Lactobacillus acidophilus C4 ameliorates constipation in mice.

Irritable bowel syndrome (IBS) and chronic idiopathic constipation ((CIC) also referred to as functional constipation) are two of the most common functional gastrointestinal disorders worldwide. IBS is a global problem, with anywhere from 5 to 15% of the general population experiencing symptoms that would satisfy a definition of IBS (1,2). In a systematic review on the global prevalence of IBS, Lovell and Ford (1) documented a pooled prevalence of 11% with all regions of the world suffering from this disorder at similar rates. Given its prevalence, the frequency of symptoms, and their associated debility for many patients and the fact that IBS typically occurs in younger adulthood, an important period for furthering education, embarking on careers, and/or raising families, the socioeconomic impact of IBS is considerable. These indirect medical costs are frequently compounded by the direct medical costs related to additional medical tests and the use of various medical and nonmedical remedies that may have limited impact. CIC is equally common; in another systematic review, Suares and Ford (3) reported a pooled prevalence of 14%, and also noted that constipation was more common in females, in older subjects, and those of lower socioeconomic status (3). Chronic constipation has also been linked to impaired quality of life (4), most notably among the elderly (5). Neither IBS nor CIC are associated with abnormal radiologic or endoscopic abnormalities, nor are they associated with a reliable biomarker; diagnosis currently rests entirely, therefore, on clinical grounds. Although a number of clinical definitions of both IBS and CIC have been proposed, the criteria developed through the Rome process, currently in its third iteration, have been those most widely employed in clinical trials and, therefore, most relevant to any review of the literature on the management of these disorders. According to Rome III, IBS is defined on the basis of the presence of: Recurrent abdominal pain or discomfort at least 3 days/month in the past 3 months associated with two or more of the following: Improvement with defecation Onset associated with a change in frequency of stool Onset associated with a change in form (appearance) of stool These criteria should be fulfilled for the past 3 months with symptom onset at least 6 months before diagnosis (6). Rome III defines functional constipation as: the presence of two or more of the following: Straining during at least 25% of defecations Lumpy or hard stools in at least 25% of defecations Sensation of incomplete evacuation for at least 25% of defecations Sensation of anorectal obstruction/blockage for at least 25% of defecations Manual maneuvers to facilitate at least 25% of defecations (e.g., digital evacuation, support of the pelvic floor) Fewer than three defecations per week Furthermore, loose stools are rarely present without the use of laxatives and there are insufficient criteria for IBS. Again, these criteria should be fulfilled for the past 3 months with symptom onset at least 6 months before diagnosis (6). In Rome III, IBS is subtyped according to predominant bowel habit as IBS with constipation (IBS-C), IBS with diarrhea (IBS-D), mixed type (IBS-M), and unclassified (IBS-U). The definition of bowel habit type is, in turn, based on the patient's description of stool form by referring to the Bristol Stool Scale (7). The recognition that IBS sufferers segregate into subtypes according to predominant bowel habit, together with research findings suggesting that IBS-C and IBS-D may be pathophysiologically distinct entities (8,9,10), led to the development of therapies specifically directed at each of these subtypes. Nonetheless, it is worth noting that symptoms may not be stable over a lifetime and individuals may exhibit one IBS subtype during a period, and then a different IBS subtype during another period in their lives. However, although there is general awareness of the Rome criteria, they are infrequently employed in the assessment of IBS and CIC in clinical practice (11). To provide more "clinician friendly" definitions, as well as to permit inclusion of studies that predated the Rome process, American College of Gastroenterology Task Forces suggested the following definitions in prior systematic reviews: IBS is defined by: abdominal discomfort associated with altered bowel habits (12). Constipation is defined as: a symptom-based disorder defined as unsatisfactory defecation and is characterized by infrequent stools, difficult stool passage, or both. Difficult stool passage includes straining, a sense of difficulty passing stool, incomplete evacuation, hard/lumpy stools, prolonged time to stool, or need for manual maneuvers to pass stool. CIC is defined as the presence of these symptoms for at least 3 months (13). It is important to note that the Rome III criteria state that individuals with chronic constipation do not fulfill criteria for IBS, with pain or discomfort being a major determinant in the latter. In practice, a clear separation between CIC and IBS with constipation may be challenging and studies have shown, not only considerable overlap between these entities (14,15,16), but also a significant tendency for patients to migrate between these diagnoses over time (15). It is appropriate therefore that in this update of prior American College of Gastroenterology monographs on IBS and CIC, these entities be addressed in the same exercise (12,13,17). The goal of this exercise, therefore, was to update the most recent systematic reviews commissioned by the American College of Gastroenterology on IBS from 2009 (17) and CIC from 2005 (13). METHODS We have conducted a series of systematic reviews on the efficacy of therapy in IBS and CIC. There have been several systematic reviews of therapy for IBS and CIC published in the past 5 years (18,19,20,21,22). There have been considerable data published in the intervening time, and hence we have, therefore, updated all these systematic reviews of IBS and CIC and synthesized the data, including the information from new trials, where appropriate. The primary objective of this exercise was to assess the efficacy of available therapies in treating IBS and CIC compared with placebo or no treatment. The secondary objectives included assessing the efficacy of available therapies in treating IBS according to predominant stool pattern reported (IBS with constipation, IBS with diarrhea, and mixed IBS), as well as assessing adverse events with therapies for both IBS and CIC. Systematic review methodology We evaluated manuscripts that studied adults (aged >16 years) using any definition of IBS or CIC. For IBS, this included a clinician-defined diagnosis, the Manning criteria (23), the Kruis score (24), or Rome I (25), II (26), or III (6) criteria. For CIC, this included symptoms diagnosed by any of the Rome criteria (6,25,26), as well as a clinician-defined diagnosis. We included only parallel-group randomized controlled trials (RCTs) comparing active intervention with either placebo or no therapy. Crossover trials were eligible for inclusion, provided extractable data were provided at the end of the first treatment period, before crossover. For IBS, the following treatments were considered: Diet and dietary manipulation Fiber Interventions that modify the microbiota: probiotics, prebiotics, antibiotics Antispasmodics Peppermint oil Loperamide Antidepressants Psychological therapies, including hypnotherapy Serotonergic agents Prosecretory agents Polyethylene glycol For CIC, the following were considered: Fiber Osmotic and stimulant laxatives 5-HT4 agonists Prosecretory agents Biofeedback Bile acid transporter inhibitors Probiotics Subjects needed to be followed up for at least 1 week. To be eligible, trials needed to include one or more of the following outcome measures: Global assessment of improvement in IBS or CIC symptoms Improvement in abdominal pain for IBS Global IBS symptom or abdominal pain scores for IBS Mean number of stools per week during therapy for CIC Search strategy for identification of studies MEDLINE (1946 to October 2013), EMBASE and EMBASE Classic (1947 to October 2013), and the Cochrane central register of controlled trials were searched. Studies on IBS were identified with the terms irritable bowel syndrome and functional diseases, colon (both as medical subject headings (MeSH) and free text terms), and IBS, spastic colon, irritable colon, and functional adj5 bowel (as free text terms). For RCTs of dietary manipulation, these were combined using the set operator AND with studies identified with the terms: diet, fat-restricted, diet, protein-restricted, diet, carbohydrate-restricted, diet, gluten-free, diet, macrobiotic, diet, vegetarian, diet, Mediterranean, diet fads, gluten, fructose, lactose intolerance, or lactose (both as MeSH and free text terms), or the following free text terms: FODMAP$, glutens, food adj5 intolerance, food allergy, or food hypersensitivity. For RCTs of fiber, antispasmodics, and peppermint oil, these were combined using the set operator AND with studies identified with the terms: dietary fiber, cereals, psyllium, methylcellulose, sterculia, karaya gum, parasympatholytics, hyoscyamine, scopolamine, trimebutine, muscarinic antagonists, or butylscopolammonium bromide (both as MeSH and free text terms), or the following free text terms: bulking agent, psyllium fiber, fiber, husk, bran, ispaghula, wheat bran, calcium polycarbophil, spasmolytics, spasmolytic agents, antispasmodics, mebeverine, alverine, pinaverium bromide, otilonium bromide, cimetropium bromide, hyoscine butyl bromide, butylscopolamine, peppermint oil, or colpermin. For RCTs of probiotics, these were combined using the set operator AND with studies identified with the terms: Saccharomyces, Lactobacillus, Bifidobacterium, Escherichia coli, or probiotics (both as MeSH and free text terms). For RCTs of prebiotics and synbiotics, these were combined using the set operator AND with studies identified with the term: prebiotic (both MeSH and free text terms) or synbiotic (both MeSH and free text terms). For RCTs of antibiotics, these were combined using the set operator AND with studies identified with the terms: anti-bacterial agents, penicillins, cephalosporins, rifamycins, quinolones, nitroimidazoles, tetracycline, doxycycline, amoxicillin, ciprofloxacin, metronidazole, or tinidazole (both as MeSH and free text terms), or the following free text terms: antibiotic or rifamixin. For RCTs of loperamide, these were combined using the set operator AND with studies identified with the terms: loperamide or antidiarrheals (both as MeSH and free text terms), or the following free text terms: imodium or lopex. For RCTs of antidepressants and psychological therapies, including hypnotherapy, these were combined using the set operator AND with studies identified with the terms: psychotropic drugs, antidepressive agents, antidepressive agents (tricyclic), desipramine, imipramine, trimipramine, doxepin, dothiepin, nortriptyline, amitriptyline, selective serotonin reuptake inhibitors, paroxetine, sertraline, fluoxetine, citalopram, venlafaxine, cognitive therapy, psychotherapy, behavior therapy, relaxation techniques, or hypnosis (both as MeSH and free text terms), or the following free text terms: behavioral therapy, relaxation therapy, or hypnotherapy. For RCTs of serotonergic agents, these were combined using the set operator AND with studies identified with the terms: serotonin antagonists, serotonin agonists, cisapride, receptors (serotonin, 5-HT3), or receptors (serotonin, 5-HT4) (both as MeSH and free text terms), or the following free text terms: 5-HT3, 5-HT4, alosetron, cilansetron, ramosetron, prucalopride, mosapride, or renzapride. For RCTs of pro-secretory agents, these were combined using the set operator AND with studies identified with the following free text terms: linaclotide or lubiprostone. For RCTs of polyethylene glycol (PEG), these were combined using the set operator AND with studies identified with the term polyethylene glycol (both as a MeSH and free text term). Studies on CIC were identified with the terms constipation or gastrointestinal transit (both as MeSH and free text terms), or functional constipation, idiopathic constipation, chronic constipation, or slow transit (as free text terms). For the search involving biofeedback, the free text terms dyssynergia, pelvic floor dysfunction, anismus, and outlet obstruction were also added. For RCTs of