Microbiome Restoration Research Articles

Not only for corals: exploring the uptake of beneficial microorganisms for corals by sponges.

Microbiome restoration using beneficial microorganisms for corals (BMCs) comprise a promising strategy to help corals cope with anthropogenic stressors. However, there is limited knowledge on the uptake of BMCs by nontarget animals, especially sponges. This study explores whether sponges can acquire BMCs upon direct application and whether inoculations affect sponge health. A 4-week field experiment applying BMCs to Stylissa carteri and Callyspongia crassa assessed three conditions: no inoculation, and BMCs inoculation once and thrice a week. BMC-related strains were naturally present in the seawater and the microbiome of S. carteri. These strains were enriched in response to the inoculation only in the S. carteri microbiome. Microbiomes of both sponges were restructured; sponges were visually healthy and efficiently pumped water at the end of the experiment. These results suggest that sponges can be enriched with BMC-related strains, and that BMC application on nearby corals is unlikely to negatively affect sponge health.

The Impact of Yoyo Dieting and Resistant Starch on Weight Loss and Gut Microbiome in C57Bl/6 Mice.

Cyclic weight loss and subsequent regain after dieting and non-dieting periods, a phenomenon termed yoyo dieting, places individuals at greater risk of metabolic complications and alters gut microbiome composition. Resistant starch (RS) improves gut health and systemic metabolism. This study aimed to investigate the effect of yoyo dieting and RS on the metabolism and gut microbiome. C57BL/6 mice were assigned to 6 diets for 20 weeks, including control, high fat (HF), yoyo (alternating HF and control diets every 5 weeks), control with RS, HF with RS, and yoyo with RS. Metabolic outcomes and microbiota profiling using 16S rRNA sequencing were examined. Yoyo dieting resulted in short-term weight loss, which led to improved liver health and insulin tolerance but also a greater rate of weight gain compared to continuous HF feeding, as well as a different microbiota profile that was in an intermediate configuration between the control and HF states. Mice fed HF and yoyo diets supplemented with RS gained less weight than those fed without RS. RS supplementation in yoyo mice appeared to shift the gut microbiota composition closer to the control state. In conclusion, yoyo dieting leads to obesity relapse, and increased RS intake reduces weight gain and might help prevent rapid weight regain via gut microbiome restoration.

Dietary pectin and inulin: A promising adjuvant supplement for collagen-induced arthritis through gut microbiome restoration and CD4+ T cell reconstitution

Dietary strategies rich in fiber have been demonstrated to offer benefits to individuals afflicted with rheumatoid arthritis (RA). However, the specific mechanisms through which a high-fiber diet (HFD) mitigates RA's autoimmunity remain elusive. Herein, we investigate the influence of pectin- and inulin-rich HFD on collagen-induced arthritis (CIA). We establish that HFD significantly alleviates arthritis in CIA mice by regulating the Th17/Treg balance. The rectification of aberrant T cell differentiation by the HFD is linked to the modulation of gut microbiota, augmenting the abundance of butyrate in feces. Concurrently, adding butyrate to the drinking water mirrors the HFD's impact on ameliorating CIA, encompassing arthritis mitigation, regulating intestinal barrier integrity, and restoring the Th17/Treg equilibrium. Butyrate reshapes the metabolic profile of CD4+ T cells in an AMPK-dependent manner. Our research underscores the importance of dietary interventions in rectifying gut microbiota for RA management and offers an explanation of how diet-derived microbial metabolites influence RA's immune-inflammatory-reaction.

Systematic review: effect of probiotics on antibiotic-induced microbiomedisruption.

