Microbiota-Derived Tryptophan Metabolite Indole-3-Propionic Acid-Emerging Role in Neuroprotection
Abstract
1. Introduction
2. IPA Synthesis and Tissue Levels
3. Targets of IPA
3.1. Aryl Hydrocarbon Receptor
3.2. Pregnane X Receptor
3.3. Free Radical Scavenging
3.4. Anti-Inflammatory Properties
3.5. KYNA
4. IPA and Neurodegeneration
4.1. Alzheimer’s Disease (AD)
4.2. Parkinson’s Disease (PD)
4.3. Hypoxia/Ischemia
4.4. Other Disorders
5. Conclusions
Future Directions
Author Contributions
Funding
Institutional Review Board Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
3-HK | 3-hydroxykynurenine |
ABG-001 | tetradecyl 2,3-dihydroxybenzoate |
acdA | acyl-coenzyme A dehydrogenase |
AChE | acetylcholinesterase |
ACSBG1 | acyl-CoA synthetase, bubblegum family, member 1 gene |
AD | Alzheimer’s disease |
ADRA2B | adrenoceptor alpha 2B |
AhR | aryl hydrocarbon receptor |
Apo-E4 | apolipoprotein E4 |
APP | amyloid-beta precursor protein |
ArAT | aromatic amino acid aminotransferase |
Aβ | β-amyloid |
BBB | blood–brain barrier |
BChE | butyrylcholinesterase |
BDNF: | brain-derived neurotrophic factor |
CSF | cerebrospinal fluid |
CYP1A1 | cytochrome P450, family 1, subfamily A, polypeptide 1 |
CYP3A | cytochrome P450, family 3, subfamily A |
EC50 | half maximal effective concentration |
ECM | extracellular matrix |
EDSS | Expanded Disability Status Scale |
fldBC | phenyllactate dehydratase BC |
FOXO3a | forkhead box O3 |
GPR | G-protein-coupled receptor |
HCAR3 | hydroxycarboxylic acid receptor 3 |
HD | Huntington’s disease |
HK2 | hexokinase 2 |
Hsc70 | heat shock cognate 70 kDa protein |
IA | indoleacrylic acid |
IAA | indole-3-acetic acid |
IDO1 | indoleamine 2,3-dioxygenase 1 |
IFN-γ | interferon gamma |
IL-1β/4/6/10 | interleukin 1β/4/6/10 |
IL4I1 | interleukin 4-induced 1 |
ILA | indolelactic acid |
ILDH | indole-lactate dehydrogenase |
iNOS | inducible nitric oxide synthase |
IPA | indole-3-propionic acid |
IPAM | indolepropionamide |
iPROACT-pilot | Indole-3-PROpionic Acid Clinical Trials-a Pilot Study |
IPyA | indole-3-pyruvic acid |
JAK1/2 | Janus kinase 1/2 |
KATs | kynurenine aminotransferases |
KMO | kynurenine 3-monooxygenase |
KP | kynurenine pathway |
KYNA | kynurenic acid |
LC3 | light chain 3 |
LPS | lipopolysaccharide |
MAO | monoamino-oxidase |
MCAO | middle cerebral artery occlusion |
MCP-1/CCL2 | monocyte chemoattractant protein-1 |
MMP | matrix metalloproteinase; |
NAD | nicotinamide adenine dinucleotide |
NF-κB | nuclear factor kappa-light-chain-enhancer of activated B cells |
NGF | nerve growth factor |
NLRP3 | NLR family pyrin domain containing 3 |
NMDA | N-methyl-D-aspartate type |
NR1I2 | nuclear receptor subfamily 1 group I member 2 gene |
Oatp1a4 | organic anion-transporting polypeptide 1a4 |
PD | Parkinson’s disease |
PKM2 | pyruvate kinase muscle isozyme |
PPARα | peroxisome proliferator-activated receptor α |
PXR | pregnane X receptor |
QUIN | quinolinic acid |
RAGE | receptor for advanced glycation end-products |
ROS | reactive oxygen species |
SCD2/3 | stearoyl-CoA desaturase 2/3 gene |
SIRT1 | sirtuin 1 |
STAT3/6 | signal transducer and activator of transcription 3/6 |
