Recommendations to Improve Quality of Probiotic Systematic Reviews With Meta-Analyses.

Importance: Systematic reviews and meta-analyses often report conflicting results when assessing evidence for probiotic efficacy, partially because of the lack of understanding of the unique features of probiotic trials. As a consequence, clinical decisions on the use of probiotics have been confusing. Objective: To provide recommendations to improve the quality and consistency of systematic reviews with meta-analyses on probiotics, so evidence-based clinical decisions can be made with more clarity. Evidence Review: For this consensus statement, an updated literature review was conducted (January 1, 2020, to June 30, 2022) to supplement a previously published 2018 literature search to identify areas where probiotic systematic reviews with meta-analyses might be improved. An expert panel of 21 scientists and physicians with experience on writing and reviewing probiotic reviews and meta-analyses was convened and used a modified Delphi method to develop recommendations for future probiotic reviews. Findings: A total of 206 systematic reviews with meta-analysis components on probiotics were screened and representative examples discussed to determine areas for improvement. The expert panel initially identified 36 items that were inconsistently reported or were considered important to consider in probiotic meta-analyses. Of these, a consensus was reached for 9 recommendations to improve the quality of future probiotic meta-analyses. Conclusions and Relevance: In this study, the expert panel reached a consensus on 9 recommendations that should promote improved reporting of probiotic systematic reviews with meta-analyses and, thereby, assist in clinical decisions regarding the use of probiotics.

Look What the Cat Dragged in! Recurrent Clostridioides difficile from a Household Cat.

BACKGROUND Clostridioides difficile (C. difficile) is a bacterium that is well known for causing serious diarrheal infections and can even lead to colon cancer if left untreated. Disruption of the normal healthy bacteria in the colon can lead to development of C. difficile colitis. Risk factors for C. difficile infections (CDI) include recent antibiotic exposure, hospital or nursing home stays, inflammatory bowel disease (IBD), or impaired immunity. There is an increasing incidence of community-associated CDI (CA-CDI) in individuals without the common risk factors, which has implicated natural reservoirs, zoonoses, originating from animals such as domestic cats and dogs, livestock, shellfish, and wild animals. CASE REPORT A previously healthy 31-year-old woman with recurrent CA-CDI suspected to be acquired from a household cat represents a novel presentation. The patient had an initial case of severe diarrhea following recent antibiotic exposure, was briefly monitored in hospital, and was diagnosed with CDI. She was trialed on oral vancomycin, which resulted in temporary resolution of her symptoms. Her symptoms recurred, however, and did not improve despite treatment with multiple therapeutic options over a period of months. Ultimately, the patient was not able to achieve long-term resolution of her symptoms until her newly adopted pet cat was treated by a veterinarian. CONCLUSIONS In conclusion, this case report explores the epidemiologic risk factors of zoonotic CA-CDI and the importance of early identification, evaluation, and prevention of disease. This case demonstrates the significance of thorough history taking, contact (pet) tracing, and proper treatment of recurrent CA-CDI.

Efficacy of Probiotics in Irritable Bowel Syndrome: Systematic Review and Meta-analysis.

BACKGROUND & AIMS: Some probiotics may be beneficial in irritable bowel syndrome (IBS), but differences in species and strains used, as well as endpoints reported, have hampered attempts to make specific recommendations as to which should be preferred. We updated our previous meta-analysis examining this issue. METHODS: MEDLINE, EMBASE, and the Cochrane Controlled Trials Register were searched (up to March 2023). Randomized controlled trials (RCTs) recruiting adults with IBS, comparing probiotics with placebo were eligible. Dichotomous symptom data were pooled to obtain a relative risk of global symptoms, abdominal pain, or abdominal bloating or distension persisting after therapy, with a 95% confidence interval (CI). Continuous data were pooled using a standardized mean difference with a 95% CI. Adverse events data were also pooled. RESULTS: We identified 82 eligible trials, containing 10,332 patients. Only 24 RCTs were at low risk of bias across all domains. For global symptoms, there was moderate certainty in the evidence for a benefit of Escherichia strains, low certainty for Lactobacillus strains and Lactobacillus plantarum 299V, and very low certainty for combination probiotics, LacClean Gold S, Duolac 7s, and Bacillus strains. For abdominal pain, there was low certainty in the evidence for a benefit of Saccharomyces cerevisae I-3856 and Bifidobacterium strains, and very low certainty for combination probiotics, Lactobacillus, Saccharomyces, and Bacillus strains. For abdominal bloating or distension there was very low certainty in the evidence for a benefit of combination probiotics and Bacillus strains. The relative risk of experiencing any adverse event, in 55 trials, including more than 7000 patients, was not significantly higher with probiotics. CONCLUSIONS: Some combinations of probiotics or strains may be beneficial in IBS. However, certainty in the evidence for efficacy by GRADE criteria was low to very low across almost all of our analyses.

