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Background Recurrent Clostridioides difficile infection, associated with dysbiosis of gut microbiota, has substantial disease burden in the USA. RBX2660 is a live biotherapeutic product consisting of a broad consortium of microbes prepared from human stool that is under investigation for the reduction of recurrent C. difficile infection. Methods A randomized, double-blind, placebo-controlled, phase III study, with a Bayesian primary analysis integrating data from a previous phase IIb study, was conducted. Adults who had one or more C. difficile infection recurrences with a positive stool assay for C. difficile and who were previously treated with standard-of-care antibiotics were randomly assigned 2:1 to receive a subsequent blinded, single-dose enema of RBX2660 or placebo. The primary endpoint was treatment success, defined as the absence of C. difficile infection diarrhea within 8 weeks of study treatment. Results Of the 320 patients screened, 289 were randomly assigned and 267 received blinded treatment ( n = 180, RBX2660; n = 87, placebo). Original model estimates of treatment success were 70.4% versus 58.1% with RBX2660 and placebo, respectively. However, after aligning the data to improve the exchangeability and interpretability of the Bayesian analysis, the model-estimated treatment success rate was 70.6% with RBX2660 versus 57.5% with placebo, with an estimated treatment effect of 13.1% and a posterior probability of superiority of 0.991. More than 90% of the participants who achieved treatment success at 8 weeks had sustained response through 6 months in both the RBX2660 and the placebo groups. Overall, RBX2660 was well tolerated, with manageable adverse events. The incidence of treatment-emergent adverse events was higher in RBX2660 recipients compared with placebo and was mostly driven by a higher incidence of mild gastrointestinal events. Conclusions RBX2660 is a safe and effective treatment to reduce recurrent C. difficile infection following standard-of-care antibiotics with a sustained response through 6 months. Clinical Trial Registration NCT03244644; 9 August, 2017. Infographic AKN5i_vZYNJMF_jRRaL_sV Video abstract: (MP4 62,291 KB) Plain Language Summary Clostridioides difficile is a diarrhea-causing bacterium that is associated with potentially serious and fatal consequences. Antibiotics used to treat or prevent infections have a side effect of damaging the healthy protective gut bacteria (microbiota). Damage to the gut microbiota can allow C. difficile to over-grow and produce toxins that injure the colon. Paradoxically, the standard of care treatment of C. difficile infection (CDI) is antibiotics. Although initially effective for the control of diarrhea, antibiotics can leave a patient at risk for CDI recurrence after antibiotic treatment is stopped. Live biotherapeutic products are microbiota-based treatments used to repair the gut microbiota. These products have been shown to reduce the recurrence of CDI. RBX2660 is an investigational microbiota-based live biotherapeutic. RBX2660 contains a diverse set of microorganisms. RBX2660 has been developed to reduce CDI recurrence in adults following antibiotic treatment for recurrent CDI. This study was conducted to demonstrate that RBX2660 is effective and safe in treating patients with recurrent CDI. Treatment was considered successful in participants who did not experience CDI recurrence within 8 weeks after administration. Overall, statistical modeling demonstrated that 70.6% of participants treated with RBX2660 and 57.5% of participants treated with placebo remained free of CDI recurrence through 8 weeks. A 13.1 percentage point increase in treatment success was observed with RBX2660 treatment compared with placebo. In participants who achieved treatment success at 8 weeks, more than 90% remained free of CDI recurrence through 6 months. The most common side effects with RBX2660 treatment were abdominal pain and diarrhea. No serious treatment-related side effects were reported. The current data from the comprehensive clinical development program support a positive benefit-risk profile for RBX2660 in the reduction of CDI recurrence in adults following antibiotic therapy for recurrent CDI.

