Microbial metabolism of dietary components to bioactive metabolites: opportunities for new therapeutic interventions (original) (raw)

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 colonocytesInhibits HDAC [43, 53, 54, 102]Activates GPR41 and GPR43 [38, 39]Activates GPR109A [40]Suppresses nuclear NF-kB activation [40, 46, 47]Modulates PPAR-γ [59, 102]	Increased intestinal barrier function [52, 59]Anti-inflammatory [44, 46, 62, 103]Anti-lipogenic [41]Improves insulin sensitivity [41, 102, 103]Increases energy expenditure [41, 102]Anti-cancer [51, 61]
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-cancerAnti-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 substrateActivates GPR43 [57, 58] and GPR41 [38, 39]Activates AMPK pathway [34]	Anti-inflammatory [57, 58]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	CytotoxicProduces 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]Anti-oxidant [134, 135, 137]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]