Constipation in Parkinson's Disease.

Constipation is one of the most common gastrointestinal features of Parkinson's disease (PD), occurring in over 50% of all PD patients during the course of their disease. Furthermore, constipation is now recognized as an important, prodromal symptom and may predate the onset of the classical motor symptoms by decades. Thereafter, the prevalence and severity of constipation in PD tend to parallel the course of both motor and nonmotor phenomena such as cognitive decline and depression. Difficult defecation (obstructed defecation, dyssynergia) is the primary pathophysiology underlying constipation and likely reflects involvement by the PD process of one or more of the many skeletal muscle groups that are involved in effecting defecation. Management of constipation in PD may be complicated by several patient factors including dysphagia, cognitive impairment, depression, and weak sphincter tone. While the armamentarium available to those who treat constipation, in general, has expanded considerably in recent years, the evidence supporting any therapy in the management of this symptom in PD has remained slim.

Face-to-face interviews versus Internet surveys: Comparison of two data collection methods in the Rome foundation global epidemiology study: Implications for population-based research.

BACKGROUND AND AIMS: The Rome Foundation Global Epidemiology Study (RFGES) assessed the prevalence, burden, and associated factors of Disorders of Gut-Brain Interaction (DGBI) in 33 countries around the world. Achieving worldwide sampling necessitated use of two different surveying methods: In-person household interviews (9 countries) and Internet surveys (26 countries). Two countries, China and Turkey, were surveyed with both methods. This paper examines the differences in the survey results with the two methods, as well as likely reasons for those differences. METHODS: The two RFGES survey methods are described in detail, and differences in DGBI findings summarized for household versus Internet surveys globally, and in more detail for China and Turkey. Logistic regression analysis was used to elucidate factors contributing to these differences. RESULTS: Overall, DGBI were only half as prevalent when assessed with household vs Internet surveys. Similar patterns of methodology-related DGBI differences were seen within both China and Turkey, but prevalence differences between the survey methods were dramatically larger in Turkey. No clear reasons for outcome differences by survey method were identified, although greater relative reduction in bowel and anorectal versus upper gastrointestinal disorders when household versus Internet surveying was used suggests an inhibiting influence of social sensitivity. CONCLUSIONS: The findings strongly indicate that besides affecting data quality, manpower needs and data collection time and costs, the choice of survey method is a substantial determinant of symptom reporting and DGBI prevalence outcomes. This has important implications for future DGBI research and epidemiological research more broadly.

The Role of Fecal Microbiota Transplantation in the Induction of Remission in Ulcerative Colitis.

BACKGROUND: Considerable research supports an important role for the microbiome and/or microbiome-host immune system interactions in the pathogenesis of inflammatory bowel disease (IBD). Consequently, microbiota-modulating interventions, such as fecal microbiota transplantation (FMT), have attracted interest in the management of IBD, including ulcerative colitis (UC). SUMMARY: While the clinical response to FMT in UC has varied between different studies, results to date may offer guidance toward optimal use of FMT. Thus, increased microbiome biodiversity, the presence of short-chain fatty acid-producing bacteria, Clostridium clusters IV and XIVa, Odoribacter splanchnicus, and reduced levels of Caudovirales bacteriophages have been identified as characteristics of the donor microbiome that predict a positive response. However, inconsistency in FMT protocol between studies confounds their interpretation, so it is currently difficult to predict response and premature to recommend FMT, in general, as a treatment for UC. Additional randomized controlled trials designed based on previous findings and employing a standardized protocol are needed to define the role of FMT in the management of UC. KEY MESSAGES: There is a well-developed rationale for the use of microbiome-modulating interventions in UC. Despite variations in study protocol and limitations in study design that confound their interpretation, FMT seems to benefit patients with UC, overall. Available data identify factors predicting FMT response and should lead to the development of optimal FMT study protocols.

