Indoles derived from intestinal microbiota act via type I interferon signaling to limit graft-versus-host disease

Abstract

<jats:title>Abstract</jats:title> <jats:p>The intestinal microbiota in allogeneic bone marrow transplant (allo-BMT) recipients modulates graft-versus-host disease (GVHD), a systemic inflammatory state initiated by donor T cells that leads to colitis, a key determinant of GVHD severity. Indole or indole derivatives produced by tryptophan metabolism in the intestinal microbiota limit intestinal inflammation caused by diverse stressors, so we tested their capacity to protect against GVHD in murine major histocompatibility complex–mismatched models of allo-BMT. Indole effects were assessed by colonization of allo-BMT recipient mice with tryptophanase positive or negative strains of Escherichia coli, or, alternatively, by exogenous administration of indole-3-carboxaldehyde (ICA), an indole derivative. Treatment with ICA limited gut epithelial damage, reduced transepithelial bacterial translocation, and decreased inflammatory cytokine production, reducing GVHD pathology and GVHD mortality, but did not compromise donor T-cell-mediated graft-versus-leukemia responses. ICA treatment also led to recipient-strain-specific tolerance of engrafted T cells. Transcriptional profiling and gene ontology analysis indicated that ICA administration upregulated genes associated with the type I interferon (IFN1) response, which has been shown to protect against radiation-induced intestinal damage and reduce subsequent GVHD pathology. Accordingly, protective effects of ICA following radiation exposure were abrogated in mice lacking IFN1 signaling. Taken together, these data indicate that indole metabolites produced by the intestinal microbiota act via type I IFNs to limit intestinal inflammation and damage associated with myeloablative chemotherapy or radiation exposure and acute GVHD, but preserve antitumor responses, and may provide a therapeutic option for BMT patients at risk for GVHD.</jats:p>

Longitudinal relationship of amino acids and indole metabolites with long-term body mass index and cardiometabolic risk markers in young individuals

“…Other studies in adults that contrast our findings include lack of association of isoleucine 35 , lack of association of methionine and tryptophan 50 , and positive relation of isoleucine 51,52 with CRP. Although no study have reported an association between indole-3-carboxaldehyde and CRP; exogenous administration of indole-3-carboxaldehyde decreased the production of several inflammatory cytokines 53 . Consistent with our findings of several amino acids being related to CRP, a review concluded that several amino acids are involved in the development of future cardiometabolic abnormalities such as IR 54 .…”

Gut dysbiosis during antileukemia chemotherapy versus allogeneic hematopoietic cell transplantation

“…The intestinal microbiota plays a number of critical roles in the maintenance of homeostasis within the digestive tract. These include colonization resistance against potential pathogens and tonic stimulation to the intestinal epithelium, which facilitates recovery after gut injury . Suppression of the intestinal microbiota and disruptions in its microbial community structure have been associated with complications of intensive antileukemia chemotherapy and allogeneic hematopoietic cell transplantation (allo‐HCT), including infections, mortality, and graft‐versus‐host disease (GVHD) .…”

“…These include colonization resistance against potential pathogens 1 and tonic stimulation to the intestinal epithelium, which facilitates recovery after gut injury. 2,3 Suppression of the intestinal microbiota and disruptions in its microbial community structure have been associated with complications of intensive antileukemia chemotherapy and allogeneic hematopoietic cell transplantation (allo-HCT), including infections, 4,5 mortality, 6 and graft-versus-host disease (GVHD). 7 Because microbiome-directed interventions are beginning to emerge with the intent of improving the outcomes of curative-intent therapy, 8,9 it is important to systematically characterize dysbiosis with respect to the nature of the insults altering the microbiome.…”

Tyrosine Supplement Ameliorates Murine aGVHD by Modulation of Gut Microbiome and Metabolome

“…[43] Previous works usually focused on studying the impacts of microbiota on the metabolites, such like indole metabolites produced by the intestinal microbiota could limit gut epithelial damage and reduce subsequent GVHD pathology via type I interferons to. [44] In our study, we set a certain metabolite tyrosine as an affecting factor for the rst time. We found that a comparatively high content of tyrosine could attenuate aGVHD clinical manifestations and improve the overall metabolites belonging to tyrosine biosynthesis pathway.…”