The microbe-derived short-chain fatty acids butyrate and propionate are associated with protection from chronic GVHD

Abstract

<jats:title>Abstract</jats:title> <jats:p>Studies of the relationship between the gastrointestinal microbiota and outcomes in allogeneic hematopoietic stem cell transplantation (allo-HCT) have thus far largely focused on early complications, predominantly infection and acute graft-versus-host disease (GVHD). We examined the potential relationship of the microbiome with chronic GVHD (cGVHD) by analyzing stool and plasma samples collected late after allo-HCT using a case-control study design. We found lower circulating concentrations of the microbe-derived short-chain fatty acids (SCFAs) propionate and butyrate in day 100 plasma samples from patients who developed cGVHD, compared with those who remained free of this complication, in the initial case-control cohort of transplant patients and in a further cross-sectional cohort from an independent transplant center. An additional cross-sectional patient cohort from a third transplant center was analyzed; however, serum (rather than plasma) was available, and the differences in SCFAs observed in the plasma samples were not recapitulated. In sum, our findings from the primary case-control cohort and 1 of 2 cross-sectional cohorts explored suggest that the gastrointestinal microbiome may exert immunomodulatory effects in allo-HCT patients at least in part due to control of systemic concentrations of microbe-derived SCFAs.</jats:p>

Associations between the Gut Microbiota, Immune Reconstitution, and Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation

“…The mechanisms by which alterations in the GM impact immune reconstitution in humans is mostly speculative. Presence of microbialderived short chain fatty acids, such as butyrate, in serum of patients have recently been shown to be inversely associated with chronic GVHD;however, the effect of butyrate on Treg reconstitution in thus study was not shown[104]. We and others have shown bacteria capable of producing riboflavin metabolites are associated with MAIT cell recovery and decreased severity of GVHD, supporting existing empirical observations in mouse models[34,59,105].…”

An Unconventional View of T Cell Reconstitution After Allogeneic Hematopoietic Cell Transplantation

“…For example, butyrate, one of the short-chain fatty acids, has been associated with immunosuppressive effects and protection against GVHD in mouse models ( 34 , 35 ), and in human post-transplantation samples, lower fecal concentrations of acetate, butyrate and propionate were associated with more severe acute GVHD ( 36 ). In a recent study from our group, butyrate and propionate concentrations in plasma were decreased at day 100 post-HCT in the patients who went on to develop chronic GVHD, supporting the hypothesis that these molecules are potentially immunomodulatory ( 37 ). Bile acids are another subset of microbiota-derived molecules with immunomodulatory potential.…”

Compilation of longitudinal microbiota data and hospitalome from hematopoietic cell transplantation patients

“…We also provide computer code written in Matlab (The Mathworks Inc., version 2018a), which exemplifies how to analyze and extract insights from the curated data tables that compose this rich longitudinal dataset. We have used these data before in several publications in the past 10 years 3,[10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27] , in part or in whole, to design lab experiments with mice that identified mechanisms such as microbiota protection against vancomycin resistant Enterococcus 17 , the impact of dietary lactose on the expansion of Enterococcus in the gut 20 , the mechanisms of resistance to colonization by Clostridioides difficile 19 , and to find microbiome risk factors for Graft-versus-host disease (GVHD)-related mortality 20,21,28 . The data compiled here include >10,000 microbiota samples and clinical metadata from >1,000 patients.…”