Probiotics in irritable bowel syndrome and inflammatory bowel disease: review of mechanisms and effectiveness.

PURPOSE OF REVIEW: The gastrointestinal (GI) microbiome has been implicated in the pathogenesis of inflammatory bowel disease (IBD) and has been linked with irritable bowel syndrome (IBS). The aim of this article is to critically review the emerging evidence for the mechanisms and effectiveness of probiotics in the management of these conditions. RECENT FINDINGS: The GI microbiome is strongly influenced by ageing, diet and disease. Probiotics may confer health effects to the host by modulating the metabolic activities of the microbiome to propagate anti-inflammatory effects and reinforce the intestinal barrier, and are considered to be safe to use. Many short-term studies have demonstrated the effectiveness of probiotics overall in IBS, with meta-analyses demonstrating efficacy across specific strains albeit with relatively small effect sizes. Within IBD, some probiotics appear to offer clinical benefit in ulcerative colitis but strain-specific effects are unclear. Evidence for the use of probiotics in Crohn's disease remains limited. SUMMARY: Probiotics offer considerable potential for the management of IBS and possibly in IBD, however, any benefits conferred appear to be strain-specific. High quality trials of specific probiotics in IBS and IBD, as well as laboratory investigations of their mechanism of action, are required in order to fully understand their potential therapeutic value.

Randomized Placebo-Controlled Phase 3 Trial of Vibrating Capsule for Chronic Constipation.

BACKGROUND & AIMS: Despite therapeutic advances, effective treatments for chronic constipation remain an unmet need. The vibrating capsule is a nonpharmacologic, orally ingested, programmable capsule that vibrates intraluminally to induce bowel movements. We aimed to determine the efficacy and safety of the vibrating capsule in patients with chronic constipation. METHODS: We conducted a phase 3, double-blind, placebo-controlled trial of patients with chronic constipation, who were randomized to receive either a vibrating or placebo capsule, once daily, 5 days a week for 8 weeks. The primary efficacy end points were an increase of 1 or more complete spontaneous bowel movements per week (CSBM1 responder) or 2 or more CSBMs per week (CSBM2) from baseline during at least 6 of the 8 weeks. Safety analyses were performed. RESULTS: Among 904 patients screened, 312 were enrolled. A greater percentage of patients receiving the vibrating capsule achieved both primary efficacy end points compared with placebo (39.3% vs 22.1%, P = .001 for CSBM1; 22.7% vs 11.4% P = .008 for CSBM2). Significantly greater improvements were seen with the vibrating capsule for the secondary end points of straining, stool consistency, and quality-of-life measures compared with placebo. Adverse events were mild, gastrointestinal in nature, and similar between groups, except that a mild vibrating sensation was reported by 11% of patients in the vibrating capsule group, but none withdrew from the trial. CONCLUSIONS: In patients with chronic constipation, the vibrating capsule was superior to placebo in improving bowel symptoms and quality of life. The vibrating capsule was safe and well tolerated. (Clinical trials.gov, Number: NCT03879239).

Impact of pre-operative transjugular intrahepatic portosystemic shunt on post-operative outcomes following non-transplant surgeries in patients with decompensated cirrhosis.