The effectiveness of probiotics in preventing or reversing antibiotic-induced microbiome disruption remains uncertain, and claims of microbiome restoration to its pre-antibiotic state may be overestimated. In this review, we aimed to assess the efficacy of probiotics in preventing or ameliorating disruptions in microbiome composition and function induced by antibiotic treatment. We searched Medline, Embase, and CENTRAL for randomised controlled and non-randomised trials. Participants were individuals of any age who were on systemic antibiotics with a low risk of baseline dysbiosis. The intervention consisted of probiotics during or after antibiotic treatment, compared to placebo, alternative interventions, or no intervention. Outcomes included microbiome composition and diversity analysed using high-throughput molecular methods, alongside microbial function and resistome assessments. Seven studies, reported in eight papers, were reviewed. One study showed probiotics counteracting antibiotic-induced diversity changes, another showed exacerbation of these changes, and four others showed no effect. Effects on taxa abundance ranged from mitigating dysbiosis to selective modulation, no effect, or delayed recovery. One study observed no impact on the resistome, while another reported an increase in antibiotic resistance genes. In conclusion, heterogeneous results preclude a definitive conclusion on the effectiveness of any specific probiotic in restoring antibiotic-exposed microbiomes. For a clearer understanding, future research should be more standardised and long-term, employing advanced methods, such as 16S rRNA gene sequencing and metagenomic sequencing. These studies should strive to include larger, diverse populations to enhance generalisability and clearly define what constitutes a healthy microbiome. Finally, linking changes in the microbiome to specific clinical outcomes is essential for clinical decision making. PROSPERO registration number: CRD42023446214.

Rise to the Challenge: Master the Management of Clostridioides difficile Infection.

Clostridioides difficile infection (CDI) is a significant public health challenge in the developed world. Although previously CDI was primarily a health care-acquired infection, there are now rising numbers of community-acquired cases in patients without traditional risk factors, such as antibiotic exposure. The landscape for the treatment of CDI has changed significantly during the past decade, including newer diagnostic tests, novel antibiotic regimens, and strategies for microbiome restoration in the form of traditional fecal microbiota transplant and approved live biotherapeutics in an effort to address the underlying pathophysiologic process of gut microbial dysbiosis. We present a concise review for clinicians on the diagnosis and management of both primary and recurrent CDI.

Systematic review of the orally administered microbiome therapeutic, fecal microbiota spores, live-brpk, to prevent recurrence of Clostridioides difficile infection in adults.

Clostridioides difficile infection (CDI) has been linked to over 200,000 cases of illness in hospitalized patients and over 20,000 deaths annually. Up to 25% of patients with an initial CDI episode will experience recurrent CDI (rCDI), which most commonly occurs in the first 8 weeks following antibiotic therapy. In patients with first or multiple rCDI, infection, the microbiome is similarly disrupted, which highlights the challenges of using antibiotics alone while underscoring the need for microbiome restoration regardless of the number of recurrences. In this systematic review, we describe the role of the gastrointestinal microbiome in CDI, and systematically review fecal microbiota spores, live-brpk (VOWST™; VOS for Vowst Oral Spores) for prevention of recurrence in rCDI. The PubMed database was searched using "recurrent Clostridioides difficile infection" AND (SER-109 OR VOS) and limited to clinical trials. The search yielded 7 results: 3 articles describing 3 clinical trials (two Phase 3 trials (ECOSPOR III and ECOSPOR IV) and one Phase 2 trial (ECOSPOR)), 1 describing follow-up of ECOSPOR III, 1 describing a post hoc analysis of comorbidities in ECOSPOR III, and 2 describing health-related quality of life in ECOSPOR III. Compared with placebo, VOS following standard-of-care antibiotics for CDI significantly reduced risk of recurrence at 8 weeks (relative risk, 0.32 (95% CI: 0.18-0.58); p < 0.001; number needed to treat: 4) with a tolerable safety profile; rCDI rates remained low through 24 weeks. The disrupted microbiome, secondary to/exacerbated by antibiotic treatment, was rapidly (i.e., Week 1) restored with VOS. Compared with placebo, VOS demonstrated greater improvements in health-related quality of life. Clinical care of patients with rCDI now includes Food and Drug Administration-approved therapeutics to address microbiome restoration. Clinical trial evidence supports use of VOS following antibiotics and importance of microbiome restoration in rCDI.