fiber, these were combined using the set operator AND with studies identified with the terms: dietary fiber, cellulose, plant extracts, psyllium, cereals, plantago, or methylcellulose (both as MeSH and free text terms), or the following free text terms: fiber, soluble fiber, insoluble fiber, bran, ispaghula, metamucil, fybogel, or ispaghula. For RCTs of osmotic and stimulant laxatives, these were combined using the set operator AND with studies identified with the terms: laxatives, cathartics, anthraquinones, phenolphthaleins, indoles, phenols, lactulose, polyethylene glycol, senna plant, senna extract, bisacodyl, phosphates, dioctyl sulfosuccinic acid, magnesium, magnesium hydroxide, sorbitol, poloxamer (both as MeSH and free text terms), or the following free text terms: sodium picosulphate, docusate, milk of magnesia, danthron, senna, and poloxalkol. For RCTs of 5-HT4 agonists, these were combined using the set operator AND with studies identified with the terms: serotonin agonists, receptors, or serotonin, 5-HT4 (both as MeSH and free text terms), or the following free text terms: prucalopride, velusetrag, or naronapride. For RCTs of pro-secretory agents, these were combined using the set operator AND with studies identified with the following free text terms: lubiprostone or linaclotide. For RCTs of biofeedback, these were combined using the set operator AND with studies identified with the MESH terms biofeedback and psychology and the following free text terms: biofeedback or neuromuscular training. For RCTs of bile acid transporter inhibitors, these were combined using the set operator AND with studies identified with the following free text terms: bile acid transporter, elobixibat, or A3309. For RCTs of probiotics, these were combined using the set operator AND with studies identified with the terms: Saccharomyces, Lactobacillus, Bifidobacterium, E. coli, or probiotics (both as MeSH and free text terms). For RCTs of prebiotics and synbiotics, these were combined using the set operator AND with studies identified with the term: prebiotic (both MESH and free text terms) or synbiotic (both MESH and free text terms). The search was limited to humans. No restrictions were applied with regard to language of publication. A recursive search of the bibliography of relevant articles was also conducted. DDW (Digestive Diseases Week) and UEGW (United European Gastroenterology Week) abstract books were hand searched between 2000 and 2013. Authors of trial reports that did not give enough detail for adequate data extraction were contacted and asked to contribute full data sets. Experts in the field were contacted for leads on unpublished studies. Trials were assessed for risk of bias according to the methods described in the Cochrane handbook [27] using the following characteristics: method used to generate the randomization schedule, method used to conceal treatment allocation, implementation of masking, completeness of follow-up, and conduct of an intention-to-treat analysis. Eligibility, quality, and outcome data were extracted by the lead reviewer (Alexander Ford) and by a masked second reviewer (Paul Moayyedi) on to specially developed forms. Any discrepancy was resolved by discussion between the two reviewers in order to reach a consensus. Data were extracted as intention-to-treat analyses, where all dropouts were assumed to be treatment failures, wherever trial reporting allowed this. Data synthesis For IBS, whenever possible, any improvement of global IBS symptoms as a binary outcome was taken as the primary outcome measure. If this was not available, improvement in abdominal pain was used. For CIC, any improvement of global CIC symptoms as a binary outcome was taken as the primary outcome measure. The impact of interventions was expressed as a relative risk (RR) of IBS or CIC symptoms not improving, together with 95% confidence intervals (CIs). If there were sufficient data, RRs were combined using the DerSimonian and Laird random effects model (28) to give a more conservative estimate of the efficacy of individual IBS therapies. For continuous data, such as global IBS symptom scores or individual IBS symptom scores, a standardized mean difference, with 95% CIs, was calculated. It should be noted that some treatments may be beneficial in IBS or CIC because of the effects on outcomes other than global symptoms or abdominal pain, but this was not evaluated and was outside of the scope of this review. Tests of heterogeneity were reported (29). When the test of heterogeneity was significant (P<0.10 and/or I2>25%), the reasons for this were explored by evaluating differences in study population, study design, or study end points in subgroup analyses. Publication bias or other causes of small study effects were evaluated using tests for funnel plot asymmetry (30), where sufficient studies were identified (31). The number needed to treat (NNT), which is the number of patients who would need to receive active therapy, over and above the control therapy, for one to experience an improvement in symptoms, and the number needed to harm (NNH), which is the number of patients who would need to receive active therapy, over and above the control therapy, for one to experience an adverse event were calculated as the inverse of the risk difference from the meta-analysis and checked using the formula: NNT = 100 / RRR × BR, where BR is baseline risk and RRR is relative risk reduction. Methodology for assessing levels of evidence and grading recommendations We used the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system for grading the quality of evidence and strength of recommendation for each medical intervention (32). The system has been widely used in evidence-based guidelines and is endorsed by all major gastrointestinal societies (http://www.gradeworkinggroup.org). The quality of the evidence is based on the study design, as well as the extent of risk of bias, inconsistency, indirectness, imprecision, and publication bias that exists for the evidence supporting the intervention (33). Quality of evidence is described as high to very low, depending on the extent to which further evidence would change the estimate of treatment effect (Box 1). The grading scheme also classifies recommendations as strong or weak, according to the quality of the evidence, applicability to all patient groups, balance of benefits and risks, patient preferences, and cost. With this graded recommendation, the clinician receives guidance about whether or not recommendations should be applied to most patients, and whether or not recommendations are likely to change in the future after production of new evidence. "Strong" recommendations represent a "recommendation that can apply to most patients in most circumstances and further evidence is unlikely to change our confidence in the estimate of treatment effect." The summary of the evidence for IBS is presented in Table 1, the reasons for the decision on the quality of that evidence in Table 2, and the reasons for the strength of recommendation in Table 3. Similarly, the summary of the evidence for CIC is presented in Table 4, the reasons for the decision on quality of the evidence in Table 5, and the reasons for the strength of recommendation in Table 6.Box 1.: Interpretation of the grading of the quality of evidenceTable 1: Summary of results of monograph on interventions for IBSTable 2: Reasons for quality of evidence of assessment for IBS data according to GRADE criteriaTable 2: Continued.Table 3: Reasons for strength of recommendation for IBS therapies according to GRADE criteriaTable 4: Summary of results of monograph on interventions for CICTable 5: Reasons for quality of evidence of assessment of data on CIC according to GRADE criteriaTable 6: Reasons for strength of recommendation for treatments of CIC according to GRADE criteriaRESULTS Irritable bowel syndrome 1. Diet and dietary manipulation in IBS (a) Role of diet in IBS: Although food intake is one of the most common precipitants of symptoms in IBS (34), responses to food and with of the diet have not typically in the of a on their IBS sufferers have their to this or guidance from dietary IBS patients that they have an to although food are in IBS although the prevalence of food in societies is between 1 and in of gastrointestinal patients that that their symptoms food or food IBS symptoms to represent food intolerance, although only of patients can the food in a on their with and a of objective evidence to a studies have that a of IBS patients dietary to an extent that may their Role of dietary manipulation in may symptoms in individual IBS Quality of very We identified RCTs that evaluated dietary intervention in IBS to data of relevant symptom data and an intervention week three RCTs involving patients The first of these addressed the impact of in IBS. In a patients with IBS were randomized to either on a diet or to receive of on of an In the reported that their symptoms were not controlled as compared with in the placebo symptom scores for abdominal pain, with stool and were in those who a The second of these studies the of food or as not by but by In a parallel-group IBS patients were randomized to either an diet based on the presence of to various or a were followed for and symptoms assessed using a global impact score and the IBS with in the diet in the diet intervention noted a significant improvement in The reported in those with high to their The third study the of and IBS patients were randomized to a diet or their diet for those randomized to the diet, reported adequate control of their symptoms compared with of the diet Stool did not between stool frequency was in the diet A significant of this study was the of the dietary the of dietary in the of symptoms, or in the of IBS, is being To two and have been addressed in clinical trials, although it is that other (e.g., of and with the may also be relevant to the effects of food or food the that any of the of an diet or of a food in IBS the data provide limited guidance on the of diet in the management of IBS. and but their in the management of IBS need to be Fiber in IBS Fiber symptom in IBS. Quality of but not bran, symptom in IBS. Quality of intake of dietary is frequently to bowel for IBS, for However, insoluble frequently and abdominal In our prior systematic review we identified two additional studies for a of RCTs involving but trials did not IBS by subtype and only two to IBS-C In the study to patients, of were IBS-C and were were randomized to one of three of the soluble psyllium, of the insoluble bran, or of a placebo for the first a of patients psyllium, but not bran, reported adequate symptom for at least compared with placebo psyllium 95% was more than placebo during the third of treatment only 3 months of symptom in the psyllium was by points compared with points in the placebo and points in the No differences were with to quality of was most common in the most because of in IBS. Data on adverse events were only provided by trials These trials evaluated patients, but as of adverse events were small in 5 of the trials, of data was not A of of patients reported adverse events compared with of in the placebo Although its use in the management of IBS is time the status of fiber, in in IBS, is from may symptoms and provide soluble and psyllium, in provide in IBS. These effects to benefits in terms of of 3. Interventions that modify the microbiota: probiotics, prebiotics, and antibiotics The that the be relevant to IBS first from the that a although of individuals who an of on to IBS IBS Although has been linked to and and in the have been described in IBS, the of the to or other symptoms in IBS, is although both small and and in the have also been linked to IBS the of to IBS and findings in to the in patient probiotics, and have been used for on an basis by IBS they have only been to in clinical The of studies in IBS challenging as studies have employed different and in various patient and in Although the suggested that more than of all IBS sufferers studies have, in to such a high prevalence of in IBS These results may to to the test that may provide an of the this provided a for assessing antibiotics in IBS. a has efficacy in clinical trials in and although significant were over placebo in global IBS symptoms as well as in it is important to note that tests for were not in these trials, the of of in IBS (a) and in IBS: There is insufficient evidence to prebiotics or in IBS. Quality of very Probiotics in as a probiotics global symptoms, and in IBS.

