lacks effective prevention therapies. The aim of this study is to determine whether a novel prebiotic blend (PB) composed of fructo-oligosaccharide (FOS), galactooligosaccharide (GOS), inulin and anthocyanins could be effective in preventing the development of IBS. We explored the possible mechanisms both in animal and in cells. Post-infectious IBS models in C57BL/6 mice were established and were pretreated with the PB, PB and probiotic strains 8 weeks in advance of infection. Eight weeks after infection, intestinal tissues were collected for assessing histomorphology, visceral sensitivity, barrier function, pro-inflammatory cytokines expression and proteomics analysis. Fecal samples were also collected for microbiota analysis. The pro-inflammatory cytokines expression in Caco-2 cells were evaluated after co-incubation with PB and Salmonella typhimurium 14028. The results showed that PB significantly decreased the pro-inflammatory cytokines both in infected Caco-2 cells and PI-IBS models. The loss of body weight, decreased expression of tight junction protein Occludin (OCLN), and changes of the microbiota composition induced by infections could be greatly improved by PB intervention (p < 0.05). The proteomics analysis revealed that this function was associated with Peroxisome proliferator-activated receptor (PPAR)γ pathway.

The current treatment landscape of irritable bowel syndrome in adults in Hong Kong: consensus statements.

OBJECTIVE: The estimated prevalence of irritable bowel syndrome in Hong Kong is 6.6%. With the increasing availability of pharmacological and non-pharmacological treatments, the Hong Kong Advisory Council on Irritable Bowel Syndrome has developed a set of consensus statements intended to serve as local recommendations for clinicians about diagnosis and management of irritable bowel syndrome. PARTICIPANTS: A multidisciplinary group of clinicians constituting the Hong Kong Advisory Council on Irritable Bowel Syndrome-seven gastroenterologists, one clinical psychologist, one psychiatrist, and one nutritionist-convened on 20 April 2017 in Hong Kong. EVIDENCE: Published primary research articles, meta-analyses, and guidelines and consensus statements issued by different regional and international societies on the diagnosis and management of irritable bowel syndrome were reviewed. CONSENSUS PROCESS: An outline of consensus statements was drafted prior to the meeting. All consensus statements were finalised by the participants during the meeting, with 100% consensus. CONCLUSIONS: Twenty-four consensus statements were generated at the meeting. The statements were divided into four parts covering: (1) patient assessment; (2) patient's psychological distress; (3) dietary and alternative approaches to managing irritable bowel syndrome; and (4) evidence to support pharmacological management of irritable bowel syndrome. It is recommended that primary care physicians assume the role of principal care provider for patients with irritable bowel syndrome. The current statements are intended to guide primary care physicians in diagnosing and managing patients with irritable bowel syndrome in Hong Kong.

GUCY2C Signaling Opposes the Acute Radiation-Induced GI Syndrome.

High doses of ionizing radiation induce acute damage to epithelial cells of the gastrointestinal (GI) tract, mediating toxicities restricting the therapeutic efficacy of radiation in cancer and morbidity and mortality in nuclear disasters. No approved prophylaxis or therapy exists for these toxicities, in part reflecting an incomplete understanding of mechanisms contributing to the acute radiation-induced GI syndrome (RIGS). Guanylate cyclase C (GUCY2C) and its hormones guanylin and uroguanylin have recently emerged as one paracrine axis defending intestinal mucosal integrity against mutational, chemical, and inflammatory injury. Here, we reveal a role for the GUCY2C paracrine axis in compensatory mechanisms opposing RIGS. Eliminating GUCY2C signaling exacerbated RIGS, amplifying radiation-induced mortality, weight loss, mucosal bleeding, debilitation, and intestinal dysfunction. Durable expression of GUCY2C, guanylin, and uroguanylin mRNA and protein by intestinal epithelial cells was preserved following lethal irradiation inducing RIGS. Oral delivery of the heat-stable enterotoxin (ST), an exogenous GUCY2C ligand, opposed RIGS, a process requiring p53 activation mediated by dissociation from MDM2. In turn, p53 activation prevented cell death by selectively limiting mitotic catastrophe, but not apoptosis. These studies reveal a role for the GUCY2C paracrine hormone axis as a novel compensatory mechanism opposing RIGS, and they highlight the potential of oral GUCY2C agonists (Linzess; Trulance) to prevent and treat RIGS in cancer therapy and nuclear disasters. Cancer Res; 77(18); 5095-106. ©2017 AACR.

Intestinal Fungal Dysbiosis Is Associated With Visceral Hypersensitivity in Patients With Irritable Bowel Syndrome and Rats.

BACKGROUND & AIMS: Visceral hypersensitivity is one feature of irritable bowel syndrome (IBS). Bacterial dysbiosis might be involved in the activation of nociceptive sensory pathways, but there have been few studies of the role of the mycobiome (the fungal microbiome) in the development of IBS. We analyzed intestinal mycobiomes of patients with IBS and a rat model of visceral hypersensitivity. METHODS: We used internal transcribed spacer 1-based metabarcoding to compare fecal mycobiomes of 18 healthy volunteers with those of 39 patients with IBS (with visceral hypersensitivity or normal levels of sensitivity). We also compared the mycobiomes of Long-Evans rats separated from their mothers (hypersensitive) with non-handled (normally sensitive) rats. We investigated whether fungi can cause visceral hypersensitivity using rats exposed to fungicide (fluconazole and nystatin). The functional relevance of the gut mycobiome was confirmed in fecal transplantation experiments: adult maternally separated rats were subjected to water avoidance stress (to induce visceral hypersensitivity), then given fungicide and donor cecum content via oral gavage. Other rats subjected to water avoidance stress were given soluble ß-glucans, which antagonize C-type lectin domain family 7 member A (CLEC7A or DECTIN1) signaling via spleen-associated tyrosine kinase (SYK), a SYK inhibitor to reduce visceral hypersensitivity, or vehicle (control). The sensitivity of mast cells to fungi was tested with mesenteric windows (ex vivo) and the human mast cell line HMC-1. RESULTS: α diversity (Shannon index) and mycobiome signature (stability selection) of both groups of IBS patients differed from healthy volunteers, and the mycobiome signature of hypersensitive patients differed from that of normally sensitive patients. We observed mycobiome dysbiosis in rats that had been separated from their mothers compared with non-handled rats. Administration of fungicide to hypersensitive rats reduced their visceral hypersensitivity to normal levels of sensitivity. Administration of cecal mycobiomes from rats that had been separated from their mothers (but not non-handled mycobiome) restored hypersensitivity to distension. Administration of soluble ß-glucans or a SYK inhibitor reduced visceral hypersensitivity, compared with controls. Particulate ß-glucan (a DECTIN-1 agonist) induced mast cell degranulation in mesenteric windows and HMC-1 cells responded to fungal antigens by release of histamine. CONCLUSIONS: In an analysis of patients with IBS and controls, we associated fungal dysbiosis with IBS. In studies of rats, we found fungi to promote visceral hypersensitivity, which could be reduced by administration of fungicides, soluble ß-glucans, or a SYK inhibitor. The intestinal fungi might therefore be manipulated for treatment of IBS-related visceral hypersensitivity.