Background: Patients with cirrhosis have a high risk for morbidity and mortality in relation to abdominal surgery. Despite improvements in surgical techniques and intensive care, major abdominal surgery still remains a challenge. Major factors determining short- and long-term survival and perioperative complications in this patient population include severity of liver dysfunction, degree of portal hypertension (PHTN), and the presence of related complications such as ascites. Elective transjugular intrahepatic portosystemic shunt (TIPS) placement prior to surgery has been reported to improve perioperative outcomes, but available data is limited to case reports and small case series. We aimed to determine the impact of elective TIPS placement on perioperative outcomes after abdominal-pelvic surgeries in patients with cirrhosis. Methods: We performed a retrospective chart review of patients who underwent elective TIPS and compared these patients with a cohort of cirrhotic patients who underwent any abdominal surgeries without TIPS placement. The primary outcomes were mortality at 30 days and 1 year following surgery. Other post-operative outcomes compared between the two groups, included: blood loss, worsening ascites, wound leak, infections, encephalopathy, liver decompensation, and length of hospitalization. Results: Among 38 patients with cirrhosis who underwent abdominal surgery, 20 patients underwent pre-operative elective TIPS placement. Demographic characteristics of the two groups were comparable including age, gender, and body mass index (BMI). The median age was 62 years with a male predominance (62.5%). Both groups had similar etiologies of cirrhosis with hepatitis C virus (HCV) (34.2%) being most common. The most frequent indications for surgery were strangulated hernia (50%) in the TIPS group and acute cholecystitis (55.6%) in the non-TIPS group. Mean pre-TIPS hepato-venous portal gradient (HVPG) was 16.5 mmHg and mean post-TIPS HVPG was 7.0 mmHg. Mortality at 1 month was not statistically different between the groups (20% vs. 5.6%, respectively, P=0.19). The 1-year mortality was also not statistically different between the two groups (20% vs. 11.1%, P=0.36). Conclusions: We found no statistically significant difference in mortality or rate of post-operative complications between patients who received pre-operative TIPS and those who did not in our age-matched cohort.

Randomised clinical trial: efficacy and safety of the live biotherapeutic product MRx1234 in patients with irritable bowel syndrome.

BACKGROUND: MRx1234 is a live biotherapeutic product that contains a strain of Blautia hydrogenotrophica. It is in development for the treatment of irritable bowel syndrome (IBS). AIMS: To assess the efficacy and safety of MRx1234 in patients with IBS with predominant constipation (IBS-C) or diarrhoea (IBS-D) METHODS: We conducted a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Patients aged 18-70 years in two parallel cohorts (IBS-C; IBS-D) were randomised (1:1) to MRx1234 or placebo for 8 weeks. The primary efficacy endpoint was overall responder rate-a composite of improved bowel habit (IBS-C: stool frequency; IBS-D: stool consistency) and abdominal pain intensity-for ≥50% of the treatment period in each cohort. Statistical testing was at a one-sided 0.10 significance level. RESULTS: Of 366 randomised patients (164 IBS-C; 202 IBS-D), 365 received any study medication (177 MRx1234, 188 placebo). Numerically, although not statistically significantly different, more patients who received MRx1234 than placebo were overall responders in the IBS-C (25.0% vs. 17.1%) and IBS-D (23.4% vs. 17.8%) cohorts. Similar results were observed in the additional combined cohort analysis (24.1% vs. 17.5%; p = 0.063). For the components of the primary endpoint, significantly more patients on MRx1234 than placebo reported improvement in bowel habit in the IBS-C, IBS-D and combined cohorts, while improvements in abdominal pain were observed in each cohort. The safety profile of MRx1234 was similar to placebo. CONCLUSIONS: MRx1234 has the potential to become a novel, safe treatment option for patients with IBS-C or IBS-D, and for those who have mixed symptoms or transition between subtypes. CLINICALTRIALS: gov #NCT03721107.

Interactions between symptoms and psychological status in irritable bowel syndrome: An exploratory study of the impact of a probiotic combination.