Background and Aims Long non-coding RNA(LncRNA) has been reported to be associated with intestinal barrier damage. The aim of this study was to explore the mechanism of lncRNA Nuclear enriched abundant transcript 1 (NEAT1) in uremic toxin-induced intestinal epithelial barrier injury. Method Human colon cancer cells (Caco-2) were used to establish intestinal epithelial injury models with the urea treatment in different conditions. Cell Counting Kit-8 (CCK-8) and Western blot screening the best concentration and time. The expressions of lncRNA NEAT1 and miR-122-5p were measured by quantitative real-time polymerase chain reaction (qRT-PCR). Western blot and immunofluorescence were used to detect the expression of tight junction proteins Occludin, ZO-1 and Claudin-1. Sodium fluorescein was used to detect the paracellular permeability of intestinal epithelial injury models. The binding of miR-122-5p to lncRNA NEAT1 and Occludin was determined by bioinformatics analysis and dual luciferase reporter assay. Results The best condition for the injury model was urea treatment in 144 mg/dl for 48 hours. With the increase of urea intervention time and concentration, the damage degree of intestinal epithelial cells is aggravated. Based on the qRT-PCR results, lncRNA NEAT1 was significantly down-regulated in the model group. Meanwhile, the tight junction proteins Occludin, ZO-1 and Claudin-1 were significantly reduced. The permeability of sodium fluorescein was significantly increased in the model group. Overexpression of lncRNA NEAT1 can alleviate the above performances. As the target gene of lncRNA NEAT1, miR-122-5p is significantly up-regulated in the model group. The dual luciferase reporter assay proved that miR-122-5p was targets to Occludin. The protective effect of overexpression lncRNA NEAT1 on intestinal epithelial barrier function is reversed by miR-122-5p mimics. Conclusion LncRNA NEAT1 protects uremic toxin-induced intestinal epithelial barrier injury by regulating miR-122-5p/Occludin axis.