286. The Effect of Fecal Microbiota Transplantation on Decolonization of Multidrug-resistant Organisms in the gut

Abstract Background Gut colonization of multidrug-resistant organisms (MDROs), such as carbapenemase-producing Enterobacteriaceae (CPE) and vancomycin-resistant Enterococci (VRE), precedes clinical infections. It increases the risk of patient-to-patient transmission of MDROs as well as clinical infections such as bacteremia. Therefore, decolonization of MDROs in the gut by restoring colonization resistance through fecal microbiota transplantation (FMT) could be an effective infection control strategy for MDROs. Methods From March 2019 to November 2022, FMT for CPE and VRE decolonization in the gut was conducted at Hallym University Chuncheon Sacred Heart Hospital. Frozen or capsulized stool (MicroBiotix FMT Delivery Microbiota Preparation) from unrelated pre-screened healthy donor was used for each FMT. The rates of and the time to successful decolonization, defined as 3 consecutive negative results from rectal swab culture repeated with 3-day intervals after the initial FMT, were investigated in CPE and VRE rectal colonizers, respectively. Results FMT was performed in 60 CPE rectal carriers (KPC=55, KPC &amp; NDM=2, KPC &amp; IMP=1, NDM=1, NDM &amp; OXA=1) and in 15 VRE rectal carriers (E. faecium=14, E. faecalis=1). Among patients with follow-up data after initial FMT, decolonization success rates for CPE and VRE rectal carriers were 44.8% (26/58) and 66.7% (10/15) at 1 month, 77.1% (37/48) and 92.9% (13/14) at 3 months, 95.5% (42/44) and 100% (14/14) at 6 months, respectively. Median and mean times to decolonization after initial FMT were 30 and 43 days in CPE rectal colonizers and 14 and 29 days in VRE rectal colonizers, respectively. FMT results for decolonization of MDROs in the gut of Chuncheon Sacred Heart Hospital (ClinicalTrials.gov number, NCT04583098) Conclusion FMT as a microbiome restoration therapy is an effective method to control CPE and VRE colonization (ClinicalTrials.gov number, NCT04583098). Disclosures All Authors: No reported disclosures

Whey Protein Hydrolysate Exerts Anti-Inflammatory Effects to Alleviate Dextran Sodium Sulfate (DSS)-Induced Colitis via Microbiome Restoration.

Whey protein hydrolysate (WPH) has been shown to have a variety of bioactivities. This study aimed to investigate the preventive effect of WPH on dextran sodium sulfate (DSS)-induced colitis in C57BL/6J mice. The results indicated that WPH intervention for 37 days was effective in delaying the development of colonic inflammation, and high doses of WPH significantly inhibited weight loss (9.16%, n = 8, p < 0.05), protected the colonic mucosal layer, and significantly reduced the levels of inflammatory factors TNF-α, IL-6, and IL-1β in mice with colitis (n = 8, p < 0.05). In addition, WPH intervention was able to up-regulate the short-chain fatty acids secretion and restore the gut microbiome imbalance in mice with colitis. Notably, high-dose WPH intervention increased the relative abundance of norank_f_Muribaculaceae by 1.52-fold and decreased the relative abundance of Romboutsia and Enterobacter by 3.77-fold and 2.45-fold, respectively, compared with the Model group. WPH intervention protected colitis mice mainly by reversing the microbiome imbalance and regulating the major histocompatibility complex (MHC) class I pathway. This study showed that WPH has anti-inflammatory activity and a promising colitis management future.

Recurrent Clostridioides difficile Infection: Current Clinical Management and Microbiome-Based Therapies.