TAA | Trp aminotransferase |
TDO | tryptophan 2,3-dioxygenase |
TGF-1 | transforming growth factor β1 |
Th17 | T helper 17 cells |
TIARSCeD | Tryptophan for Impaired AhR Signaling in Celiac Disease |
TLRs | Toll-like receptors |
TNF-α | tumor necrosis factor-α |
Treg | regulatory T cells |
Trp | tryptophan |
α7nAChR | α-7 nicotinic acetylcholine receptor |
References
- Negatu, D.A.; Gengenbacher, M.; Dartois, V.; Dick, T. Indole Propionic Acid, an Unusual Antibiotic Produced by the Gut Microbiota, with Anti-inflammatory and Antioxidant Properties. Front. Microbiol. 2020, 11, 575586. [Google Scholar] [CrossRef]
- Pappolla, M.A.; Perry, G.; Fang, X.; Zagorski, M.; Sambamurti, K.; Poeggeler, B. Indoles as essential mediators in the gut-brain axis. Their role in Alzheimer’s disease. Neurobiol. Dis. 2021, 156, 105403. [Google Scholar] [CrossRef]
- Konopelski, P.; Mogilnicka, I. Biological Effects of Indole-3-Propionic Acid, a Gut Microbiota-Derived Metabolite, and Its Precursor Tryptophan in Mammals’ Health and Disease. Int. J. Mol. Sci. 2022, 23, 1222. [Google Scholar] [CrossRef]
- Wang, Z.; Yang, S.; Liu, L.; Mao, A.; Kan, H.; Yu, F.; Ma, X.; Feng, L.; Zhou, T. The gut microbiota-derived metabolite indole-3-propionic acid enhances leptin sensitivity by targeting STAT3 against diet-induced obesity. Clin. Transl. Med. 2024, 14, e70053. [Google Scholar] [CrossRef] [PubMed]
- Zhang, L.S.; Davies, S.S. Microbial metabolism of dietary components to bioactive metabolites: Opportunities for new therapeutic interventions. Genome Med. 2016, 8, 46. [Google Scholar] [CrossRef]
- Gao, K.; Mu, C.L.; Farzi, A.; Zhu, W.Y. Tryptophan Metabolism: A Link Between the Gut Microbiota and Brain. Adv. Nutr. 2020, 11, 709–723. [Google Scholar] [CrossRef]
- Pavlova, T.; Vidova, V.; Bienertova-Vasku, J.; Janku, P.; Almasi, M.; Klanova, J.; Spacil, Z. Urinary intermediates of tryptophan as indicators of the gut microbial metabolism. Anal. Chim. Acta 2017, 987, 72–80. [Google Scholar] [CrossRef] [PubMed]
- Alexeev, E.E.; Lanis, J.M.; Kao, D.J.; Campbell, E.L.; Kelly, C.J.; Battista, K.D.; Gerich, M.E.; Jenkins, B.R.; Walk, S.T.; Kominsky, D.J.; et al. Microbiota-Derived Indole Metabolites Promote Human and Murine Intestinal Homeostasis through Regulation of Interleukin-10 Receptor. Am. J. Pathol. 2018, 188, 1183–1194. [Google Scholar] [CrossRef]
- Zhang, B.; Jiang, M.; Zhao, J.; Song, Y.; Du, W.; Shi, J. The Mechanism Underlying the Influence of Indole-3-Propionic Acid: A Relevance to Metabolic Disorders. Front. Endocrinol. 2022, 13, 841703. [Google Scholar] [CrossRef] [PubMed]
- Jiang, H.; Chen, C.; Gao, J. Extensive Summary of the Important Roles of Indole Propionic Acid, a Gut Microbial Metabolite in Host Health and Disease. Nutrients 2022, 15, 151. [Google Scholar] [CrossRef]
- Pan, Y.; Li, Y.; Peng, Z.; Zhang, X.; Ye, S.; Chen, N.; Zhang, Z.; Yang, W. Indole derivatives and their associated microbial genera are associated with the 1-year changes in cardiometabolic risk markers in Chinese adults. Nutr. J. 2024, 23, 160. [Google Scholar] [CrossRef] [PubMed]