This study was developed to provide further information on the intestinal barrier permeability and the tight junction protein expression in weaned piglets fed with different levels of soybean agglutinin (SBA). Twenty-five weaned crossbred barrows (Duroc × Landrace × Yorkshire) were selected and randomly allotted to five groups, each group with five replicates. The piglets in the control group were not fed with leguminous products. 0.05, 0.1, 0.15 and 0.2% SBA was added to the control diet to form four experimental diets, respectively. After the experimental period of 7 days (for each group), all the piglets were anesthetized with excess procaine and slaughtered. The d-lactic acid in plasma and the Ileal mucosa diamine oxidase (DAO) was analyzed to observe the change in the intestinal permeability. The tight junction proteins occludin and ZO-1 in the jejunum tissue distribution and relative expression were detected by immunohistochemistry and Western Blot. The results illustrated that a high dose of SBA (0.1–0.2%) could increase the intestinal permeability and reduce piglet intestinal epithelial tight junction protein occludin or ZO-1 expression, while low dose of SBA (0.05% of total diet) had no significant affects. The contents of DAO, d-lactic acid, occludin or ZO-1, had a linear relationship with the SBA levels (0–0.2%) in diets. The high dose SBA (0.1–0.2%) could increase the intestinal permeability and reduce piglet intestinal epithelial tight junction protein occludin or ZO-1 expression, while low dose of SBA (0.05% of total diet) had no affects.