Clostridioides difficileis one of the most important causes of healthcare-associated diarrhea. The high incidence and recurrence rates ofC. difficile infection, as well as its associated morbidity and mortality, are great concerns. The most common complication of C. difficile infection is recurrence, with rates of 20-30% after a primary infection and 60% after three or more episodes. Medical management of recurrent C. difficile infection involves a choice of therapy that is different from the antibiotic used in the primary episode. Patients with recurrent C. difficile infection also benefit from fecal microbiota transplantation or standardized microbiome restoration therapies (approved or experimental) to restore eubiosis. In contrast to antibiotics, microbiome restoration therapies restore a normal gut flora and eliminateC. difficilecolonization and infection. Fecal microbiota transplantation in recurrent C. difficile infection has demonstrated higher success rates than vancomycin, fidaxomicin, or placebo. Fecal microbiota transplantation has traditionally been considered safe, with the most common adverse reactions being abdominal discomfort,and diarrhea, and rare serious adverse events. Significant heterogeneity and a lack of standardization regarding the process of preparation, and administration of fecal microbiota transplantation remain a major pitfall. Standardized microbiome-based therapies provide a promising alternative. In the ECOSPOR III trial of SER-109, an oral formulation of bacterial spores, a significant reduction in the recurrence rate (12%) was observed compared with placebo (40%). In the phase III PUNCH CD3 trial, RBX2660 also demonstrated high efficacy rates of 70.6% versus 57.5%. Both these agents are now US Food and Drug Administration approved for recurrent C. difficile infection. Other standardized microbiome-based therapies currently in the pipeline are VE303, RBX7455, and MET-2. Antibiotic neutralization strategies, vaccines, passive monoclonal antibodies, and drug repurposing are other therapeutic strategies being explored to treat C. difficile infection.

The baseline is already shifted: marine microbiome restoration and rehabilitation as essential tools to mitigate ecosystem decline

Climate change is turning formerly pristine ecosystems into ever-changing states, causing major disturbance and biodiversity loss. Such impacted marine ecosystems and organisms exhibit clear microbiome shifts that alter their function. Microbiome-targeted interventions appear as feasible tools to support organismal and ecosystem resilience and recovery by restoring symbiotic interactions and thwarting dysbiotic processes. However, microbiome restoration and rehabilitation are perceived as drastic measures, since they alter ‘natural relationships’. What is missing from this notion is that microbiomes already drastically differ from any pre-anthropogenic state. As such, our perception and definition of even ‘pristine states’ may in fact represent an already disturbed/derived condition. Following this, we argue that restoring and rehabilitating marine microbiomes are essential tools to mitigate ecosystem and organismal decline.

Chronic mesenteric ischemia-induced intestinal dysbiosis resolved after revascularization.

Chronic mesenteric ischemia (CMI) is a debilitating condition arising from intestinal malperfusion from mesenteric artery stenosis or occlusion. Mesenteric revascularization has been the standard of care but can result in substantial morbidity and mortality. Most of the perioperative morbidity has been secondary to postoperative multiple organ dysfunction, potentially from ischemia-reperfusion injury. The intestinal microbiome is a dense community of microorganisms in the gastrointestinal tract that help regulate pathways ranging from nutritional metabolism to the immune response. We hypothesized that patients with CMI will have microbiome perturbations that contribute to this inflammatory response and could potentially normalize in the postoperative period. We performed a prospective study of patients with CMI who had undergone mesenteric bypass and/or stenting from 2019 to 2020. Stool samples were collected at three time points: preoperatively at the clinic, perioperatively within 14days after surgery, and postoperatively at the clinic at >30days after revascularization. Stool samples from healthy controls were used for comparison. The microbiome was measured using 16S rRNA sequencing on an Illumina-MiSeq sequence platform and analyzed using the QIIME2 (quantitative insights into microbial ecology 2)-DADA2 bioinformatics pipeline with the Silva database. Beta-diversity was analyzed using a principal coordinates analysis and permutational analysis of variance. Alpha-diversity (microbial richness and evenness) was compared using the nonparametric Mann-Whitney U test. Microbial taxa unique to CMI patients vs controls were identified using linear discriminatory analysis effect size analysis. P< .05 was considered statistically significant. Eight patients with CMI had undergone mesenteric revascularization (25% men; average age, 71years). Nine healthy controls were also analyzed (78% men; average age, 55years). Bacterial alpha-diversity (number of operational taxonomic units) was dramatically reduced preoperatively compared with that of the controls (P= .03). However, revascularization partially restored the species richness and evenness in the perioperative and postoperative phases. Beta-diversity was only different between the perioperative and postoperative groups (P= .03). Further analyses revealed increased abundance of Bacteroidetes and Clostridia taxa preoperatively and perioperatively compared with the controls, which was reduced during the postoperative period. The results from the present study have shown that patients with CMI have intestinal dysbiosis that resolves after revascularization. The intestinal dysbiosis is characterized by the loss of alpha-diversity, which is restored perioperatively and maintained postoperatively. This microbiome restoration demonstrates the importance of intestinal perfusion to sustain gut homeostasis and suggests that microbiome modulation could be a possible intervention to ameliorate acute and subacute postoperative outcomes in these patients.