- Dodd, D.; Spitzer, M.H.; Van Treuren, W.; Merrill, B.D.; Hryckowian, A.J.; Higginbottom, S.K.; Le, A.; Cowan, T.M.; Nolan, G.P.; Fischbach, M.A.; et al. A gut bacterial pathway metabolizes aromatic amino acids into nine circulating metabolites. Nature 2017, 551, 648–652. [Google Scholar] [CrossRef]
- Roager, H.M.; Licht, T.R. Microbial tryptophan catabolites in health and disease. Nat. Commun. 2018, 9, 3294. [Google Scholar] [CrossRef]
- Young, S.N.; Anderson, G.M.; Gauthier, S.; Purdy, W.C. The origin of indoleacetic acid and indolepropionic acid in rat and human cerebrospinal fluid. J. Neurochem. 1980, 34, 1087–1092. [Google Scholar] [CrossRef]
- Cheetham, R.D.; Mikloiche, C.; Glubiak, M.; Weathers, P. Micropropagation of a recalcitrant male asparagus clone (MD 22-8). Plant Cell Tissue Organ Cult. 1992, 31, 15–19. [Google Scholar] [CrossRef]
- Menni, C.; Hernandez, M.M.; Vital, M.; Mohney, R.P.; Spector, T.D.; Valdes, A.M. Circulating levels of the anti-oxidant indoleproprionic acid are associated with higher gut microbiome diversity. Gut. Microbes. 2019, 10, 688–695. [Google Scholar] [CrossRef]
- da Silva, T.R.; Marchesan, L.B.; Rampelotto, P.H.; Longo, L.; de Oliveira, T.F.; Landberg, R.; de Mello, V.; Spritzer, P.M. Gut microbiota and gut-derived metabolites are altered and associated with dietary intake in women with polycystic ovary syndrome. J. Ovarian Res. 2024, 17, 232. [Google Scholar] [CrossRef] [PubMed]
- Zhu, C.; Sawrey-Kubicek, L.; Beals, E.; Rhodes, C.H.; Houts, H.E.; Sacchi, R.; Zivkovic, A.M. Human gut microbiome composition and tryptophan metabolites were changed differently by fast food and Mediterranean diet in 4 days: A pilot study. Nutr. Res. 2020, 77, 62–72. [Google Scholar] [CrossRef]
- de Mello, V.D.; Paananen, J.; Lindström, J.; Lankinen, M.A.; Shi, L.; Kuusisto, J.; Pihlajamäki, J.; Auriola, S.; Lehtonen, M.; Rolandsson, O.; et al. Indolepropionic acid and novel lipid metabolites are associated with a lower risk of type 2 diabetes in the Finnish Diabetes Prevention Study. Sci. Rep. 2017, 7, 46337. [Google Scholar] [CrossRef] [PubMed]
- Huc, T.; Konop, M.; Onyszkiewicz, M.; Podsadni, P.; Szczepańska, A.; Turło, J.; Ufnal, M. Colonic indole, gut bacteria metabolite of tryptophan, increases portal blood pressure in rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2018, 315, R646–R655. [Google Scholar] [CrossRef]
- Pan, C.; Wang, J.; Mao, Z.; Jiang, X.; Xu, Y.; Zhang, Y.; Chen, L.; Zhang, Z.Y.; Wang, X. Tryptophan-Rich Diet Improves High-Fat Diet-Induced Cognitive Dysfunction and Blood-Brain Barrier Disruption in C57BL/6 Mice through FFAR3 Activation. J. Agric. Food Chem. 2025, 73, 17696–17712. [Google Scholar] [CrossRef]
- Wikoff, W.R.; Anfora, A.T.; Liu, J.; Schultz, P.G.; Lesley, S.A.; Peters, E.C.; Siuzdak, G. Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites. Proc. Natl. Acad. Sci. USA 2009, 106, 3698–3703. [Google Scholar] [CrossRef]
- Anderson, G.M. The quantitative determination of indolic microbial tryptophan metabolites in human and rodent samples: A systematic review. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 2021, 1186, 123008. [Google Scholar] [CrossRef] [PubMed]
