To identify factors that regulate gut microbiota density and the impact of varied microbiota density on health, we assayed this fundamental ecosystem property in fecal samples across mammals, human disease, and therapeutic interventions. Physiologic features of the host (carrying capacity) and the fitness of the gut microbiota shape microbiota density. Therapeutic manipulation of microbiota density in mice altered host metabolic and immune homeostasis. In humans, gut microbiota density was reduced in Crohn’s disease, ulcerative colitis, and ileal pouch-anal anastomosis. The gut microbiota in recurrent Clostridium difficile infection had lower density and reduced fitness that were restored by fecal microbiota transplantation. Understanding the interplay between microbiota and disease in terms of microbiota density, host carrying capacity, and microbiota fitness provide new insights into microbiome structure and microbiome targeted therapeutics.Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).

Clostridioides difficile infection is a leading cause of healthcare-associated infections with significant morbidity and mortality. For the past decade, the bulk of infection prevention and epidemiologic surveillance efforts have been directed toward mitigating hospital-acquired C. difficile. However, the incidence of community-associated infection is on the rise. Patients with community-associated C. difficile tend to be younger and have lower mortality rate. Rates of recurrent C. difficile infection overall have decreased in the United States, but future research and public health endeavors are needed to standardize and improve disease detection, stratify risk factors in large-scale population studies, and to identify regional and local variations in strain types, reservoirs and transmission routes to help characterize and combat the changing epidemiology of C. difficile.

To the Editor-Clostridioides difficile infection (CDI) is the most common healthcare-associated infection in the United States. 1 CDI affects 13 in every 1,000 patients, and~75% of cases are classified as hospital onset. Antimicrobial stewardship and compliance with hand hygiene and personal protective equipment (PPE) protocols are paramount in efforts to reduce horizontal CDI transmission. 2 As an epicenter of the coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), New York City hospitals saw a dramatic increase in admissions and ICU utilization. 3 To understand the impact of COVID-19 on hospital-onset CDI, we examined antibiotic prescribing patterns, standardized infection ratios (SIRs), and baseline variables in hospitalized adult patients prior to and during the COVID-19 pandemic. We hypothesized that increased antibiotics exposure during the COVID-19 pandemic would lead to a higher incidence of CDI in hospitalized patients. We conducted a retrospective cohort analysis at a high-volume tertiary-care center comparing a pre-COVID-19 cohort (February-June 2019) of all adult patients who were diagnosed with CDI on admission or during their hospitalization with a cohort during the COVID-19 pandemic (February-June 2020). Baseline categorical variables were compared using χ 2 tests and continuous variables were compared using the Student t test and Mann-Whitney-Wilcoxon test. All analysis was performed in SAS version 9.4 software (SAS Institute, Cary, NC). Primary outcomes of interest included rates of hospital-onset CDI (HO-CDI, defined as a positive C. difficile test over 3 days after admission), 4 antibiotic prescribing and length of stay. HO-CDI incidence was described by the standardized infection ratios (SIR), which adjusts for facility and patient-level factors that contribute to hospitalonset infection risk within each facility. Antibiotic prescriptions were measured by antibiotic days per 1,000 days present. The study was approved by the Institutional Review Board of the Icahn School of Medicine at Mount Sinai. Overall, HO-CDI SIR 5 was not statistically different during the COVID-19 period than during the 2019 period (P = 0.69)

