aGvHD,   cGvHD

The role of butyrogenic bacteria after the onset of acute graft-versus-host disease (aGvHD)

Butyrate is a short chain fatty acid and represents a preferred energy source for the gut epithelium; it is also a histone deacetylase inhibitor and agonist for peroxisome proliferator-activated receptors. Butyrate is secreted by butyrogenic bacteria and its administration, in mice, after allogeneic hematopoietic cell transplant (allo-HCT) improved intestinal epithelial cells junctional integrity and decreased apoptosis and the severity of graft-versus-host disease (GvHD), suggesting that microbial metabolites can mitigate GvHD.1

In this paper, Jonathan L. Golob, Division of Infectious Diseases, Department of Medicine, University of Michigan, Ann Arbor, MI, and colleagues investigated the role of butyrogenic organisms in the development of steroid-refractory acute GvHD (SR-aGvHD), associated with high morbidity and mortality, or chronic GvHD (cGvHD) of the gut.Although butyrate has positive effects on the gut, its presence in the context of colitis inhibits healing of the murine gut.3 Thus, response to butyrate could be helpful or harmful in relation to the status of the colonic mucosa.

Study design and patients2

  • In a cohort of 210 allo-HCT recipients, 27 had severe aGvHD of the gut (stage ≥ 2) and of those, 4 had cGvHD and 11 had SR-aGvHD
  • Weekly stool specimens were collected from before transplant through day 100 post-transplant. DNA extraction and 16S rRNA gene amplicon sequencing were performed
  • For each stool specimen was determined the cumulative relative abundance of butyrogens
  • An in vitro differentiation model of the human colon was employed to assess the effect of butyrate on human colonic stem cells

Results2

  • An increased risk of developing SR-aGvHD (p<05) was observed in patients with increased relative abundance of butyrogenic bacteria in the gut microbiome within 21 days after the onset of severe aGvHD
  • The formation of tight junctions in the in vitro model of human colon cells is associated with epithelial differentiation. The presence of physiologic concentrations of butyrate at the start of epithelial differentiation impaired the formation of a tight epithelial barrier (p<05)

Conclusion

Butyrate is helpful in prevention of aGvHD1 but its presence after the onset of severe aGvHD of the gut affects the formation of a tight epithelial and impairs colonic mucosal recovery from aGvHD.2 Thus, once aGvHD has started, butyrogens may lead to increased risk for SR-aGvHD and potentially cGvHD.2 Therefore, microbiota-derived metabolites that are beneficial in health can lead to worsened outcomes after the onset of the disease. However, a butyrogen in the stool can be inactive and carefully preserved specimens are required to measure butyrate levels.

References
  1. Mathewson N.D. et al., Gut microbiome-derived metabolites modulate intestinal epithelial cell damage and mitigate graft-versus-host disease. Nat Immunol. 2016 Mar 21; 17(5):505–513. DOI: 10.1038/ni.3400
  2. Golob J.L. et al., Butyrogenic bacteria after acute graft-versus-host disease (GVHD) are associated with the development of steroid-refractory GVHD. Blood Adv. 2019 Oct 8; 3(19):2866–2869. DOI: 10.1182/bloodadvances.2019000362
  3. Kaiko G.E. et al. The colonic crypt protects stem cells from microbiota-derived metabolites. Cell. 2016 Jun 16; 165(7):1708–1720. DOI: 10.1016/j.cell.2016.05.018
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