- Konopelski, P.; Konop, M.; Gawrys-Kopczynska, M.; Podsadni, P.; Szczepanska, A.; Ufnal, M. Indole-3-Propionic Acid, a Tryptophan-Derived Bacterial Metabolite, Reduces Weight Gain in Rats. Nutrients 2019, 11, 591. [Google Scholar] [CrossRef]
- Rosas, H.D.; Doros, G.; Bhasin, S.; Thomas, B.; Gevorkian, S.; Malarick, K.; Matson, W.; Hersch, S.M. A systems-level “misunderstanding”: The plasma metabolome in Huntington’s disease. Ann. Clin. Transl. Neurol. 2015, 2, 756–768. [Google Scholar] [CrossRef] [PubMed]
- Tuomainen, M.; Lindström, J.; Lehtonen, M.; Auriola, S.; Pihlajamäki, J.; Peltonen, M.; Tuomilehto, J.; Uusitupa, M.; de Mello, V.D.; Hanhineva, K. Associations of serum indolepropionic acid, a gut microbiota metabolite, with type 2 diabetes and low-grade inflammation in high-risk individuals. Nutr. Diabetes 2018, 8, 35. [Google Scholar] [CrossRef]
- Chen, S.J.; Chen, C.C.; Liao, H.Y.; Wu, Y.W.; Liou, J.M.; Wu, M.S.; Kuo, C.H.; Lin, C.H. Alteration of Gut Microbial Metabolites in the Systemic Circulation of Patients with Parkinson’s Disease. J. Park. Dis. 2022, 12, 1219–1230. [Google Scholar] [CrossRef] [PubMed]
- Poeggeler, B.; Pappolla, M.A.; Hardeland, R.; Rassoulpour, A.; Hodgkins, P.S.; Guidetti, P.; Schwarcz, R. Indole-3-propionate: A potent hydroxyl radical scavenger in rat brain. Brain Res. 1999, 815, 382–388. [Google Scholar] [CrossRef] [PubMed]
- Poeggeler, B.; Reiter, R.J.; Tan, D.X.; Chen, L.D.; Manchester, L.C. Melatonin, hydroxyl radical-mediated oxidative damage, and aging: A hypothesis. J. Pineal Res. 1993, 14, 151–168. [Google Scholar] [CrossRef]
- Hwang, I.K.; Yoo, K.Y.; Li, H.; Park, O.K.; Lee, C.H.; Choi, J.H.; Jeong, Y.G.; Lee, Y.L.; Kim, Y.M.; Kwon, Y.G.; et al. Indole-3-propionic acid attenuates neuronal damage and oxidative stress in the ischemic hippocampus. J. Neurosci. Res. 2009, 87, 2126–2137. [Google Scholar] [CrossRef]
- Sehgal, R.; de Mello, V.D.; Männistö, V.; Lindström, J.; Tuomilehto, J.; Pihlajamäki, J.; Uusitupa, M. Indolepropionic Acid, a Gut Bacteria-Produced Tryptophan Metabolite and the Risk of Type 2 Diabetes and Non-Alcoholic Fatty Liver Disease. Nutrients 2022, 14, 4695. [Google Scholar] [CrossRef]
- Xue, H.; Chen, X.; Yu, C.; Deng, Y.; Zhang, Y.; Chen, S.; Chen, X.; Chen, K.; Yang, Y.; Ling, W. Gut Microbially Produced Indole-3-Propionic Acid Inhibits Atherosclerosis by Promoting Reverse Cholesterol Transport and Its Deficiency Is Causally Related to Atherosclerotic Cardiovascular Disease. Circ. Res. 2022, 131, 404–420. [Google Scholar] [CrossRef]
- Kim, C.S.; Jung, S.; Hwang, G.S.; Shin, D.M. Gut microbiota indole-3-propionic acid mediates neuroprotective effect of probiotic consumption in healthy elderly: A randomized, double-blind, placebo-controlled, multicenter trial and in vitro study. Clin. Nutr. 2023, 42, 1025–1033. [Google Scholar] [CrossRef]
- Sathyasaikumar, K.V.; Blanco-Ayala, T.; Zheng, Y.; Schwieler, L.; Erhardt, S.; Tufvesson-Alm, M.; Poeggeler, B.; Schwarcz, R. The Tryptophan Metabolite Indole-3-Propionic Acid Raises Kynurenic Acid Levels in the Rat Brain In Vivo. Int. J. Tryptophan Res. 2024, 17, 11786469241262876. [Google Scholar] [CrossRef]
