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Previous studies have shown that the gut microbiota of patients with acute myeloid leukemia (AML) is disrupted during induction chemotherapy; however, the durability of microbiota changes is unknown. This is an important knowledge gap, because reduced microbiota diversity at the time of stem cell transplantation weeks to months after the initial chemotherapy has been associated with higher mortality after transplantation. By sequencing the gut microbiota in 410 longitudinal stool samples from 52 patients with AML, we found that, during inpatient chemotherapy, the gut microbiota is stressed beyond its ability to recover its original state. Despite major reductions in antibiotic pressure and other disturbances to the microbiota after hospital discharge, the trajectory of microbiota recovery yields new communities that are highly dissimilar to baseline. This lasting shift in the gut microbiota is relevant for subsequent phases of curative therapy and is a potential target for novel microbiota protective/restorative interventions. This trial was registered at www.clinicaltrials.gov as #NCT03316456.

Background Neutropenic fever (NF) occurs in >70% of hematopoietic cell transplant (HCT) recipients, without a documented cause in most cases. Antibiotics used to prevent and treat NF disrupt the gut microbiota; these disruptions predict a higher posttransplantation mortality rate. We hypothesized that specific features in the gut microbial community may mediate the risk of NF. Methods We searched a large gut microbiota database in allogeneic HCT recipients (12 546 stool samples; 1278 patients) to find pairs with NF (cases) versus without NF (controls) on the same day relative to transplantation and with a stool sample on the previous day. A total of 179 such pairs were matched as to the underlying disease and graft source. Several other important clinical variables were similar between the groups. Results The gut microbiota of cases on the day before NF occurrence had a lower abundance of Blautia than their matched controls on the same day after transplantation, suggesting a protective role for Blautia. Microbiota network analysis did not find any differences in community structure between the groups, suggesting a single-taxon effect. To identify putative mechanisms, we searched a gut microbiome and serum metabolome database of patients with acute leukemia receiving chemotherapy and identified 139 serum samples collected within 24 hours after a stool sample from the same patient. Greater Blautia abundances predicted higher levels of next-day citrulline, a biomarker of total enterocyte mass. Conclusions These findings support a model in which Blautia protects against NF by improving intestinal health. Therapeutic restoration of Blautia may help prevent NF, thus reducing antibiotic exposures and transplantation-related deaths.

Despite antibiotic prophylaxis, most patients with acute leukemia receiving mucotoxic chemotherapy develop neutropenic fever (NF), many cases of which remain without a documented etiology. Antibiotics disrupt the gut microbiota, with adverse clinical consequences, such as Clostridioides difficile infection. A better understanding of NF pathogenesis could inform the development of novel therapeutics without deleterious effects on the microbiota. We hypothesized that metabolites absorbed from the gut to the bloodstream modulate pyrogenic and inflammatory pathways. Longitudinal profiling of the gut microbiota in 2 cohorts of patients with acute leukemia showed that Akkermansia expansion in the gut was associated with an increased risk for NF. As a prototype mucolytic genus, Akkermansia may influence the absorption of luminal metabolites; thus, its association with NF supported our metabolomics hypothesis. Longitudinal profiling of the serum metabolome identified a signature associated with gut Akkermansia and 1 with NF. Importantly, these 2 signatures overlapped in metabolites in the γ-glutamyl cycle, suggesting oxidative stress as a mediator involved in Akkermansia-related NF. In addition, the level of gut microbial–derived indole compounds increased after Akkermansia expansion and decreased before NF, suggesting their role in mediating the anti-inflammatory effects of Akkermansia, as seen predominantly in healthy individuals. These results suggest that Akkermansia regulates microbiota-host metabolic cross talk by modulating the mucosal interface. The clinical context, including factors influencing microbiota composition, determines the type of metabolites absorbed through the gut barrier and their net effect on the host. Our findings identify novel aspects of NF pathogenesis that could be targets for precision therapeutics. This trial was registered at www.clinicaltrials.gov as #NCT03316456.