Current Regulation and Initial Considerations for Successful Development and Commercialization of Microbiome Therapies

The gut microbiome is frequently referred to as the “second brain” or “second genome,” referring to the impact of the gut microbiota on our health. The microbiome is formed at birth, grows with the host, and is impacted by environmental variables such as nutrition, antibiotics, and lifestyle. Understanding the host health-gut microbiota correlation opens the possibility of modifying the gut microbiome to manage an individual’s health. Several techniques, such as probiotic, prebiotic, synbiotic, and faecal microbiota transplantation (FMT), are explored to alleviate the dysbiosis-related negative consequences and restore the gut microbiota in humans. While microbiome-based medicines have made remarkable progress in the last decade, from prebiotics and probiotics to live biotherapeutics, there are still safety concerns and regulatory issues to be addressed. The FMT treatment is currently experimental and lacks authorization, posing numerous ethical, legal, and social challenges that must be resolved as part of an effective regulatory policy response. This study gives an outline of our current understanding of microbiome restoration approaches as well as safety concerns regarding how these approaches are regulated. It presents an outline of the contemporary gut microbiome therapeutic development landscape and an assessment of the commercialization hurdles encountered.

Active Clinical Trials in Hepatic Encephalopathy: Something Old, Something New and Something Borrowed.

Hepatic encephalopathy (HE) is a potentially reversible neurocognitive syndrome that occurs in patients with acute or chronic liver disease. Currently, most of the therapies for HE aim to reduce ammonia production or increase its elimination. To date, only two agents have been approved as treatments for HE: lactulose and rifaximin. Many other drugs have also been used, but data to support their use are limited, preliminary or lacking. The aim of this review is to provide an overview and discussion of the current development of treatments for HE. Data from ongoing clinical trials in HE were obtained from the ClinicalTrials.gov website, and a breakdown analysis of studies that were active on August 19th, 2022, was performed. Seventeen registered and ongoing clinical trials for therapeutics targeting HE were identified. More than 75% of these agents are in phase II (41.2%) or in phase III (34.7%). Among them, there are many old acquaintances in the field, such as lactulose and rifaximin, some new entries such as fecal microbiota transplantation and equine anti-thymocyte globulin, an immunosuppressive agent, but also some therapies borrowed from other conditions, such as rifamycin SV MMX and nitazoxanide, two antimicrobial agents FDA approved for the treatment of some types of diarrheas or VE303 and RBX7455, two microbiome restoration therapies, currently used as treatment of high-risk Clostridioides difficile infections. If working, some of these drugs could soon be used as valid alternatives to current therapies when ineffective or be approved as novel therapeutic approaches to improve the quality of life of HE patients.

The microbiome-gut-brain axis in epilepsy: pharmacotherapeutic target from bench evidence for potential bedside applications.