Poor sanitation is thought to be a major cause of enteric infections among young children. However, there are no previously published randomized trials to measure the health impacts of large-scale sanitation programs. India's Total Sanitation Campaign (TSC) is one such program that seeks to end the practice of open defecation by changing social norms and behaviors, and providing technical support and financial subsidies. The objective of this study was to measure the effect of the TSC implemented with capacity building support from the World Bank's Water and Sanitation Program in Madhya Pradesh on availability of individual household latrines (IHLs), defecation behaviors, and child health (diarrhea, highly credible gastrointestinal illness [HCGI], parasitic infections, anemia, growth). We conducted a cluster-randomized, controlled trial in 80 rural villages. Field staff collected baseline measures of sanitation conditions, behaviors, and child health (May-July 2009), and revisited households 21 months later (February-April 2011) after the program was delivered. The study enrolled a random sample of 5,209 children <5 years old from 3,039 households that had at least one child <24 months at the beginning of the study. A random subsample of 1,150 children <24 months at enrollment were tested for soil transmitted helminth and protozoan infections in stool. The randomization successfully balanced intervention and control groups, and we estimated differences between groups in an intention to treat analysis. The intervention increased percentage of households in a village with improved sanitation facilities as defined by the WHO/UNICEF Joint Monitoring Programme by an average of 19% (95% CI for difference: 12%-26%; group means: 22% control versus 41% intervention), decreased open defecation among adults by an average of 10% (95% CI for difference: 4%-15%; group means: 73% intervention versus 84% control). However, the intervention did not improve child health measured in terms of multiple health outcomes (diarrhea, HCGI, helminth infections, anemia, growth). Limitations of the study included a relatively short follow-up period following implementation, evidence for contamination in ten of the 40 control villages, and bias possible in self-reported outcomes for diarrhea, HCGI, and open defecation behaviors. The intervention led to modest increases in availability of IHLs and even more modest reductions in open defecation. These improvements were insufficient to improve child health outcomes (diarrhea, HCGI, parasite infection, anemia, growth). The results underscore the difficulty of achieving adequately large improvements in sanitation levels to deliver expected health benefits within large-scale rural sanitation programs. ClinicalTrials.gov NCT01465204. Please see later in the article for the Editors' Summary.

Background. Patients with recurrent Clostridium difficile infection (CDI) have a > 60% risk of relapse, as conventional therapies do not address the underlying gastrointestinal dysbiosis. This exploratory study evaluated the safety and efficacy of bacterial spores for preventing recurrent CDI. Methods. Stool specimens from healthy donors were treated with ethanol to eliminate pathogens. The resulting spores were fractionated and encapsulated for oral delivery as SER-109. Following their response to standard-of-care antibiotics, patients in cohort 1 were treated with SER-109 on 2 consecutive days (geometric mean dose, 1.7 × 10⁹ spores), and those in cohort 2 were treated on 1 day (geometric mean dose, 1.1 × 10⁸ spores). The primary efficacy end point was absence of C. difficile-positive diarrhea during an 8-week follow-up period. Microbiome alterations were assessed. Results. Thirty patients (median age, 66.5 years; 67% female) were enrolled, and 26 (86.7%) met the primary efficacy end point. Three patients with early, self-limiting C. difficile-positive diarrhea did not require antibiotics and tested negative for C. difficile at 8 weeks; thus, 96.7% (29 of 30) achieved clinical resolution. In parallel, gut microbiota rapidly diversified, with durable engraftment of spores and no outgrowth of non-spore-forming bacteria found after SER-109 treatment. Adverse events included mild diarrhea, abdominal pain, and nausea. Conclusions. SER-109 successfully prevented CDI and had a favorable safety profile, supporting a novel microbiome-based intervention as a potential therapy for recurrent CDI.

