| Metabolite . | Proposed Mechanism of Action . | Host Target . | Microbial Association . | Pediatric Considerations . | HCT Associations . | SOT Associations . |
|---|---|---|---|---|---|---|
| Arginine | Arginine and polyamine derivatives inhibit pro-inflammatory (M1) macrophage activation | Macrophages | Bifidobacterium, Ruminococcus, Streptococcus mutans | Increased arginine metabolites in adult HCT recipients who did not develop GVHD [54]; higher arginine biosynthesis gene abundance predicted lower risk of acute GVHD in pediatric HCT recipients [41] | ||
| Aryl hydrocarbon receptor ligands | Contextual, as T-cell ligands can result in the induction of FOXP3+ regulatory T cells; antigen-presenting cell ligands can increase IL-22 production | T and B cells, dendritic cells, macrophages, and mucosal cells | Widespread production | Diet influences ligand formation (eg, broccoli, parsley); potential for age-related variation | Metabolomic analysis of adult HCT recipients with acute GVHD showed decreased production of aryl hydrocarbon receptor ligands [54] | |
| Inosine (or degradation products xanthine and hypoxanthine) | Interacts with adenosine α-2A receptor to stimulate Th1 differentiation (when co-stimulation is present); may require reduced gut integrity to translocate systemically [104] | T cells | Bifidobacterium pseudolongum; Akkermansia muciniphila; Lactobacillus johnsonii | Inosine-producing bacteria may vary across age groups (more prevalent in infants) | Theoretical role in acute rejection among SOT recipients [65] | |
| Phenylacetylglutamine | Microbial phenylpyruvic acid production converted by host to phenylacetylglutamine which signals via α-2A, α-2B, and β2 adrenergic receptors and increases platelet adhesion and thrombus formation | Platelets | Widespread production by Bacteroides species and Clostridium asparagiforme | Diet plays a key role as is derived from phenylalanine-rich foods; potential for age-related variation | Theoretical role in vasculopathy during chronic organ rejection or transplant-associated thrombotic microangiopathy [65] | |
| Secondary bile acids | Promote regulatory T-cell induction by direct binding to RORγT to block Th17 differentiation, increasing mitochondrial reactive oxygen species production, or binding to farnesoid X receptor in dendritic cells to decrease immunostimulation | T cells or dendritic cells | Clostridium; Parabacteroides; Bacteroides dorei; Alistipes; Lachnospiraceae; Hungatella hathewayi; Odoribacter laneus | Low levels of secondary bile acids were observed during early infancy but stable high levels by 3 years of age [105] | Metabolomic analysis of adult HCT recipients with acute GVHD showed alterations in bile acids [54] | |
| Short-chain fatty acids | Promote peripheral regulatory T-cell generation, suppress Th17 generation, modulate macrophage function; butyrate may promote gut integrity | T cells, macrophages, intestinal epithelial cells | Widespread production | Children generally have higher abundances of bacteria that produce short-chain fatty acids in their microbiomes [41] | Mixed response: may protect against acute GVHD among adults [106], but also associated with risk of steroid-refractory acute GVHD [107]; linked to respiratory viral infections in adult HCT recipients [44] but not in pediatrics cohorts [41] | Loss of short-chain fatty acid producers associated with mycophenolate-induced enteropathy [108] |
| Sulfobactin B | Interacts with transcription factors (eg, NFκβ) and DNA polymerase inhibitor to decrease response of macrophages to damage-associated molecular pattern (DAMP) signaling | Macrophages | Alistipes, Odoribacter, Chryseobacterium | Potential role in graft survival in murine models [64] |
| Metabolite . | Proposed Mechanism of Action . | Host Target . | Microbial Association . | Pediatric Considerations . | HCT Associations . | SOT Associations . |
|---|---|---|---|---|---|---|
| Arginine | Arginine and polyamine derivatives inhibit pro-inflammatory (M1) macrophage activation | Macrophages | Bifidobacterium, Ruminococcus, Streptococcus mutans | Increased arginine metabolites in adult HCT recipients who did not develop GVHD [54]; higher arginine biosynthesis gene abundance predicted lower risk of acute GVHD in pediatric HCT recipients [41] | ||
| Aryl hydrocarbon receptor ligands | Contextual, as T-cell ligands can result in the induction of FOXP3+ regulatory T cells; antigen-presenting cell ligands can increase IL-22 production | T and B cells, dendritic cells, macrophages, and mucosal cells | Widespread production | Diet influences ligand formation (eg, broccoli, parsley); potential for age-related variation | Metabolomic analysis of adult HCT recipients with acute GVHD showed decreased production of aryl hydrocarbon receptor ligands [54] | |
| Inosine (or degradation products xanthine and hypoxanthine) | Interacts with adenosine α-2A receptor to stimulate Th1 differentiation (when co-stimulation is present); may require reduced gut integrity to translocate systemically [104] | T cells | Bifidobacterium pseudolongum; Akkermansia muciniphila; Lactobacillus johnsonii | Inosine-producing bacteria may vary across age groups (more prevalent in infants) | Theoretical role in acute rejection among SOT recipients [65] | |
