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Allogeneic Stem Cell Transplant Outcomes Improve With Diverse Gut Microbes, Immune Cells

NEW YORK – A team from Weill Cornell Medical College, Memorial Sloan Kettering Cancer Center, and elsewhere has demonstrated that interactions between the gut microbial community and the immune system can influence an individual's response to a bone marrow transplant to treat leukemia, lymphoma, multiple myeloma, and other blood conditions.

Past studies have suggested ties between microbial diversity and favorable allogeneic hematopoietic stem cell transplantation (allo-HCT) outcomes, or transplants involving stem cells from healthy donors. For their new study, the researchers set out to characterize fecal microbiome features alongside immune cell features and clinical outcomes in allo-HCT recipients — work they presented in Science Translational Medicine on Wednesday.

"Given that the recovering immune system is so important for optimal patient outcomes, we sought to answer the question: 'Is the microbiome linked with the recovering immune system in patients?'" co-senior and co-corresponding author Kate Markey, a researcher affiliated with Weill Cornell, MSK, Fred Hutchinson Cancer Research Center, and the University of Washington, explained in an email.

"We specifically focused on the immune populations that we know respond to products of the microbiome: a special family of T cells known as unconventional T cells," Markey added, noting that those T cells respond to a smaller set of specific antigens than the more flexible, "conventional" T cells.

Using targeted 16S ribosomal RNA sequencing on fecal samples, as well as flow cytometry-based immune cell profiling in peripheral blood samples, the team searched for outcome-related features in 174 allo-HCT recipients. The analyses pointed to an uptick in mucosal-associated invariant T (MAIT) immune cells in individuals with lower rates of acute graft-versus-host disease complications, better stem cell transplant outcomes, and increased survival times.

The current findings suggested that those MAIT cells, in turn, tended to be more common in individuals with diverse microbial communities in their gut. High blood levels of MAIT also appeared to correspond with enhanced levels of T cells from a subpopulation dubbed Vd2 cells, which also appeared to be linked to reduced graft-versus-host disease.

"Immune profiling of conventional and unconventional immune cell subsets revealed that the prevalence of Vd2 cells, the major circulating subpopulation of gamma-delta T cells, closely correlated with the frequency of MAIT cells and was associated with less [acute graft-versus-host disease]," the authors reported, adding that a "diverse intestinal microbiome with the capacity to produce activating ligands for MAIT and Vd2 cells appeared to be necessary for the maintenance of these populations after allo-HCT."

Prior research suggested that MAIT cells may interact with microbe-produced riboflavin pathway metabolites, while Vd2 T cells have their own suite of metabolite interactions.

Among other gut microbial ties, the team found that higher-than-usual MAIT levels in blood samples from the allo-HCT recipients tended to correspond with the presence of gut bugs from the Bacteroidetes phylum, while decreased blood levels of the T cells turned up in those with Firmicutes-rich gut microbiomes.

Along with metabolomic analyses on fecal samples from dozens of allo-HCT recipients with particularly high or low levels of T cells linked to good outcomes, the investigators turned to single-cell RNA sequencing experiments to profile MAIT and Vd2 T cells from five transplant recipients with favorable outcomes.

Somewhat unexpectedly, the seemingly protective MAIT and Vd2 cells had expression signatures that appeared pro-inflammatory rather than protective, Markey wrote, noting the signature the team uncovered would be expected to be "far from protective."

From these and other findings, they speculated that enhanced gut microbiome diversity or the presence of molecules produced by at least some of these microbes might offer an avenue for improving allo-HCT outcomes.

"There is a growing awareness in the transplant field that a healthy, diverse microbiome is linked with good outcome," Markey wrote. "Ways to prevent damage and restore a healthy microbiome are both going to be important and are the subject of active clinical trials now." She added that the hope is to be able to develop specific and precise microbiome-related therapies to improve patient outcomes.

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