Across low-income and middle-income countries (LMICs), one in ten deaths in children younger than 5 years is attributable to diarrhoea. The substantial between-country variation in both diarrhoea incidence and mortality is attributable to interventions that protect children, prevent infection, and treat disease. Identifying subnational regions with the highest burden and mapping associated risk factors can aid in reducing preventable childhood diarrhoea. We used Bayesian model-based geostatistics and a geolocated dataset comprising 15 072 746 children younger than 5 years from 466 surveys in 94 LMICs, in combination with findings of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017, to estimate posterior distributions of diarrhoea prevalence, incidence, and mortality from 2000 to 2017. From these data, we estimated the burden of diarrhoea at varying subnational levels (termed units) by spatially aggregating draws, and we investigated the drivers of subnational patterns by creating aggregated risk factor estimates. The greatest declines in diarrhoeal mortality were seen in south and southeast Asia and South America, where 54·0% (95% uncertainty interval [UI] 38·1–65·8), 17·4% (7·7–28·4), and 59·5% (34·2–86·9) of units, respectively, recorded decreases in deaths from diarrhoea greater than 10%. Although children in much of Africa remain at high risk of death due to diarrhoea, regions with the most deaths were outside Africa, with the highest mortality units located in Pakistan. Indonesia showed the greatest within-country geographical inequality; some regions had mortality rates nearly four times the average country rate. Reductions in mortality were correlated to improvements in water, sanitation, and hygiene (WASH) or reductions in child growth failure (CGF). Similarly, most high-risk areas had poor WASH, high CGF, or low oral rehydration therapy coverage. By co-analysing geospatial trends in diarrhoeal burden and its key risk factors, we could assess candidate drivers of subnational death reduction. Further, by doing a counterfactual analysis of the remaining disease burden using key risk factors, we identified potential intervention strategies for vulnerable populations. In view of the demands for limited resources in LMICs, accurately quantifying the burden of diarrhoea and its drivers is important for precision public health. Bill & Melinda Gates Foundation.

We conducted a controlled before-and-after trial to evaluate the impact of an onsite urban sanitation intervention on the prevalence of enteric infection, soil transmitted helminth re-infection, and diarrhea among children in Maputo, Mozambique. A non-governmental organization replaced existing poor-quality latrines with pour-flush toilets with septic tanks serving household clusters. We enrolled children aged 1–48 months at baseline and measured outcomes before and 12 and 24 months after the intervention, with concurrent measurement among children in a comparable control arm. Despite nearly exclusive use, we found no evidence that intervention affected the prevalence of any measured outcome after 12 or 24 months of exposure. Among children born into study sites after intervention, we observed a reduced prevalence of Trichuris and Shigella infection relative to the same age group at baseline (<2 years old). Protection from birth may be important to reduce exposure to and infection with enteric pathogens in this setting.

Background Our study aimed to determine the effect of probiotic consumption containing six viable microorganisms of 30 × 10 10  cfu Lactobacillus and Bifidobacteria strains for six months on clinical outcomes and inflammatory cytokines (TNF-α, IFN-γ, IL-6, IL-10, IL-12, IL-17A, IL-17C and IL-22) in patients with colorectal cancer. Methods Fifty-two patients with colorectal cancer were randomized at four weeks after surgery to receive either a placebo ( n  = 25) or 30 billion colony-forming unit (CFU) of a mixture of six viable strains including 107 mg of Lactobacillus acidophilus BCMC® 12,130, Lactobacillus lactis BCMC® 12,451, Lactobacillus casei subsp BCMC® 12,313, Bifidobacterium longum BCMC® 02120, Bifidobacterium bifidum BCMC® 02290 and Bifidobacterium infantis BCMC® 02129 ( n  = 27). Patients were instructed to take the product orally twice daily for six months. Infection status, diarrhea or hospital admission were recorded throughout the study. Blood was taken pre- and post-intervention to measure TNF-α, IFN-γ, IL-6, IL-10, IL-12, IL-17A, IL-17C and IL-22 using ELISA multiplex kit. Results The majority of cases (~ 70%) were in Duke’s C colorectal cancer for both groups. No surgical infection occurred and no antibiotics were required. Chemotherapy induced diarrhea was observed in both groups. Significant reduction in the level of pro-inflammatory cytokine, TNF-α, IL-6, IL-10, IL-12, IL-17A, IL-17C and IL-22 were observed in CRC patients who received probiotics as compared to pre-treatment level ( P  < 0.05). However, there was no significant difference in the IFN-γ in both groups. Conclusions We have shown that probiotics containing six viable microorganisms of Lactobacillus and Bifidobacteria strains are safe to be consumed at four weeks after surgery in colorectal cancer patients and have reduced pro-inflammatory cytokines (except for IFN-gamma). Probiotic may modify intestinal microenvironment resulting in a decline in pro-inflammatory cytokines. Trial registration NCT03782428 ; retrospectively registered on 20th December 2018.