The gut-brain axis augments the bidirectional communication between the gut and brain and modulates gut homeostasis and the central nervous system through the hypothalamic-pituitary-adrenal axis, enteroendocrine system, neuroendocrine system, inflammatory and immune pathways. Preclinical and clinical reports showed that gut dysbiosis might play a major regulatory role in neurological diseases such as epilepsy, Parkinson's, multiple sclerosis, and Alzheimer's disease. Epilepsy is a chronic neurological disease that causes recurrent and unprovoked seizures, and numerous risk factors are implicated in developing epilepsy. Advanced consideration of the gut-microbiota-brain axis can reduce ambiguity about epilepsy pathology, antiepileptic drugs, and effective therapeutic targets. Gut microbiota sequencing analysis reported that the level of Proteobacteria, Verrucomicrobia, Fusobacteria, and Firmicutes was increased and the level of Actinobacteria and Bacteroidetes was decreased in epilepsy patients. Clinical and preclinical studies also indicated that probiotics, ketogenic diet, faecal microbiota transplantation, and antibiotics can improve gut dysbiosis and alleviate seizure by enhancing the abundance of healthy biota. This study aims to give an overview of the connection between gut microbiota, and epilepsy, how gut microbiome changes may cause epilepsy, and whether gut microbiome restoration could be used as a treatment for epilepsy.

Application of Phytogenic Liquid Supplementation in Soil Microbiome Restoration in Queensland Pasture Dieback.

Pasture production is vital in cattle farming as it provides animals with food and nutrients. Australia, as a significant global beef producer, has been experiencing pasture dieback, a syndrome of deteriorating grassland that results in the loss of grass and the expansion of weeds. Despite two decades of research and many remediation attempts, there has yet to be a breakthrough in understanding the causes or mechanisms involved. Suggested causes of this phenomenon include soil and plant microbial pathogens, insect infestation, extreme heat stress, radiation, and others. Plants produce a range of phytomolecules with antifungal, antibacterial, antiviral, growth-promoting, and immunostimulant effects to protect themselves from a range of environmental stresses. These products are currently used more in human and veterinary health than in agronomy. In this study, we applied a phytogenic product containing citric acid, carvacrol, and cinnamaldehyde, to investigate its ability to alleviate pasture dieback. The phytogenic liquid-based solution was sprayed twice, one week apart, at 5.4 L per hectare. The soil microbial community was investigated longitudinally to determine long-term effects, and pasture productivity and plant morphometric improvements were explored. The phytogenic liquid significantly improved post-drought recovery of alpha diversity and altered temporal and spatial change in the community. The phytogenic liquid reduced biomarker genera associated with poor and polluted soils and significantly promoted plant and soil beneficial bacteria associated with plant rhizosphere and a range of soil benefits. Phytogenic liquid application produced plant morphology improvements and a consistent enhancement of pasture productivity extending beyond 18 months post-application. Our data show that phytogenic products used in the livestock market as an alternative to antibiotics may also have a beneficial role in agriculture, especially in the light of climate change-related soil maintenance and remediation.

Fecal Microbiota Transplantation.

Fecal microbiota transplantation (FMT) is the process of transplanting stool from a healthy donor into the gut of a patient for therapeutic purposes. Current guidelines recommend FMT for the prevention of multiply recurrent Clostridioides difficile infection (CDI) after two recurrences, with cure rates approaching 90%. Emerging evidence also supports the use of FMT in the management of severe and fulminant CDI, resulting in decreased mortality and colectomy rates compared with standard of care approach. FMT shows promise as salvage therapy for critically-ill, refractory CDI patients who are poor surgical candidates. FMT should be considered early in the clinical course of severe CDI, preferably within 48 hours of failing to respond to antibiotic therapy and volume resuscitation. Besides CDI, ulcerative colitis was more recently identified as a potential treatment target for FMT. Several live biotherapeutics for microbiome restoration are on the horizon.