| Phenylacetylglutamine | Microbial phenylpyruvic acid production converted by host to phenylacetylglutamine which signals via α-2A, α-2B, and β2 adrenergic receptors and increases platelet adhesion and thrombus formation | Platelets | Widespread production by Bacteroides species and Clostridium asparagiforme | Diet plays a key role as is derived from phenylalanine-rich foods; potential for age-related variation | Theoretical role in vasculopathy during chronic organ rejection or transplant-associated thrombotic microangiopathy [65] | |
| Secondary bile acids | Promote regulatory T-cell induction by direct binding to RORγT to block Th17 differentiation, increasing mitochondrial reactive oxygen species production, or binding to farnesoid X receptor in dendritic cells to decrease immunostimulation | T cells or dendritic cells | Clostridium; Parabacteroides; Bacteroides dorei; Alistipes; Lachnospiraceae; Hungatella hathewayi; Odoribacter laneus | Low levels of secondary bile acids were observed during early infancy but stable high levels by 3 years of age [105] | Metabolomic analysis of adult HCT recipients with acute GVHD showed alterations in bile acids [54] | |
| Short-chain fatty acids | Promote peripheral regulatory T-cell generation, suppress Th17 generation, modulate macrophage function; butyrate may promote gut integrity | T cells, macrophages, intestinal epithelial cells | Widespread production | Children generally have higher abundances of bacteria that produce short-chain fatty acids in their microbiomes [41] | Mixed response: may protect against acute GVHD among adults [106], but also associated with risk of steroid-refractory acute GVHD [107]; linked to respiratory viral infections in adult HCT recipients [44] but not in pediatrics cohorts [41] | Loss of short-chain fatty acid producers associated with mycophenolate-induced enteropathy [108] |
| Sulfobactin B | Interacts with transcription factors (eg, NFκβ) and DNA polymerase inhibitor to decrease response of macrophages to damage-associated molecular pattern (DAMP) signaling | Macrophages | Alistipes, Odoribacter, Chryseobacterium | Potential role in graft survival in murine models [64] |
GVHD, graft-versus-host disease; HCT, hematopoietic cell transplantation; SOT, solid organ transplantation.
| Metabolite . | Proposed Mechanism of Action . | Host Target . | Microbial Association . | Pediatric Considerations . | HCT Associations . | SOT Associations . |
|---|---|---|---|---|---|---|
| Arginine | Arginine and polyamine derivatives inhibit pro-inflammatory (M1) macrophage activation | Macrophages | Bifidobacterium, Ruminococcus, Streptococcus mutans | Increased arginine metabolites in adult HCT recipients who did not develop GVHD [54]; higher arginine biosynthesis gene abundance predicted lower risk of acute GVHD in pediatric HCT recipients [41] | ||
| Aryl hydrocarbon receptor ligands | Contextual, as T-cell ligands can result in the induction of FOXP3+ regulatory T cells; antigen-presenting cell ligands can increase IL-22 production | T and B cells, dendritic cells, macrophages, and mucosal cells | Widespread production | Diet influences ligand formation (eg, broccoli, parsley); potential for age-related variation | Metabolomic analysis of adult HCT recipients with acute GVHD showed decreased production of aryl hydrocarbon receptor ligands [54] | |
| Inosine (or degradation products xanthine and hypoxanthine) | Interacts with adenosine α-2A receptor to stimulate Th1 differentiation (when co-stimulation is present); may require reduced gut integrity to translocate systemically [104] | T cells | Bifidobacterium pseudolongum; Akkermansia muciniphila; Lactobacillus johnsonii | Inosine-producing bacteria may vary across age groups (more prevalent in infants) | Theoretical role in acute rejection among SOT recipients [65] | |
| Phenylacetylglutamine | Microbial phenylpyruvic acid production converted by host to phenylacetylglutamine which signals via α-2A, α-2B, and β2 adrenergic receptors and increases platelet adhesion and thrombus formation | Platelets | Widespread production by Bacteroides species and Clostridium asparagiforme | Diet plays a key role as is derived from phenylalanine-rich foods; potential for age-related variation | Theoretical role in vasculopathy during chronic organ rejection or transplant-associated thrombotic microangiopathy [65] | |
| Secondary bile acids | Promote regulatory T-cell induction by direct binding to RORγT to block Th17 differentiation, increasing mitochondrial reactive oxygen species production, or binding to farnesoid X receptor in dendritic cells to decrease immunostimulation | T cells or dendritic cells | Clostridium; Parabacteroides; Bacteroides dorei; Alistipes; Lachnospiraceae; Hungatella hathewayi; Odoribacter laneus | Low levels of secondary bile acids were observed during early infancy but stable high levels by 3 years of age [105] | Metabolomic analysis of adult HCT recipients with acute GVHD showed alterations in bile acids [54] | |