The current study aims to evaluate the potential roles of taking probiotics postoperatively in attenuating the gastrointestinal complications and disturbed gut microbiota in colorectal cancer (CRC) patients undergoing chemotherapy. One hundred eligible CRC patients who were treated with radical surgery and needed to receive chemotherapy were recruited. Half of them were randomly assigned to the Probio group to take a probiotic combination from post-operation to the end of the first chemotherapeutic course. The other half of patients taking placebo instead were classified as the Placebo group. Gastrointestinal complications such as nausea, acid reflux, abdominal pain, abdominal distention, constipation, and diarrhea were recorded during chemotherapy. Fecal samples were collected preoperatively and after the first cycle of postoperative chemotherapy for 16S rRNA high-throughput sequencing and short-chain fatty acids (SCFAs) analysis. Results showed that probiotics administration could effectively reduce chemotherapy-induced gastrointestinal complications, particularly in diarrhea (p < 0.01). Additionally, chemotherapy also reduced the bacterial diversity indexes of the gut microbiota in CRC patients, which could be significantly increased by taking probiotics. Moreover, this chemotherapy caused significant changes in the composition of the gut microbiota, as indicated by decreased phylum levels of Firmicutes and increased Bacteroidetes, Proteobacteria, and Verrucomicrobia. In particular, several bacterial genera such as Akkermansia and Clostridium were significantly increased, while Prevotella, Lactobacillus, and Roseburia were decreased (p < 0.05). However, probiotic administration could effectively restore these taxa changes both at the phylum and genus levels, and mildly increase the genus levels of Bifidobacterium, Streptococcus, and Blautia. Furthermore, probiotics could also promote the production of SCFAs, particularly increasing acetate, butyrate, and propionate (p < 0.0001). These results support the beneficial effects of the probiotic interventions as novel alternative or complementary strategies in chemoprevention.

Antibiotic-associated diarrhoea (AAD) occurs most frequently in older (≥65 years) inpatients exposed to broad-spectrum antibiotics. When caused by Clostridium difficile, AAD can result in life-threatening illness. Although underlying disease mechanisms are not well understood, microbial preparations have been assessed in the prevention of AAD. However, studies have been mostly small single-centre trials with varying quality, providing insufficient data to reliably assess effectiveness. We aimed to do a pragmatic efficacy trial in older inpatients who would be representative of those admitted to National Health Service (NHS) and similar secondary care institutions and to recruit a sufficient number of patients to generate a definitive result. We did a multicentre, randomised, double-blind, placebo-controlled, pragmatic, efficacy trial of inpatients aged 65 years and older and exposed to one or more oral or parenteral antibiotics. A computer-generated randomisation scheme was used to allocate participants (in a 1:1 ratio) to receive either a multistrain preparation of lactobacilli and bifidobacteria, with a total of 6 × 1010 organisms, one per day for 21 days, or an identical placebo. Patients, study staff, and specimen and data analysts were masked to assignment. The primary outcomes were occurrence of AAD within 8 weeks and C difficile diarrhoea (CDD) within 12 weeks of recruitment. Analysis was by modified intention-to-treat. This trial is registered, number ISRCTN70017204. Of 17 420 patients screened, 1493 were randomly assigned to the microbial preparation group and 1488 to the placebo group. 1470 and 1471, respectively, were included in the analyses of the primary endpoints. AAD (including CDD) occurred in 159 (10·8%) participants in the microbial preparation group and 153 (10·4%) participants in the placebo group (relative risk [RR] 1·04; 95% CI 0·84–1·28; p=0·71). CDD was an uncommon cause of AAD and occurred in 12 (0·8%) participants in the microbial preparation group and 17 (1·2%) participants in the placebo group (RR 0·71; 95% CI 0·34–1·47; p=0·35). 578 (19·7%) participants had one or more serious adverse event; the frequency of serious adverse events was much the same in the two study groups and none was attributed to participation in the trial. We identified no evidence that a multistrain preparation of lactobacilli and bifidobacteria was effective in prevention of AAD or CDD. An improved understanding of the pathophysiology of AAD is needed to guide future studies. Health Technology Assessment programme; National Institute for Health Research, UK.

