A screen of Crohn's disease-associated microbial metabolites identifies ascorbate as a novel metabolic inhibitor of activated human T cells

Abstract

Microbial metabolites are an emerging class of mediators influencing CD4+ T cell function. To advance the understanding of direct causal microbial factors contributing to Crohn’s disease, we screened 139 predicted Crohn’s disease-associated microbial metabolites for their bioactivity on human CD4+ T cell functions induced by disease-associated T helper 17 (Th17) polarizing conditions. We observed 15 metabolites with CD4+ T cell bioactivity, 3 previously reported and 12 unprecedented. A deeper investigation of the microbe-derived metabolite, ascorbate, revealed its selective inhibition on activated human CD4+ effector T cells, including IL-17A-, IL-4-, and IFNγ-producing cells. Mechanistic assessment suggested the apoptosis of activated human CD4+ T cells associated with selective inhibition of energy metabolism. These findings suggest a substantial rate of relevant T cell bioactivity among Crohn’s disease-associated microbial metabolites, and evidence for novel modes of bioactivity, including targeting of T cell energy metabolism.

Strategies to Dissect Host-Microbial Immune Interactions That Determine Mucosal Homeostasis vs. Intestinal Inflammation in Gnotobiotic Mice

“…Bacterial metabolites mediate many of the protective functions of resident bacteria and are notably abnormal in the dysbiosis associated with IBD (51,52). Metabolites with known immunoprotective activities include the short chain fatty acids (SCFAs), butyrate and propionate, tryptophan metabolites, particularly indoles that serve as AhR ligands, sphingolipids and bile acid derivatives (49,50,(53)(54)(55)(56)(57)(58).…”

“…Metabolites with known immunoprotective activities include the short chain fatty acids (SCFAs), butyrate and propionate, tryptophan metabolites, particularly indoles that serve as AhR ligands, sphingolipids and bile acid derivatives (49,50,(53)(54)(55)(56)(57)(58). However, this is a rapidly developing field with new bacterial metabolites associated with IBD and yet unknown functions being frequently described (51,52,59). We provide several examples of how gnotobiotic mice can help dissect functions of two key immunoprotective bacterial metabolites, SCFA and indoles, since we discussed functional studies of sphingolipids in a previous section.…”

Microbial Strain Engraftment, Persistence and Replacement after Fecal Microbiota Transplantation

“…Besides taxonomic changes at the level of increased or decreased species relative abundances (Figure 6Cand Table S10), the MGH03D-associated microbiota was functionally characterized by the enrichment and depletion of genes from several metabolic pathways (Figure S5andTable S10). These included functions involved in host-microbe interactions (sialic acids biosynthesis; (Varki and Gagneux, 2012) ) and pathways that were previously associated with IBD, such as for the biosynthesis of biotin(Das et al, 2019) and ascorbate, which has been identified as a microbial metabolite in Crohn's disease patients with inhibitory effects on activated human CD4+ effector T cells(Chang et al, 2019) . Together, these functions are suggestive of a pro-inflammatory microbiota milieu that was transferred from MGH03D via FMT and prevented resolution of rCDI symptoms in some post-FMT patients.In summary, species and strain-level microbiota analysis indicates that failure to treat rCDI by FMT is associated with reduced donor-derived microbiota fractions in patients immediately after treatment; yet FMT from questionable donors can result in the adoption of atypical donor microbiota profiles in post-FMT patients, independently of treatment success, potentially inducing a pro-inflammatory microbiota milieu and failure to resolve rCDI symptoms, at least in some patients.…”

Demystifying the manipulation of host immunity, metabolism, and extraintestinal tumors by the gut microbiome

“…Similarly, ascorbate is considered a bioactive microbial metabolite related to CD and can induce T cell apoptosis by targeting the energy metabolism of activated effector CD4 + T cells. 212 In addition, circulating metabolites such as mevalonate and dimethylglycine, which are produced by a consortium of 11 rare bacteria (predominately Bacteroidetes) isolated from healthy individuals feces, seem to potentiate the systemic development of IFN-γ + CD8+ T cells, thereby combating the intracellular pathogen Listeria monocytogenes (L. monocytogenes) and enhancing ICI-mediated anti-tumor immunity in mice with melanoma. 43,213 This groundbreaking research has demonstrated that rare microbiome members potentially harbor profound effects on host immunity.…”