Background: Chronic inflammation is increasingly recognized as a key factor in the progression of diabetic kidney disease (DKD). By discovering that the regulation of gut microbiota plays an important role in diabetic kidney disease, human umbilical cord mesenchymal stem cells (HU-MSCs) explore the mechanism of fibrosis in diabetic kidney disease through the regulation of chronic inflammation, providing new clinical insights for the prediction, diagnosis, and treatment of diabetic kidney disease.Objectives: This study explores the regulatory effects of HU-MSCs on gut microbiota and their protective role on the intestinal barrier in diabetic nephropathy rats.Material and Method: Diabetic kidney disease (DKD) was induced in SD rats via intraperitoneal injection of streptozotocin. Three groups were established: control group, diabetic kidney disease (DKD) group,and treatment group (DKD+HU-MSCs) (10 rats each). After diabetic kidney disease (DKD) modeling, rats in the treatment group (DKD+HU-MSCs) received 2×106 HU-MSCs via tail vein injection weekly for four weeks. Blood, urine, kidney, and colon tissues were collected post-treatment. Pathological changes were observed microscopically; immunohistochemistry detected tight junction proteins ZO-1 and Occludin in colon tissues. DiR-labeled HU-MSCs distributionwas assessed with in vivo imaging, and immunohistochemistry evaluated human mesenchymal stem cell markers CD44 and CD90. Fecal samples underwent metagenomic sequencing for gut microbiota analysis.Results: HU-MSCs transplantation significantly reduced Blood Urea Nitrogen (BUN), Serum Creatinine (SCr), and 24-hour urinary protein levels (all P < 0.05) and improved renal pathology. Markers CD44 and CD90 were present in DKD rat colon tissues. Tight junction proteins Occludin and ZO-1 were decreased in DKD rats but increased following HU-MSCs treatment. Metagenomic analysis showed enhanced abundance of beneficial bacteria (Bifidobacterium and Lactobacillus) with HU-MSCs. Urinary protein was positively correlated with Prevotella and negatively with Ligilactobacillus (p < 0.05).Conclusions: HU-MSCs may improve intestinal barrier function in diabetic kidney disease (DKD) rats by restoring gut microbiota structure and increasing intestinal tight junction proteins, offering a potential pathway for enhancing renal function.

Purpose: Functional constipation (FC) as defined by Rome III has an estimated prevalence of 4.6 % in the US. There are minimal data on the economic impact on our healthcare system and effect on Quality of Life (QOL) related to this disorder. The purpose of this study was to quantify the cost and effect of FC on QOL in a group of urban, African American citizens. Methods: At our tertiary center we prospectively identified 102 patients who met the Rome III criteria for FC and 100 age and sex matched controls with normal bowel function as assessed by the Bristol Stool Scale. We administered a detailed questionnaire to both groups. Questions investigated demographics, 6 co-morbid conditions (CHF, COPD, CAD, DJD, low back pain, depression), and direct medical costs specifically related to FC (co-pays, deductibles, and time missed from work). The SF-36 v2 was used to assess QOL. The study had a power of 0.81 to detect a 3 point difference (considered clinically meaningful) between the groups in the Mental (MCS) and Physical (PCS) Component Summary scores. These represent measures of physical and mental well-being. MCS and PCS scores were adjusted for co-morbidities using factorial ANOVA. Results: The mean age (56 years), proportion males (46%), and BMI were nearly identical (P > 0.7) between the groups. There were no differences in educational level or median income, but those with FC were more likely to be divorced (21.6% vs. 11.0%; P=0.006) and to have at least one comorbidity (56.9% vs. 23.0 %; P< 0.001). Overall, 14.7% of FC subjects had ≥ 3 physician visits/yr for FC treatment. Due to FC, 16.7% missed ≥ 1 day of work/yr and 8.8% missed ≥ 5 days/yr. For FC subjects, 78.4% were taking a laxative medication at a median direct cost of $ 92 /yr. Unadjusted PCS (47.1 vs. 43.2; P=0.005) and MCS (50.5 vs. 43.4; P< 0.001) QOL scores were significantly lower in FC subjects than controls. After adjustment for co-morbidities, the MCS (P=0.004) but not PCS (P=0.55) scores remained significantly lower in FC subjects. FC, but not control subjects, had MCS scores significantly lower than national healthy controls matched for age and gender. Conclusion: After adjustment for co-morbidities, patients in our group with FC had significantly lower scores for mental well-being than a matched control group and nationwide healthy matched controls. The impact on overall physical well-being did not differ. Direct costs of FC in our group appeared to be modest for the majority with this disorder. Disclosure: Dr Friedenberg-Grant/Research Support: Takeda Pharmaceuticals North America. This research was supported by an industry grant from Takeda Pharmaceuticals North America, Deerfield, IL, USA.

