Multi-omics analysis of a fecal microbiota transplantation trial identifies novel aspects of acute graft-versus-host disease pathogenesis.

Acute graft-versus-host disease (aGVHD) is a major complication of allogeneic hematopoietic cell transplantation (alloHCT) associated with gut microbiota disruptions. However, whether therapeutic microbiota modulation prevents aGVHD is unknown. We conducted a randomized, placebo-controlled trial of third-party fecal microbiota transplantation (FMT) administered at the peak of microbiota injury in 100 patients with acute myeloid leukemia receiving induction chemotherapy and alloHCT recipients. Despite improvements in microbiome diversity, expansion of commensals, and shrinkage of potential pathogens, aGVHD occurred more frequently after FMT than placebo. Although this unexpected finding could be explained by clinical differences between the two arms, we asked whether a microbiota explanation might be also present. To this end, we performed multi-omics analysis of pre- and post-intervention gut microbiome and serum metabolome. We found that post-intervention expansion of Faecalibacterium, a commensal genus with gut-protective and anti-inflammatory properties under homeostatic conditions, predicted a higher risk for aGVHD. Faecalibacterium expansion occurred predominantly after FMT and was due to engraftment of unique donor taxa, suggesting that donor Faecalibacterium-derived antigens might have stimulated allogeneic immune cells. Faecalibacterium and ursodeoxycholic acid (an anti-inflammatory secondary bile acid) were negatively correlated, offering an alternative mechanistic explanation. In conclusion, we demonstrate context dependence of microbiota effects where a normally beneficial bacteria may become detrimental in disease. While FMT is a broad, community-level intervention, it may need precision engineering in ecologically complex settings where multiple perturbations (e.g. antibiotics, intestinal damage, alloimmunity) are concurrently in effect.

Long- and short-term effects of fecal microbiota transplantation on antibiotic resistance genes: results from a randomized placebo-controlled trial.

In small series, third-party fecal microbiota transplantation (FMT) has been successful in decolonizing the gut from clinically relevant antibiotic resistance genes (ARGs). Less is known about the short- and long-term effects of FMT on larger panels of ARGs. We analyzed 226 pre- and post-treatment stool samples from a randomized placebo-controlled trial of FMT in 100 patients undergoing allogeneic hematopoietic cell transplantation or receiving anti-leukemia induction chemotherapy for 47 ARGs. These patients have heavy antibiotic exposure and a high incidence of colonization with multidrug-resistant organisms. Samples from each patient spanned a period of up to 9 months, allowing us to describe both short- and long-term effects of FMT on ARGs, while the randomized design allowed us to distinguish between spontaneous changes vs. FMT effect. We find an overall bimodal pattern. In the first phase (days to weeks after FMT), low-level transfer of ARGs largely associated with commensal healthy donor microbiota occurs. This phase is followed by long-term resistance to new ARGs as stable communities with colonization resistance are formed after FMT. The clinical implications of these findings are likely context-dependent and require further research. In the setting of cancer and intensive therapy, long-term ARG decolonization could translate into fewer downstream infections.

Potential of Fecal Microbiota Transplantation to Prevent Acute GVHD: Analysis from a Phase II Trial.

PURPOSE: Intestinal microbiota disruptions early after allogeneic hematopoietic cell transplantation have been associated with increased risk for acute GVHD (aGVHD). In our recent randomized phase II trial of oral, encapsulated, third-party fecal microbiota transplantation (FMT) versus placebo, FMT at the time of neutrophil recovery was safe and ameliorated dysbiosis. Here, we evaluated in post hoc analysis whether donor microbiota engraftment after FMT may protect against aGVHD. EXPERIMENTAL DESIGN: We analyzed pre- and post-FMT stool samples and estimated donor microbiota engraftment (a preplanned secondary endpoint) by determining the fraction of post-FMT microbiota formed by unique donor taxa (donor microbiota fraction; dMf). RESULTS: dMf was higher in patients who later developed grade I or no aGVHD (median 33.9%; range, 1.6%-74.3%) than those who developed grade II-IV aGVHD (median 25.3%; range, 2.2%-34.8%; P = 0.006). The cumulative incidence of grade II-IV aGVHD by day 180 was lower in the group with greater-than-median dMf than the group with less-than-median dMf [14.3% (95% confidence interval, CI, 2.1-37.5) vs. 76.9% (95% CI, 39.7-92.8), P = 0.008]. The only determinant of dMf in cross-validated least absolute shrinkage and selection operator (LASSO)-regularized regression was the patient's pre-FMT microbiota diversity (Pearson correlation coefficient -0.82, P = 1.6 × 10-9), indicating more potent microbiota modulation by FMT in patients with more severe dysbiosis. Microbiota network analysis revealed major rewiring including changes in the most central nodes, without emergence of keystone species, as a potential mechanism of FMT effect. CONCLUSIONS: FMT may have protective effects against aGVHD, especially in patients with more severe microbiota disruptions.

Lupus Podocytopathy: A Rare Cause of Nephrotic Syndrome in Patients with Systemic Lupus Erythematosus.

Lupus podocytopathy, a unique form of lupus nephritis, mimics minimal change disease (MCD) or primary focal segmental glomerulosclerosis (FSGS) and represents approximately 1% of lupus nephritis biopsies. Lupus podocytopathy is characterized by diffuse epithelial cell foot process effacement without immune complex deposition or with only mesangial immune complex deposition. We present the case of a young woman with systemic lupus erythematosus (SLE) who presented with nephrotic syndrome and acute kidney injury (AKI) and was subsequently diagnosed with lupus podocytopathy.