Gut microbiota and microbiota-based therapies for Clostridioides difficile infection.

Clostridioides difficile infection poses significant clinical challenges due to its recurrent nature. Current antibiotic management does not address the underlying issue, that of a disturbed gastrointestinal microbiome, called dysbiosis. This provides a supportive environment for the germination of C. difficile spores which lead to infection and toxin production as well as an array of other health conditions. The use of microbiome restoration therapies such as live biotherapeutics can reverse dysbiosis and lead to good clinical outcomes. Several such therapies are under clinical investigation.

Microbial ecology between Clostridioides difficile and gut microbiota.

Clostridioides difficile colonizes a polymicrobial environment in the intestine and is a causative agent for antibiotic-associated diarrhea (AAD) and pseudomembranous colitis (PMC). The most important virulence factors of C. difficile are bacterial toxins, and three toxins (toxin A, toxin B, and binary toxin) are produced by toxigenic strains. Other virulence factors include spores, flagella, capsules, biofilms, hydrolytic enzymes and adhesins. C. difficile infection (CDI) is specifically diagnosed by anaerobic culture and toxin detection by either nucleic acid amplification test (NAAT) or enzyme-linked immunosorbent assay (ELISA). For treatment of CDI, metronidazole, vancomycin and fidaxomicin are used based on the severity of CDI. Mutual interaction between C. difficile and gut microbiota is associated with pathogenesis of CDI, and decreased microbial diversity with altered gut microbiome was detected in CDI patients. Restoration of certain gut microbiota is considered to be potentially effective for the prevention and treatment of CDI, and an ideal goal for CDI patients is restoration of the gut microbiota to a healthy state. Fecal microbiota transplantation (FMT) is a highly successful method of microbiome restoration and has been reported to be effective for the prevention of recurrent CDI. In addition, approaches to restoring the gut microbiota by using probioitcs and live biotherapeutic products (LBPs) are currently being studied to examine the effect on CDI. Further microbial ecological research on C. difficile and gut microbiota could lead to a better understanding of the pathogenesis and treatment of CDI.

522. Significant Improvement in Health-Related Quality of Life (HRQL) with RBX2660: Results from a Phase 3 Randomized, Placebo-Controlled Trial in Recurrent Clostridioides Difficile Infection (PUNCH CD3)