Background: Recurrent and severe Clostridium difficile infections (CDI) are treated with fecal microbiota transplant (FMT). Uncertainty exists regarding FMT effectiveness for CDI with underlying inflammatory bowel disease (IBD) and regarding its effects on disease activity and effectiveness in transferring the donor microbiota to patients with and without IBD.Methods: Subjects with and without IBD who underwent FMT for recurrent or severe CDI between 2013 and 2016 at The Mount Sinai Hospital were followed for up to 6 months. The primary outcome was CDI recurrence 6 months after FMT. Secondary outcomes were (1) CDI recurrence 2 months after FMT; (2) frequency of IBD flare after FMT; (3) microbiota engraftment after FMT; (and 4) predictors of CDI recurrence.Results: One hundred thirty-four patients, 46 with IBD, were treated with FMT. Follow-up was available in 83 and 118 patients at 6 and 2 months, respectively. There was no difference in recurrence in patients with and without IBD at 6 months (38.7% vs 36.5%; P > 0.99) and 2 months (22.5% vs 17.9%; P = 0.63). Proton pump inhibitor use, severe CDI, and comorbid conditions were predictors of recurrence. Pre-FMT microbiota was not predictive of CDI recurrence. Subjects with active disease requiring medication escalation had reduced engraftment, with no difference in engraftment based on CDI recurrence or IBD endoscopic severity at FMT. Conclusions:Inflammatory bowel disease did not affect CDI recurrence rates 6 months after FMT. Pre-FMT microbiota was not predictive of recurrence, and microbial engraftment was impacted in those requiring IBD treatment escalation, though not by CDI recurrence or IBD disease severity.

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Disorders of gut-brain interaction (DGBI), also known as functional gastrointestinal (GI) disorders, affect about 40% of the global population. 1 DGBIs occur as a result of complex interactions between biological, psychological, and social factors. 2 The treatment paradigm for DGBIs has advanced to encompass pharmacologic approaches (e.g., neuromodulators targeting central modulation of pain processing pathways) as well as non-pharmacologic modalities such as brain-gut behavior therapies (BGBT) and dietary modifications. A recent expert review outlined best practices for treating patients with DGBI including developing a collaborative patient-provider relationship, being able to explain the gut-brain axis in a patient-friendly way, leveraging non-pharmacologic modalities such as BGBT early on when appropriate, and being familiar with a few neuromodulators including dosing and side effects. 3 Despite increased understanding of the framework and breadth of treatment options for DGBI, patients are still inadequately treated

Summary 34To identify factors that regulate the absolute microbiota and the impact of varied microbiota density on health, we assayed 35 gut microbiota density across mammals, disease, and therapeutic interventions. Physiologic features of the host (carrying 36 capacity) and the fitness of the gut microbiota shape microbiota density. Therapeutic manipulation of microbiota density in 37 mice altered host metabolic and immune homeostasis. In humans, gut microbiota density was reduced in Crohn's disease, 38 ulcerative colitis, and ileal pouch-anal anastomosis. The gut microbiota in recurrent Clostridium difficile infection had lower 39 density and reduced fitness that were restored by fecal microbiota transplantation. Understanding the interplay between 40 microbiota and disease through the conceptual framework of microbiota density, host carrying capacity, and microbiota fitness 41 could provide biomarkers to identify candidates for microbiota therapeutics and monitor their response.

Goals: We performed a systematic review with meta-analysis to examine the efficacy and safety of oral fecal microbiota transplantation (FMT) capsules for recurrent Clostridioides difficile infection (rCDI). Background: FMT through colonoscopy is established as effective and safe in treating multiple recurrences of CDI, but consensus has not been established on delivery through oral capsules. Study: A systematic literature search was performed with multiple databases including MEDLINE and EMBASE to identify original studies including at least 10 patients that investigated the role of oral FMT capsules to treat rCDI. Cure rates were pooled by a random effects model and publication bias was assessed with the Egger test. Secondary analyses assessed for differences between capsule preparation (frozen vs. lyophilized stool) and delivery modality (capsule vs. colonoscopy). Results: Fifteen studies (12 case series and 3 randomized controlled trials) encompassing 763 patients were identified for inclusion. Significant variability existed in baseline patient characteristics and protocols. Meta-analysis of proportions showed efficacy of oral FMT capsules to be 0.821 (95% confidence interval: 0.762-0.874). No evidence for publication bias was found (P=0.51). Secondary analyses did not find significant differences in efficacy. Fourteen adverse events leading to death or hospitalization were noted, none of which were attributed to FMT. Conclusions: Oral FMT capsules for rCDI are promising because of ease of administration and noninvasive delivery. We found an overall efficacy of 82.1% with a low rate of serious adverse events. Further studies are needed to optimize protocols and outcomes.