The epidemiology and effects of functional constipation (FC) on Chinese people remain unclear. To investigate the epidemiology of FC and its distinction from constipation-predominant irritable bowel syndrome (IBS-C) in China. A cross-sectional survey was conducted in a representative adult Chinese population (n = 16,078), which was selected from five regions using randomised, stratified, multistage sampling methodology. All respondents completed the modified Rome II questionnaire; 20% were asked to complete the 36-item Short Form (SF-36) and the Epworth Sleepiness Scale (ESS). Overall, 948 respondents (6%) had FC and FC was more prevalent in women than in men (8% vs. 4%, P < 0.001). Straining and hard stools were the two most frequent symptoms. FC was associated significantly with dyspepsia and abdominal bloating. All SF-36 domain scores were lower for respondents with FC than for those without. The prevalence of clinically meaningful daytime sleepiness was significantly higher in respondents with FC than in those without (22% vs. 14%, P = 0.003). Respondents with FC were more likely to strain, but less likely to have a feeling of incomplete emptying after a bowel movement than those with IBS-C. Respondents with IBS-C experienced similar demographics, quality of life and daytime sleepiness to those with FC. The prevalence of FC in China is substantially lower than that in Western countries. FC has negative effects on quality of life and daytime sleepiness. The demographics and burden of illness are similar between FC and IBS-C, although the clinical symptoms are somewhat different.

Iron supplementation has been an intervention to improve iron storage and prevent iron deficiency anaemia in weaned piglets. NRC has set recommended nutrient intake (RNI) and tolerable upper intake levels (UL). The purpose of this study was to investigate the potential harm of UL iron to the gut and microbes of weaned piglets. Thirty 23-day old weaned piglets assigned to three dietary treatments: a basal diet supplemented with 100 (RNI), 300, or 3000 (UL) mg FeSO4/kg diet for 28 days. Piglets were then euthanized, and the gut and cecum microbes were collected. UL iron significantly reduced the height of the villi in the duodenum, ileum, and jejunum of weaned piglets, and showed duodenal mitochondrial swelling (P &amp;lt; 0.05). The addition of UL iron to the diet significantly reduced the expression of tight junction proteins Claudin-1, Occludin, and ZO-1 in weaned piglet duodenal mucosa (P &amp;lt; 0.05). The protein levels of DMT1 and Zip14 decreased (P &amp;lt; 0.05), and the protein levels of ferritin increased in the duodenal mucosa of UL iron fed weaned piglets (P &amp;lt; 0.05). Moreover, UL iron also increased the content of ROS and MDA and decreased the activity of SOD in the weaned piglet duodenal mucosa (P &amp;lt; 0.05). Additionally, UL iron significantly increased intestinal microbial diversity and species richness in weaned piglets. At the phylum level, UL iron supplementation was associated with a significant increase in Proteobacteria relative abundance, and significantly decreased the relative abundance of Firmicutes (P &amp;lt; 0.05). At the genus level, the relative abundance of Clostridiales, Faecalibacterium, and Prevotellaceae decreased significantly (P &amp;lt; 0.05), while the relative abundance of Desulfovibrio and Anaerovibrio increased significantly (P &amp;lt; 0.05). In conclusion, UL iron caused damage to the intestinal villi, damaged the intestinal barrier, reduced iron absorption, induced oxidative stress, led to histopathological changes, and modified the intestinal microbial structure in weaned piglets.

Functional constipation (FC) is a common condition in children. Physiotherapy added to standard care for childhood FC shows positive results in the hospital. Evidence for the (cost)effectiveness of physiotherapy in primary care is lacking. This dissertation describes the (cost)effectiveness of physiotherapy for childhood FC in primary care, the impact of FC on the quality of life (QoL) of the child, and the prevalence of bladder problems in children with FC. The majority of children in primary care are still having functional constipation related symptoms 8 months after they consulted the general practitioner, or they are using laxatives. Physiotherapy added to standard care by the general practitioner is not significantly better than standard care alone. In children with chronic FC physiotherapy may be (cost)effective compared to standard care alone, but this needs further investigation. Therefore, we recommend GPs to pay more attention to the possible chronicity of FC in children. Active monitoring of FC-related symptoms is necessary to ensure persistent or relapsing symptoms are identified and treated on time. Furthermore, this dissertation shows that the assessment of the QoL of a child with FC can differ significantly between the child-itself and the parents. Moreover, children with FC have more often bladder problems compared to children without FC. Therefore, we recommend clinicians to ask both the child and the parent(s) to get an impression of the impact of the FC on the child’s QoL, and to be alert for bladder problems in children with FC.