| Short-chain fatty acids | Promote peripheral regulatory T-cell generation, suppress Th17 generation, modulate macrophage function; butyrate may promote gut integrity | T cells, macrophages, intestinal epithelial cells | Widespread production | Children generally have higher abundances of bacteria that produce short-chain fatty acids in their microbiomes [41] | Mixed response: may protect against acute GVHD among adults [106], but also associated with risk of steroid-refractory acute GVHD [107]; linked to respiratory viral infections in adult HCT recipients [44] but not in pediatrics cohorts [41] | Loss of short-chain fatty acid producers associated with mycophenolate-induced enteropathy [108] |
| Sulfobactin B | Interacts with transcription factors (eg, NFκβ) and DNA polymerase inhibitor to decrease response of macrophages to damage-associated molecular pattern (DAMP) signaling | Macrophages | Alistipes, Odoribacter, Chryseobacterium | Potential role in graft survival in murine models [64] |
| Metabolite . | Proposed Mechanism of Action . | Host Target . | Microbial Association . | Pediatric Considerations . | HCT Associations . | SOT Associations . |
|---|---|---|---|---|---|---|
| Arginine | Arginine and polyamine derivatives inhibit pro-inflammatory (M1) macrophage activation | Macrophages | Bifidobacterium, Ruminococcus, Streptococcus mutans | Increased arginine metabolites in adult HCT recipients who did not develop GVHD [54]; higher arginine biosynthesis gene abundance predicted lower risk of acute GVHD in pediatric HCT recipients [41] | ||
| Aryl hydrocarbon receptor ligands | Contextual, as T-cell ligands can result in the induction of FOXP3+ regulatory T cells; antigen-presenting cell ligands can increase IL-22 production | T and B cells, dendritic cells, macrophages, and mucosal cells | Widespread production | Diet influences ligand formation (eg, broccoli, parsley); potential for age-related variation | Metabolomic analysis of adult HCT recipients with acute GVHD showed decreased production of aryl hydrocarbon receptor ligands [54] | |
| Inosine (or degradation products xanthine and hypoxanthine) | Interacts with adenosine α-2A receptor to stimulate Th1 differentiation (when co-stimulation is present); may require reduced gut integrity to translocate systemically [104] | T cells | Bifidobacterium pseudolongum; Akkermansia muciniphila; Lactobacillus johnsonii | Inosine-producing bacteria may vary across age groups (more prevalent in infants) | Theoretical role in acute rejection among SOT recipients [65] | |
| Phenylacetylglutamine | Microbial phenylpyruvic acid production converted by host to phenylacetylglutamine which signals via α-2A, α-2B, and β2 adrenergic receptors and increases platelet adhesion and thrombus formation | Platelets | Widespread production by Bacteroides species and Clostridium asparagiforme | Diet plays a key role as is derived from phenylalanine-rich foods; potential for age-related variation | Theoretical role in vasculopathy during chronic organ rejection or transplant-associated thrombotic microangiopathy [65] | |
| Secondary bile acids | Promote regulatory T-cell induction by direct binding to RORγT to block Th17 differentiation, increasing mitochondrial reactive oxygen species production, or binding to farnesoid X receptor in dendritic cells to decrease immunostimulation | T cells or dendritic cells | Clostridium; Parabacteroides; Bacteroides dorei; Alistipes; Lachnospiraceae; Hungatella hathewayi; Odoribacter laneus | Low levels of secondary bile acids were observed during early infancy but stable high levels by 3 years of age [105] | Metabolomic analysis of adult HCT recipients with acute GVHD showed alterations in bile acids [54] | |
| Short-chain fatty acids | Promote peripheral regulatory T-cell generation, suppress Th17 generation, modulate macrophage function; butyrate may promote gut integrity | T cells, macrophages, intestinal epithelial cells | Widespread production | Children generally have higher abundances of bacteria that produce short-chain fatty acids in their microbiomes [41] | Mixed response: may protect against acute GVHD among adults [106], but also associated with risk of steroid-refractory acute GVHD [107]; linked to respiratory viral infections in adult HCT recipients [44] but not in pediatrics cohorts [41] | Loss of short-chain fatty acid producers associated with mycophenolate-induced enteropathy [108] |
| Sulfobactin B | Interacts with transcription factors (eg, NFκβ) and DNA polymerase inhibitor to decrease response of macrophages to damage-associated molecular pattern (DAMP) signaling | Macrophages | Alistipes, Odoribacter, Chryseobacterium | Potential role in graft survival in murine models [64] |
GVHD, graft-versus-host disease; HCT, hematopoietic cell transplantation; SOT, solid organ transplantation.
This PDF is available to Subscribers Only
View Article Abstract & Purchase OptionsFor full access to this pdf, sign in to an existing account, or purchase an annual subscription.