BACKGROUND: Stress is an exacerbator of irritable bowel syndrome (IBS) symptoms, and anxiety and depression are co-morbidities. Bifidobacterium longum strains 1714® and 35642® attenuate stress responses in healthy people and reduce symptoms in IBS, respectively. Here, we explore relationships between the psychological and visceral effects of the two strains (COMBO) in IBS subjects and biomarkers of stress and inflammation. METHODS: We recruited 40 patients with IBS (Rome III) and mild to moderate anxiety (HADS-A) and/or depression (HADS-D) and 57 asymptomatic female controls with low or moderate stress. IBS patients were fed COMBO (1 × 109 cfu/day) for 8 weeks with an 8-week washout. IBS symptoms, psychometric measures, salivary cortisol awakening response (CAR), and plasma inflammatory biomarkers were assessed every 4 weeks. KEY RESULTS: Compared to healthy controls, IBS subjects had a blunted CAR. Treatment with COMBO restored CAR and improved IBS symptoms compared to baseline during the treatment phase. The COMBO reduced HADS-D, HADS-A score, and TNF-α, while sleep quality improved significantly from baseline to the end of the intervention. Surprisingly, these parameters improved further once treatment ended and maintained this improvement by Week 16. CONCLUSIONS AND INFERENCES: These findings suggest that the stress response is a major driver of IBS symptoms. The time course of the beneficial effect of COMBO on IBS symptoms suggests that this is achieved through a restoration of the stress response. In contrast, the time course of the effects of COMBO on anxiety and depression in IBS paralleled an anti-inflammatory effect as indicated by a reduction in circulating levels of TNF-α.

Safety of Percutaneous Endoscopic Gastrostomy Placement in Patients With SARS-CoV-2 Infection.

Background: Coronavirus disease 2019 (COVID-19) can lead to ventilator-dependent chronic respiratory failure and a need for tube feeding. Percutaneous endoscopic gastrostomy (PEG) placement provides more sustainable longer-term enteral access with fewer side effects compared to the long-term nasogastric tube placement. Bleeding is a recognized complication of PEG placement, and many COVID-19 patients are on antiplatelets/anticoagulants, yet minimal data exist on the safety of PEG tube placement in this context. Methods: A retrospective chart review identified patients who underwent PEG placement between January 2020 and January 2021 at a single institution. Success was defined as PEG placement and use to provide enteral nutrition with no complications requiring removal within 4 weeks. Results: Thirty-six patients with and 104 age- and sex-matched patients without COVID-19 infection were included. More COVID-19 patients were obese, on anticoagulants, had low serum albumin levels and had a tracheostomy in place. Of those patients, 8.3% with COVID-19 developed PEG-related complications compared to 16.3% without (P = 0.28). PEG success rates in patients with and without COVID-19 were similar at 97.2% and 92.3%, respectively (P = 0.44). Conclusion: PEG tube placement is comparatively safe in COVID-19 patients who need long-term enteral access.

DNA sensor-associated type I interferon signaling is increased in ulcerative colitis and induces JAK-dependent inflammatory cell death in colonic organoids.

DNA sensor pathways can initiate inflammasome, cell death, and type I interferon (IFN) signaling in immune-mediated inflammatory diseases (IMIDs), including type I interferonopathies. We investigated the involvement of these pathways in the pathogenesis of ulcerative colitis (UC) by analyzing the expression of DNA sensor, inflammasome, and type I IFN biomarker genes in colonic mucosal biopsy tissue from control (n = 31), inactive UC (n = 31), active UC (n = 33), and a UC single-cell RNA-Seq dataset. The effects of type I IFN (IFN-ß), IFN-γ, and TNF-α on gene expression, cytokine production, and cell death were investigated in human colonic organoids. In organoids treated with cytokines alone, or in combination with NLR family pyrin domain-containing 3 (NLRP3), caspase, or JAK inhibitors, cell death was measured, and supernatants were assayed for IL-1ß/IL-18/CXCL10. The expression of DNA sensor pathway genes-PYHIN family members [absent in melanoma 2 (AIM2), IFI16, myeloid cell nuclear differentiation antigen (MNDA), and pyrin and HIN domain family member 1 (PYHIN1)- as well as Z-DNA-binding protein 1 (ZBP1), cyclic GMP-AMP synthase (cGAS), and DDX41 was increased in active UC and expressed in a cell type-restricted pattern. Inflammasome genes (CASP1, IL1B, and IL18), type I IFN inducers [stimulator of interferon response cGAMP interactor 1 (STING), TBK1, and IRF3), IFNB1, and type I IFN biomarker genes (OAS2, IFIT2, and MX2) were also increased in active UC. Cotreatment of organoids with IFN-ß or IFN-γ in combination with TNFα increased expression of IFI16, ZBP1, CASP1, cGAS, and STING induced cell death and IL-1ß/IL-18 secretion. This inflammatory cell death was blocked by the JAK inhibitor tofacitinib but not by inflammasome or caspase inhibitors. Increased type I IFN activity may drive elevated expression of DNA sensor genes and JAK-dependent but inflammasome-independent inflammatory cell death of colonic epithelial cells in UC.NEW & NOTEWORTHY This study found that patients with active UC have significantly increased colonic gene expression of cytosolic DNA sensor, inflammasome, STING, and type I IFN signaling pathways. The type I IFN, IFN-ß, in combination with TNF-α induced JAK-dependent but NLRP3 and inflammasome-independent inflammatory cell death of colonic organoids. This novel inflammatory cell death phenotype is relevant to UC immunopathology and may partially explain the efficacy of the JAKinibs tofacitinib and upadacitinib in patients with UC.