Background: Functional constipation is a chronic constipation without any aetiology. Rome IV criteria defined functional constipation as having hard or lumpy stools, excessive straining during defecation, less than three bowel movements per week and an obstructive feeling during evacuation. Pathophysiology of functional constipation includes eating disorders, physical inactivity, fibre-deficient diet, family history and behavioural factors like stool withholding attitude. Physical therapy interventions can play a vital role in relieving functional constipation and improving quality of life. Objective: To investigate the comparative effects of thoracolumbar manipulation versus abdominal massage on functional constipation and quality of life. Methodology: This double-blinded, randomised controlled trial was conducted in the independent hospital physiotherapy department of Faisalabad with concealed allocation. A consecutive sample of 40 patients with functional constipation based on Rome IV criteria was taken. Patients were referred from gastroenterologists and general physicians and were randomly allocated by a universal lottery method to group A (lower thoracic-lumber manipulation, 3 sessions per week) and group B (abdominal massage for 15 minutes, 3 sessions per week). The Constipation Scoring System and Patient Assessment of Constipation Quality of Life Questionnaire were evaluated at baseline, 2 weeks, and 4 weeks after treatment. A total of 12 sessions in 4 weeks were provided to patients. Data was analysed by using non-parametric tests, Kruskal-Wallis Test and Friedman Test and SPSS version 25. Results: The age of the participants in both groups was the mean and standard deviations (29.23±3.23). Within-group analysis showed a significant relationship in both groups (Group A manipulation and Group B abdominal massage) (p&lt;0.05). Constipation scoring system and patient assessment of constipation showed significant value (p&lt;0.00), indicating that statistically significant relation between both groups. Conclusion: This study concluded that abdominal massage is a superior method to deal with functional constipation patients as compared to Maitland lower thoracolumbar manipulations.

This study aims to investigate therapeutic effects and involved molecular mechanisms of Banxia Xiexin Decoction (BXD) in reducing gastrointestinal complications associated with sepsis. Sepsis is a common critical illness that threatens patient survival and costs society a lot. This syndrome is a prominent cause of death in ICUs due to its high mortality rate, which exceeds 30% after 28 days and 35.5% after 90 days. Sepsis remains a major medical challenge despite a 20%-30% drop in fatality rates due to a better understanding of its physiological and pathological features and better therapeutic techniques. There is no pharmacological treatment for sepsis, highlighting the need for more study. We explored the protecting effects of BXD on intestinal functionality in sepsis by investigating its roles in the regulation of mitochondrial autophagy and mitochondrial functioning in small intestinal epithelial cells, primarily via the PINK1/Parkin signaling pathway. We established a cell model of Human Intestinal Epithelial Cell (HIEC) injury induced by lipopolysaccharide (LPS) and a cecal ligation and perforation (CLP) sepsis model in Sprague Dawley (SD) rats. The cell model and animal model of sepsis were divided into control groups and different treatment groups that received different doses of BXD. We utilized HIECs with PINK1 knockdown to assess BXD's protective effects on the sepsis intestinal barrier and its regulatory mechanism both on the PINK1/Parkin signaling pathway, exploring both its facilitative and inhibitory effects. ELISA method was used to measure inflammatory markers IL-6, IL-1β, and intestinal injury-related molecules IFABP and DAO. Pathological assessments were performed with H&E staining, and tight junction proteins ZO-1 and Occludin were detected using immunohistochemical staining. Mitochondrial membrane protein TOM20 was detected through immunofluorescence staining. Mitochondrial membrane potential and autophagy were assessed via flow cytometry. The expression levels of PINK1, Park, LC3, and p62 proteins and mRNA, integral to the PINK1/Parkin autophagy pathway, were evaluated using Western Blot and RT-PCR. Compared to the control group, BXD therapy significantly lowered serum DAO, IFABP, and DA. The BXD therapy group showed a more significant and sustained drop in IL-6 and IL-1β levels than the control group. The BXD therapy reduced intestinal mucosa damage by lowering DAO and IFABP. BXD also restored tight junction proteins ZO-1 and Occludin, improving intestinal mucosal barrier function. In septic rats, BXD therapy lowered serum IL-6 and IL-1β levels, avoiding inflammation and reducing intestinal damage. BXD enhanced TOM20, which protected intestinal epithelial cell mitochondria against decreasing mitochondrial membrane potential. BXD increased the PINK1/Parkin mitochondrial autophagy pathway at the molecular level. Mitochondrial autophagy can repair mitochondria, reduce oxidative stress, maintain mitochondrial homeostasis, and help intestinal epithelial cells survive and function. BXD could improve intestinal mucosal damage and systemic inflammation caused by sepsis. BXD mainly promotes the PINK1/Parkin mitophagy pathway by upregulating PINK1 protein.

Background: Functional constipation (FC) is one of the most common complaints in childhood. The aim of this study was the evaluation of the quality of life in children with chronic FC and their family members. Methods: In this study, 100 children from 2-18 years of age (57 males, 43 females) with chronic FC were selected. The Child Health Questionnaire - Parent Form 50 questionnaire was used for quality of life assessment in children and their family members. Quality of life scores were compared with 100 healthy children from 2-18 years of age. The questionnaire consists of 15 domains, each of which ranges in score from zero to 100. A higher score represents a better quality of life. Results: Quality of life scores in all 15 domains were significantly lower in children with FC than in healthy children (P&lt;0.001). Scores of physical functioning, behavior, and mental health were lower in children with FC and fecal incontinence compared to children with FC alone (P&lt;0.05). Conclusion: FC impacts on quality of life of the affected children and their family members. Practitioners should be aware of its effects on quality of life to improve the disease course with early assessment and treatment.