Randomized Double-Blind Phase II Trial of Fecal Microbiota Transplantation Versus Placebo in Allogeneic Hematopoietic Cell Transplantation and AML.

PURPOSE: Gut microbiota injury in allogeneic hematopoietic cell transplantation (HCT) recipients and patients with AML has been associated with adverse clinical outcomes. Previous studies in these patients have shown improvements in various microbiome indices after fecal microbiota transplantation (FMT). However, whether microbiome improvements translate into improved clinical outcomes remains unclear. We examined this question in a randomized, double-blind, placebo-controlled phase II trial. METHODS: Two independent cohorts of allogeneic HCT recipients and patients with AML receiving induction chemotherapy were randomly assigned in a 2:1 ratio to receive standardized oral encapsulated FMT versus placebo upon neutrophil recovery. After each course of antibacterial antibiotics, patients received a study treatment. Up to three treatments were administered within 3 months. The primary end point was 4-month all-cause infection rate. Patients were followed for 9 months. RESULTS: In the HCT cohort (74 patients), 4-month infection density was 0.74 and 0.91 events per 100 patient-days in FMT and placebo arms, respectively (infection rate ratio, 0.83; 95% CI, 0.48 to 1.42; P = .49). In the AML cohort (26 patients), 4-month infection density was 0.93 in the FMT arm and 1.25 in the placebo arm, with an infection rate ratio of 0.74 (95% CI, 0.32 to 1.71; P = .48). Unique donor bacterial sequences comprised 25%-30% of the fecal microbiota after FMT. FMT improved postantibiotic recovery of microbiota diversity, restored several depleted obligate anaerobic commensals, and reduced the abundance of expanded genera Enterococcus, Streptococcus, Veillonella, and Dialister. CONCLUSION: In allogeneic HCT recipients and patients with AML, third-party FMT was safe and ameliorated intestinal dysbiosis, but did not decrease infections. Novel findings from this trial will inform future development of FMT trials.

Renal Injury in All-Comers After Transcatheter Aortic Valve Replacement: A Systematic Review and Meta-Analysis.

Background Acute kidney injury (AKI) following aortic valve replacement is associated with poor prognosis. Transcatheter aortic valve replacement (TAVR) is a novel strategy with a percutaneous approach and early recovery time. We conducted this meta-analysis to compare TAVR to surgical aortic valve replacement (SAVR) and their respective renal outcomes. Methods We searched for randomized controlled trials (RCTs) using MEDLINE, PUBMED, and Google Scholar databases from their inception till April 6, 2019, and included eight trials comparing TAVR to SAVR in cases that reported AKIs. Results We found a significant reduction in AKI after TAVR compared to SAVR at 30 days [n = 66 vs. n = 160, respectively; odds ratio (OR) = 0.38, 95% confidence interval (CI) = 0.28-0.51; p: <0.00001, I2 = 0%]. At one year, a trend towards reduced renal failure was noted in the TAVR arm compared to the SAVR arm (n = 74 vs. n = 129, respectively; OR = 0.57, 95% CI = 0.32-1.01; p = 0.05, I2 = 69%). Conclusion Based on our findings and analysis, we have concluded that TAVR is associated with significantly reduced renal injury at 30 days when compared to SAVR.

Genome-wide association studies on the phyllosphere microbiome: Embracing complexity in host-microbe interactions.

Environmental sequencing shows that plants harbor complex communities of microbes that vary across environments. However, many approaches for mapping plant genetic variation to microbe-related traits were developed in the relatively simple context of binary host-microbe interactions under controlled conditions. Recent advances in sequencing and statistics make genome-wide association studies (GWAS) an increasingly promising approach for identifying the plant genetic variation associated with microbes in a community context. This review discusses early efforts on GWAS of the plant phyllosphere microbiome and the outlook for future studies based on human microbiome GWAS. A workflow for GWAS of the phyllosphere microbiome is then presented, with particular attention to how perspectives on the mechanisms, evolution and environmental dependence of plant-microbe interactions will influence the choice of traits to be mapped.

Incidental findings on MRI scans of patients presenting with audiovestibular symptoms.

BACKGROUND: The evaluation of patients presenting with audiovestibular symptoms usually includes MRI of the internal auditory meatus, the cerebellopontine angle and the brain. A significant percentage of these scans will present unexpected, incidental findings, which could have important clinical significance. OBJECTIVE: To determine the frequency and clinical significance of incidental findings on MRI scans of patients with audiovestibular symptoms. MATERIALS AND METHODS: A retrospective analysis of 200 serial MRI scans. RESULTS: Gender distribution: equal. Age range: 17-82 years. One-hundred and four scans (52%) were normal and 1 scan (0.5%) demonstrated a unilateral vestibular schwannoma. Ninety-five scans (47.5%) demonstrated incidental findings. Sixty-six of these (33%) were considered of ishaemic origin and did not require further action. Five (2.5%) scans demonstrated significant findings which warranted appropriate referral; Two Gliomas (1%), 2 cases of extensive White Matter Lesions (1%), 1 lipoma (0.5%). The remaining scans demonstrated various other findings. CONCLUSION: Investigation of patients with audiovestibular symptoms with MRI scans revealed incidental findings in a significant percentage (47.5%). The majority of these findings were benign warranting no further action and only 2.5% required further referral. It is the responsibility of the referring Otolaryngologist to be aware of these findings, to be able to assess their significance, to inform the patient and if needed to refer for further evaluation.