•Probiotics reduced grade 3–4 diarrhea after irinotecan based chemotherapy.•Probiotics reduced all grades of diarrhea and enterocolitis compared to placebo.•Patients on probiotics used less antidiarrheal drugs compared to placebo.•Probiotics could reduce gastrointestinal toxicity of irinotecan based therapy. Diarrhea is one of the dose limiting toxicity of irinotecan. SN-38 is main irinotecan metabolite responsible for diarrhea development, which is excreted in glucuronidated form into the intestine. This study aimed to determine the effectiveness of the probiotics in the prevention of irinotecan induced diarrhea due to reduction of intestinal beta-d-glucuronidase activity. Between January 2011 and December 2013, 46 patients with colorectal cancer starting a new line of irinotecan based therapy were included. Patients were randomized 1:1 to probiotics (PRO) or placebo (PLA). Probiotic formula Colon Dophilus™, was administered at a dose of 10×109CFU of bacteria tid, orally for 12 weeks of chemotherapy. The study was prematurely terminated due to slow accrual, when 46 of 220 planned patients were accrued. Twenty-three patients were randomized to PRO and 23 patients to PLA. Administration of probiotics compared to placebo led to a reduction in the incidence of severe diarrhea of grade 3 or 4 (0% for PRO vs. 17.4% for PLA, p=0.11), as well as reduction of the overall incidence of diarrhea (39.1% for PRO vs. 60.9% for PLA, p=0.24) and incidence of enterocolitis (0% for PRO vs. 8.7% for PLA). Patients on PRO used less antidiarrheal drugs compared to PLA. There was no infection caused by probiotic strains recorded. Administration of probiotics in patients with colorectal cancer treated with irinotecan-based chemotherapy is safe and could lead to a reduction in the incidence and severity of gastrointestinal toxicity.

Abstract Background Lewis and secretor histo–blood group antigens (HBGAs) have been associated with decreased susceptibility to P[8] genotype rotavirus (RV) infections. Efficacy of vaccines containing attenuated P[8] strains is decreased in low-income countries. Host phenotype might impact vaccine efficacy (VE) by altering susceptibility to vaccination or RV diarrhea (RVD). We performed a substudy in a monovalent RV vaccine (RV1) efficacy trial in Bangladesh to determine the impact of Lewis and secretor status on risk of RVD and VE. Methods In infants randomized to receive RV1 or no RV1 at 10 and 17 weeks with 1 year of complete active diarrheal surveillance, we performed Lewis and secretor phenotyping and genotyped the infecting strain of each episode of RVD. Results A vaccine containing P[8] RV protected secretors and nonsecretors similarly. However, unvaccinated nonsecretors had a reduced risk of RVD (relative risk, 0.53 [95% confidence interval, .36–.79]) mediated by complete protection from P[4] but not P[8] RVs. This effect reduced VE in nonsecretors to 31.7%, compared to 56.2% among secretors, and decreased VE for the overall cohort. Conclusions Host HBGA status may impact VE estimates by altering susceptibility to RV in unvaccinated children; future trials should therefore account for HBGA status. Clinical Trials Registration NCT01375647. Histo–blood group antigens were associated with genotype-specific susceptibility to rotavirus infections. Nonsecretors were at decreased risk of P[4] infections, while Lewis-negative children were at increased risk of P[6] infections. These effects may impact oral rotavirus vaccine efficacy estimates.