Neutropenic fever (NF) is a common complication of chemotherapy in patients with cancer which often prolongs hospitalization and worsens the quality of life. Although an empiric antimicrobial approach is used to prevent and treat NF, a clear etiology cannot be found in most cases. Emerging data suggest an altered microbiota-host crosstalk leading to NF. We profiled the serum metabolome and gut microbiome in longitudinal samples before and after NF in patients with acute myeloid leukemia, a prototype setting with a high incidence of NF. We identified a circulating metabolomic shift after NF, with a minimal signature containing 18 metabolites, 13 of which were associated with the gut microbiota. Among these metabolites were markers of intestinal epithelial health and bacterial metabolites of dietary tryptophan with known anti-inflammatory and gut-protective effects. The level of these metabolites decreased after NF, in parallel with biologically consistent changes in the abundance of mucolytic and butyrogenic bacteria with known effects on the intestinal epithelium. Together, our findings indicate a metabolomic shift with NF which is primarily characterized by a loss of microbiota-derived protective metabolites rather than an increase in detrimental metabolites. This analysis suggests that the current antimicrobial approach to NF may need a revision to protect the commensal microbiota.

Induction chemotherapy for patients with acute myeloid leukemia (AML) is a unique clinical scenario. These patients spend several weeks in the hospital, receiving multiple antibiotics, experiencing gastrointestinal mucosal damage, and suffering severe impairments in their immune system and nutrition. These factors cause major disruptions to the gut microbiota to a level rarely seen in other clinical conditions. Thus, the study of the gut microbiota in these patients can reveal novel aspects of microbiota-host relationships. When combined with the circulating metabolome, such studies could shed light on gut microbiota contribution to circulating metabolites. Collectively, gut microbiota and circulating metabolome are known to regulate host physiology. We have previously deposited amplicon sequences from 566 fecal samples from 68 AML patients. Here, we provide sample-level details and a link, using de-identified patient IDs, to additional data including serum metabolomics (260 samples from 36 patients) and clinical metadata. The detailed information provided enables comprehensive multi-omics analysis. We validate the technical quality of these data through 3 examples and demonstrate a method for integrated analysis.

Background The magnitude of microbiota perturbations after exposure to antibiotics varies among individuals. It has been suggested that the composition of pre-treatment microbiota underpins personalized responses to antibiotics. However, this hypothesis has not been directly tested in humans. In this high-throughput amplicon study, we analyzed 16S ribosomal RNA gene sequences of 260 stool samples collected twice weekly from 39 patients with acute leukemia during their ~ 4 weeks of hospitalization for chemotherapy while they received multiple antibiotics. Results Despite heavy and sustained antibiotic pressure, microbial communities in samples from the same patient remained more similar to one another than to those from other patients. Principal component mixed effect regression using microbiota and granular antibiotic exposure data showed that microbiota departures from baseline depend on the composition of the pre-treatment microbiota. Penalized generalized estimating equations identified 6 taxa within pre-treatment microbiota that predicted the extent of antibiotic-induced perturbations. Conclusions Our results indicate that specific species in pre-treatment microbiota determine personalized microbiota responses to antibiotics in humans. Thus, precision interventions targeting pre-treatment microbiota may prevent antibiotic-induced dysbiosis and its adverse clinical consequences.

COVID-19 precautions decrease social connectedness. It has been proposed that these measures alter the gut microbiota, with potential clinical consequences. We tested this hypothesis in patients with acute myeloid leukemia (AML) receiving inpatient chemotherapy, a population with extensive exposure to the nosocomial setting and at high risk for infections. Hospitalized patients with AML contributed stool samples to a biorepository protocol that was initiated before COVID-19 and continued without change through the pandemic. Patient-, disease-, and treatment-related characteristics remained the same in the two eras and the only change in clinical care was the implementation of COVID-19 precautions in March 2020. The incidence of all-cause nosocomial infections during the pandemic was lower than in the pre-COVID-19 era. Multivariable analysis revealed an imprint of COVID-19 precautions in the gut microbiota as a viable mechanistic explanation. In conclusion, COVID-19 precautions alter the gut microbiota, thereby mediating pathogen susceptibility and nosocomial infections.