The serotonin receptor 3E variant is a risk factor for female IBS-D.

Irritable bowel syndrome (IBS) is a gut-brain disorder of multifactorial origin. Evidence of disturbed serotonergic function in IBS accumulated for the 5-HT3 receptor family. 5-HT3Rs are encoded by HTR3 genes and control GI function, and peristalsis and secretion, in particular. Moreover, 5-HT3R antagonists are beneficial in the treatment of diarrhea predominant IBS (IBS-D). We previously reported on functionally relevant SNPs in HTR3A c.-42C > T (rs1062613), HTR3C p.N163K (rs6766410), and HTR3E c.*76G > A (rs56109847 = rs62625044) being associated with IBS-D, and the HTR3B variant p.Y129S (rs1176744) was also described within the context of IBS. We performed a multi-center study to validate previous results and provide further evidence for the relevance of HTR3 genes in IBS pathogenesis. Therefore, genotype data of 2682 IBS patients and 9650 controls from 14 cohorts (Chile, Germany (2), Greece, Ireland, Spain, Sweden (2), the UK (3), and the USA (3)) were taken into account. Subsequent meta-analysis confirmed HTR3E c.*76G > A (rs56109847 = rs62625044) to be associated with female IBS-D (OR = 1.58; 95% CI (1.18, 2.12)). Complementary expression studies of four GI regions (jejunum, ileum, colon, sigmoid colon) of 66 IBS patients and 42 controls revealed only HTR3E to be robustly expressed. On top, HTR3E transcript levels were significantly reduced in the sigma of IBS patients (p = 0.0187); more specifically, in those diagnosed with IBS-D (p = 0.0145). In conclusion, meta-analysis confirmed rs56109847 = rs62625044 as a risk factor for female IBS-D. Expression analysis revealed reduced HTR3E levels in the sigmoid colon of IBS-D patients, which underlines the relevance of HTR3E in the pathogenesis of IBS-D.

Recognizing and Defining Occasional Constipation: Expert Consensus Recommendations.

Constipation is a common problem, affects 15% of the population, and is often self-diagnosed and self-managed. Over the past 3 decades, there have been significant advances in our understanding and management of chronic constipation, with the emerging recognition that occasional constipation (OC) is another subtype that falls outside current classifications. The purpose of this review was to describe the process of developing and proposing a new definition for OC based on expert consensus and taking into consideration the multifactorial nature of the problem such as alterations in bowel habit that include stool frequency and difficulty with stool passage, perception of the sufferer, duration of symptoms, and potential responsiveness to treatment. Leading gastroenterologists from 5 countries met virtually on multiple occasions through an online digital platform to discuss the problem of OC and recommended a practical, user-friendly definition: "OC can be defined as intermittent or occasional symptomatic alteration(s) in bowel habit. This includes a bothersome reduction in the frequency of bowel movements and/or difficulty with passage of stools but without alarming features. Bowel symptoms may last for a few days or a few weeks, and episodes may require modification of lifestyle, dietary habits and/or use of over-the-counter laxatives or bulking agents to restore a satisfactory bowel habit." Prospective studies are required to validate this definition and determine OC prevalence in the community. This review highlights current knowledge gaps and could provide impetus for future research to facilitate an improved understanding of OC and development of evidence-based management guidelines.