Irritable bowel syndrome with constipation (IBS-C) and chronic idiopathic constipation (CIC) are two common functional gastrointestinal disorders that impair quality of life and pose a significant economic burden to the health care system. Current therapeutic options include lifestyle modifications, over-the-counter (OTC) agents, antispasmodics, serotonin agonists, and lubiprostone and linaclotide, two prosecretory prescription drugs approved for the treatment of IBS-C and CIC. This review discusses the efficacy and safety of current treatments and emerging therapies for the treatment of IBS-C and CIC, with a focus on the prosecretory agents. A search of the PubMed database (1966-November 2014) was performed to identify relevant articles; clinical trials on emerging agents were also identified by searching the ClinicalTrials.gov registry. OTC laxatives may relieve constipation but do not treat abdominal pain and discomfort. Antispasmodics may provide short-term relief in patients with IBS-C, but their utility is limited by anticholinergic adverse effects. Tricyclic antidepressants, selective serotonin reuptake inhibitors, and serotonin-norepinephrine reuptake inhibitors have shown benefit in providing global symptom relief and in improving abdominal discomfort, but further research is needed. Phase III clinical trials have demonstrated the efficacy of lubiprostone and linaclotide relative to placebo for the short-term treatment of IBS-C and CIC, with improvements reported in stool frequency, perceived constipation severity, and abdominal pain and discomfort. Relatively small response rates, higher costs, and adverse effects associated with lubiprostone and linaclotide will likely render these agents suitable as second-line therapies in the treatment of IBS-C and CIC. Emerging potential treatment options include prucalopride, plecanatide, elobixibat, and tenapanor. Several of these emerging therapies have novel mechanisms of action and may show promise in patients with IBS-C and CIC who have not responded to other therapies.

BackgroundEmerging evidence has demonstrated the impact of psychological stress on intestinal microbiota, however, the precise mechanisms are not fully understood. Enteric glia, a unique type of peripheral glia found within the enteric nervous system (ENS), play an active role in enteric neural circuits and have profound effects on gut functions. In the present study, we tested the hypothesis that enteric glia are involved in the alterations in the intestinal microflora and barrier induced by chronic water-avoidance stress (WAS) in the gut. Methods and resultsWestern blotting and immunohistochemical (IHC) staining were used to examine the expression of glial fibrillary acidic protein (GFAP), nitric oxide synthetase (NOS) and choline acety1transferase (ChAT) in colon tissues. 16S rDNA sequencing was performed to analyse the composition of the intestinal microbiota in rats. Changes in the tight junction proteins Occludin, Claudin1 and proliferating cell nuclear antigen (PCNA) in the colon tissues were detected after WAS. The abundance of Firmicutes, Proteobacteria, Lactobacillus and Lachnospiraceae_NK4A136 decreased significantly, whereas the abundance of Actinobacteria, Ruminococcaceae_UCG−005 and Christensenellaceae-R-7 increased significantly in stressed rats. Meanwhile, the expression of Occludin, Claudin1 and PCNA significantly decreased after WAS. Treatment with L-A-aminohexanedioic acid (L-AA), a gliotoxin that blunts astrocytic function, obviously decreased the abundance of Actinobacteria, Ruminococcaceae_UCG−005 and Christensenel-laceae_R-7 in stressed rats and significantly increased the abundance of Proteobacteria, Lactobacillus and Lachnospiraceae_NK4A136. In addition, the protein expression of colon Occludin, Claudin1, and PCNA increased after intraperitoneal injection of L-AA. Furthermore, the expression level of NOS in colon tissues was significantly decreased, whereas that of ChAT was significantly increased following L-AA treatment. ConclusionsOur results showed that enteric glial cells may contribute to WAS-induced changes in the intestinal microbiota and barrier function by modulating the activity of NOS and cholinergic neurones in the ENS.

The Rome III classification system treats functional constipation (FC) and irritable bowel syndrome with constipation (IBS-C) as distinct disorders, but this distinction appears artificial, and the same drugs are used to treat both. This study's hypothesis is that FC and IBS-C defined by Rome III are not distinct entities. In all, 1,100 adults with a primary care visit for constipation and 1,700 age- and gender-matched controls from a health maintenance organization completed surveys 12 months apart; 66.2% returned the first questionnaire. Rome III criteria identified 231 with FC and 201 with IBS-C. The second survey was completed by 195 of the FC and 141 of the IBS-C cohorts. Both surveys assessed the severity of constipation and IBS, quality of life (QOL), and psychological distress. (i) Overlap: if the Rome III requirement that patients meeting criteria for IBS cannot be diagnosed with FC is suspended, 89.5% of IBS-C cases meet criteria for FC and 43.8% of FC patients fulfill criteria for IBS-C. (ii) No qualitative differences between FC and IBS-C: 44.8% of FC patients report abdominal pain, and paradoxically IBS-C patients have more constipation symptoms than FC. (iii) Switching between diagnoses: by 12 months, 1/3 of FC transition to IBS-C and 1/3 of IBS-C change to FC. Patients identified by Rome III criteria for FC and IBS-C are not distinct groups. Revisions to the Rome III criteria, possibly including incorporation of physiological tests of transit and pelvic floor function, are needed.

Chronic idiopathic constipation (CIC) is a prevalent disorder affecting productivity, quality of life, and health care resource utilization. Nurse practitioners (NPs) play a critical function in managing patients presenting with CIC, with roles including evaluation, diagnosis, treatment decisions, and patient education. For adults with inadequate response or tolerability issues using over-the-counter treatments, three prescription agents (plecanatide, linaclotide, and lubiprostone) are available in the United States to treat CIC, of which plecanatide was mostly recently approved. This review provides NPs with a current overview and summary of plecanatide in the current treatment landscape for CIC. PubMed was searched for the literature regarding clinical practice guidelines and published trial data for lubiprostone, linaclotide, and plecanatide in CIC. Efficacy and safety comparisons between prescription agents are limited beacause of the differences in trial duration and primary end points (all different). Generally, plecanatide and linaclotide demonstrated similar efficacy, with plecanatide demonstrating lower rates of adverse events. The success of CIC treatment can be affected by patient adherence to the regimen, which is dependent on the efficacy and tolerability of treatment. Plecanatide is a promising option for patients whose CIC symptoms are not adequately controlled using their current treatment approach.