Antibiotic treatment can deplete the commensal bacteria of a patient’s gut microbiota and, paradoxically, increase their risk of subsequent infections. In allogeneic hematopoietic stem cell transplantation (allo-HSCT), antibiotic administration is essential for optimal clinical outcomes but significantly disrupts intestinal microbiota diversity, leading to loss of many beneficial microbes. Although gut microbiota diversity loss during allo-HSCT is associated with increased mortality, approaches to reestablish depleted commensal bacteria have yet to be developed. We have initiated a randomized, controlled clinical trial of autologous fecal microbiota transplantation (auto-FMT) versus no intervention and have analyzed the intestinal microbiota profiles of 25 allo-HSCT patients (14 who received auto-FMT treatment and 11 control patients who did not). Changes in gut microbiota diversity and composition revealed that the auto-FMT intervention boosted microbial diversity and reestablished the intestinal microbiota composition that the patient had before antibiotic treatment and allo-HSCT. These results demonstrate the potential for fecal sample banking and posttreatment remediation of a patient’s gut microbiota after microbiota-depleting antibiotic treatment during allo-HSCT.

Highlights d Characterization of 273 human-derived Lachnospiraceae isolates d There is significant inter-and intra-species genomic diversity d Strain level differences may influence the development of therapeutic consortia

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Highlights d Infected Mo-DCs and neutrophils secrete CXCL9 and -10 through Dectin-1 and IFN signaling d CXCL9 and -10 promote the entry of circulating CXCR3 + pDCs into the lung d Lung-infiltrating CXCR3 + pDCs are essential for host defense against A. fumigatus d pDCs activate neutrophil NADPH oxidase activity to promote sterilizing immunity

Allogeneic hematopoietic cell transplantation (allo-HCT) induces profound shifts in the intestinal bacterial microbiota. The dynamics of intestinal fungi and their impact on clinical outcomes during allo-HCT are not fully understood. Here, we combined parallel high-throughput fungal ITS1 amplicon sequencing, bacterial 16S amplicon sequencing, and fungal cultures of 1279 fecal samples from a cohort of 156 allo-HCT patients to reveal potential trans-kingdom dynamics and their association with patient outcomes. We saw that the overall density and the biodiversity of intestinal fungi were stable during allo-HCT, but the species composition changed drastically from day to day. We identified a subset of patients with fungal dysbiosis defined by culture positivity (n=53) and stable expansion of Candida parapsilosis complex species (n=19). They presented with distinct trans-kingdom microbiota profiles, characterized by a decreased intestinal bacterial biomass. These patients had worse overall survival and higher transplant-related mortality independent of candidemia. This expands our understanding of the clinical significance of the mycobiota and suggests that targeting fungal dysbiosis may help to improve long-term patient survival.