Abstract Background Recurrence of Clostridioides difficile infection (rCDI) is common - up to 35% of patients may recur. RBX2660 is a microbiota restoration therapy to reduce rCDI. Here we report 8 weeks HRQL results using the Clostridioides difficile Health-related Quality-of-Life Questionnaire (Cdiff32), a disease-specific instrument, from PUNCH CD3 (a randomized, double-blinded, placebo-controlled RBX2660 Phase 3 trial, NCT03244644). Methods Cdiff32 includes three domains (physical, mental, and social) and a total score (all range from 0 to 100 [100 best possible]). Changes in Cdiff32 from baseline to week 8 were compared between RBX2660 and placebo (PBO) using unadjusted and adjusted analyses controlling for baseline score, demographic and disease characteristics. Per trial protocol, missing data were imputed via last observation carried forward (LOCF); as-observed data were also analyzed. Patients experiencing recurrence after blinded treatment received open-label RBX2660 per physician discretion; these participants were excluded unless, per LOCF, data were available from the blinded period for week 8 use. Results A total of 206 patients (140 RBX2660, 66 PBO) were included, with similar age (mean±SD) 61.1±16.9 yrs (RBX2660) and 57.3±16.4 yrs (PBO) and baseline Cdiff32 scores. More than half of the patients had multiple comorbidities. Cdiff32 scores improved significantly from baseline to weeks 1, 4, and 8 for both arms, with greater improvements for RBX2660 through week 8 (Figs. 1 &amp; 2). At week 8, statistical differences were found for mental domain (unadjusted: 8.01±3.64; adjusted: 7.07, 95% confidence interval: [0.28, 13.86], both P&amp;lt; 0.05) and total score (adjusted: 6.11, [0.14, 12.08], P&amp;lt; 0.05), all favoring RBX2660. Results were similar for the as-observed analyses, with the adjusted physical domain also statistically favoring RBX2660. Conclusion Most patients in this study reported improved HRQL. Improvements were observed in both arms, but RBX2660-treated patients had more robust and sustained improvements with statistically significant differences in Cdiff32 scores. This study suggests that microbiome restoration therapy might positively affect HRQL; future research may link these improvements directly with microbiota changes. Disclosures Paul Feuerstadt, MD, FACG, AGAF, Ferring/Rebiotix Pharmaceuticals: Advisor/Consultant|Ferring/Rebiotix Pharmaceuticals: Grant/Research Support|Merck and Co: Advisor/Consultant|SERES Therapeutics: Advisor/Consultant|SERES Therapeutics: Grant/Research Support|Takeda Pharmaceuticals: Advisor/Consultant Erik R. Dubberke, MD, MSPH, Abbott: Advisor/Consultant|Ferring: Advisor/Consultant|Ferring: Grant/Research Support|Merck: Advisor/Consultant|Pfizer: Advisor/Consultant|Pfizer: Grant/Research Support|Seres: Advisor/Consultant|Summit: Advisor/Consultant|Synthetic Biologics: Grant/Research Support Amy Guo, PhD, Ferring Pharmaceuticals: Employee Adam Harvey, PhD, Ferring Pharmaceuticals: Employment Min Yang, MD, PhD, Analysis Group, Inc.: I am an employee of Analysis Group, Inc., which has received consulting fees from Ferring for the conduct of this study. Viviana García-Horton, PhD, Analysis Group, Inc.: Employee of Analysis Group, Inc., which received consulting fees from Ferring for the conduct of this study. Mirko Fillbrunn, PhD, Analysis Group, Inc.: I am an employee of Analysis Group, Inc., which has received consulting fees from Ferring for the conduct of this study. Glenn S. Tillotson, PhD, Ferring Pharmaceuticals: Advisor/Consultant|Paratek Pharmaceuticals: Grant/Research Support|Spero Pharmaceuticals: Advisor/Consultant|Taro Pharmaceuticals: Advisor/Consultant Lindy Bancke, PharmD, Rebiotix, a Ferring Company: Employee Kevin W. Garey, PharmD, MS, Acurx: Grant/Research Support|cidara: Advisor/Consultant|cidara: Grant/Research Support|Paratek: Grant/Research Support|Seres Health: Grant/Research Support|Summit: Grant/Research Support.

Defending Earth's terrestrial microbiome.

Microbial life represents the majority of Earth's biodiversity. Across disparate disciplines from medicine to forestry, scientists continue to discover how the microbiome drives essential, macro-scale processes in plants, animals and entire ecosystems. Yet, there is an emerging realization that Earth's microbial biodiversity is under threat. Here we advocate for the conservation and restoration of soil microbial life, as well as active incorporation of microbial biodiversity into managed food and forest landscapes, with an emphasis on soil fungi. We analyse 80 experiments to show that native soil microbiome restoration can accelerate plant biomass production by 64% on average, across ecosystems. Enormous potential also exists within managed landscapes, as agriculture and forestry are the dominant uses of land on Earth. Along with improving and stabilizing yields, enhancing microbial biodiversity in managed landscapes is a critical and underappreciated opportunity to build reservoirs, rather than deserts, of microbial life across our planet. As markets emerge to engineer the ecosystem microbiome, we can avert the mistakes of aboveground ecosystem management and avoid microbial monocultures of single high-performing microbial strains, which can exacerbate ecosystem vulnerability to pathogens and extreme events. Harnessing the planet's breadth of microbial life has the potential to transform ecosystem management, but it requires that we understand how to monitor and conserve the Earth's microbiome.