Table 2 Microbial metabolites: their synthesis, mechanisms of action, and effects on health and disease
(Co-) Metabolites | Microbial phyla/species | Molecular targets | Effects on health & disease |
|---|---|---|---|
Butyrate
Synthesized predominantly via butyryl-CoA:acetate CoA transferase pathway [37] | Bacteriodes Ruminococcaceae Lachnospiraceae | Energy source for colonocytes Inhibits HDAC [43, 53, 54, 102] Activates GPR41 and GPR43 [38, 39] Activates GPR109A [40] | Increased intestinal barrier function [52, 59] Anti-inflammatory [44, 46, 62, 103] Anti-lipogenic [41] Improves insulin sensitivity [41, 102, 103] |
Propionate
Synthesized predominantly via succinate pathway [36] | Propionibacterium Bacteroides Negativicutes, Selenomonas ruminantium, Roseburia inulinivorans Escherichia coli | Activates GPR41 [89] and GPR43 [38, 39] Upregulates GLP-1, PYY, leptin [34] Increases oxidative stress, alters phospholipid composition, induces inflammation in the brain [179] | Anti-inflammatory [56] Anti-cancer Anti-lipogenic [41] Improves insulin sensitivity [41] Increases energy expenditure [41] Increases satiety [104] Associated with autistic spectrum disorder [179] |
Acetate
Synthesized directly from acetyl-CoA or from CO2 via the Wood-Ljungdahl pathway [34] | Most anaerobic gut bacteria studied produce acetate | Energy substrate Activates GPR43 [57, 58] and GPR41 [38, 39] Activates AMPK pathway [34] | Anti-lipogenic [41] Improves insulin sensitivity [41] Increases energy expenditure [41] Reduces glycemia in diabetic rodent models [34] Protects against asthma [90] |
TMA
Cleavage from choline via CutC & CutD [108] and from L-carnitine via YeaW & YeaX or CntA & CntB [111] | Desulfovibrio Proteus mirabilis Ruminococcus Akkermansia muciniphilia | TAAR5 [118] Potentially others | Excessive levels lead to fish malodor syndrome |
TMAO
Oxidized from TMA by FMO3 in liver [120] | Osmolyte [116] Mechanisms remains unknown | Accelerates atherosclerosis [15, 112, 115] Contributes to kidney dysfunction and chronic kidney disease [116] | |
Indole
Synthesized from tryptophan via tryptophanase | Lactobacillus Bifidobacterium longum Bacteroides fragilis, Parabacteroides distasonis Clostridium bartlettii E. hallii | Activates AhR [125] Modulates GLP-1 secretion [131] | Maintains host-microbe homeostasis at mucosal surface [125–127] Signals with intestinal L cells to influence host metabolism [131] |
Indole sulfate
Hepatic sulfonation from indole | Cytotoxic Produces free radicals [142] Stimulates endothelial release of microparticles [140] Enhances monocyte adhesion to vascular endothelium [141] | Induces renal and vascular dysfunction [139–141] Associated with chronic kidney disease [138] Associated with cardiovascular disease [141] | |
Indole-3-aldehyde
Synthesized from tryptophan via unidentified enzymes | Lactobacillus | Activates AhR resulting in IL-22 production [125] | Maintains host-microbe homeostasis at mucosal surface [125] |
IPA
Synthesized from tryptophan | Clostridium sporogenes | Activates PXR [132] Scavenges hydroxyl radicals [134] Reduces DNA damage and lipid peroxidation in neurons [135] Inhibits beta-amyloid fibril formation [134] | Maintains intestinal barrier function and mucosal homeostasis [132] Protects against ischemia-induced neuronal damage [134] Potential therapy for Alzheimer’s disease [134] |
PCS
Hepatic sulfination of p-cresol, which is synthesized from tyrosine by hydroxyphenylacete decarboxylase [144] | Clostridium difficile | Damages cell membranes [154] Induces apoptosis [155] Activates NADPH oxidase [156] Activates JNK and p38-MAPK [157] Activates Rho-K [158] Activate EGF receptor [159] | Accumulates in and predicts chronic kidney disease [146–149] |
EPS
Hepatic sulfination of 4-ethylphenol, potentially from paracoumaric acid via decarboxylase and vinyl phenol reductase or from genistein | Produced by unknown commensal bacteria | No specific molecular targets identified but assumed to be similar to para-cresol sulfate | Associated with autistic spectrum disorder [28] Potential uremic toxin [153] |
HYA
Derived from linoleic acid via linoleate isomerase activity [169] | Lactobacillus plantarum | Activates GPR40 [176] Activates Nrf2 [175] | Maintains intestinal barrier [176] Anti-inflammatory [175] |
CLA
CLnA
Derived from linoleic acid via linoleate isomerase activity [169] | Lachnospiraceae Lactobacillus Bifidobacteria Faecalibacterium prausnitzii Propionibacterium | Modulates PPARγ [171] Activates PPARα [172] Inhibits cyclooxygenase and lipoxygenase [173, 174] Modulates cytokine production and T-cell responses [180] | Reduces adiposity [170] Improves insulin sensitivity [170] Anti-cancer [170] Reduces atherosclerosis [170] Anti-inflammatory [170] |