- Chyan, Y.J.; Poeggeler, B.; Omar, R.A.; Chain, D.G.; Frangione, B.; Ghiso, J.; Pappolla, M.A. Potent neuroprotective properties against the Alzheimer beta-amyloid by an endogenous melatonin-related indole structure, indole-3-propionic acid. J. Biol. Chem. 1999, 274, 21937–21942. [Google Scholar] [CrossRef]
- Anastassova, N.; Stefanova, D.; Hristova-Avakumova, N.; Georgieva, I.; Kondeva-Burdina, M.; Rangelov, M.; Todorova, N.; Tzoneva, R.; Yancheva, D. New Indole-3-Propionic Acid and 5-Methoxy-Indole Carboxylic Acid Derived Hydrazone Hybrids as Multifunctional Neuroprotectors. Antioxidants 2023, 12, 977. [Google Scholar] [CrossRef]
- Shang, M.; Ning, J.; Zang, C.; Ma, J.; Yang, Y.; Wan, Z.; Zhao, J.; Jiang, Y.; Chen, Q.; Dong, Y.; et al. Microbial metabolite 3-indolepropionic acid alleviated PD pathologies by decreasing enteric glia cell gliosis via suppressing IL-13Rα1 related signaling pathways. Acta Pharm. Sin. B 2025, 15, 2024–2038. [Google Scholar] [CrossRef]
- Yin, J.; Zhang, Y.; Liu, X.; Li, W.; Hu, Y.; Zhang, B.; Wang, S. Gut Microbiota-Derived Indole Derivatives Alleviate Neurodegeneration in Aging through Activating GPR30/AMPK/SIRT1 Pathway. Mol. Nutr. Food Res. 2023, 67, e2200739. [Google Scholar] [CrossRef] [PubMed]
- Zhao, Q.; Chen, T.; Ni, C.; Hu, Y.; Nan, Y.; Lin, W.; Liu, Y.; Zheng, F.; Shi, X.; Lin, Z.; et al. Indole-3-propionic Acid Attenuates HI-Related Blood-Brain Barrier Injury in Neonatal Rats by Modulating the PXR Signaling Pathway. ACS Chem. Neurosci. 2022, 13, 2897–2912. [Google Scholar] [CrossRef] [PubMed]
- Karbownik, M.S.; Sokołowska, P.; Kowalczyk, E. Gut Microbiota Metabolites Differentially Release Gliotransmitters from the Cultured Human Astrocytes: A Preliminary Report. Int. J. Mol. Sci. 2023, 24, 6617. [Google Scholar] [CrossRef] [PubMed]
- Garcez, M.L.; Tan, V.X.; Heng, B.; Guillemin, G.J. Sodium Butyrate and Indole-3-propionic Acid Prevent the Increase of Cytokines and Kynurenine Levels in LPS-induced Human Primary Astrocytes. Int. J. Tryptophan Res. 2020, 13, 1178646920978404. [Google Scholar] [CrossRef]
- Mimori, S.; Kawada, K.; Saito, R.; Takahashi, M.; Mizoi, K.; Okuma, Y.; Hosokawa, M.; Kanzaki, T. Indole-3-propionic acid has chemical chaperone activity and suppresses endoplasmic reticulum stress-induced neuronal cell death. Biochem. Biophys. Res. Commun. 2019, 517, 623–628. [Google Scholar] [CrossRef] [PubMed]
- Sun, J.; Zhang, Y.; Kong, Y.; Ye, T.; Yu, Q.; Kumaran Satyanarayanan, S.; Su, K.P.; Liu, J. Microbiota-derived metabolite Indoles induced aryl hydrocarbon receptor activation and inhibited neuroinflammation in APP/PS1 mice. Brain Behav. Immun. 2022, 106, 76–88. [Google Scholar] [CrossRef]
- Li, L.; Yang, C.; Jia, M.; Wang, Y.; Zhao, Y.; Li, Q.; Gong, J.; He, Y.; Xu, K.; Liu, X.; et al. Synbiotic therapy with Clostridium sporogenes and xylan promotes gut-derived indole-3-propionic acid and improves cognitive impairments in an Alzheimer’s disease mouse model. Food Funct. 2024, 15, 7865–7882. [Google Scholar] [CrossRef]
- Zhang, Y.; Liu, T.; Pan, F.; Li, Y.; Wang, D.; Pang, J.; Sang, H.; Xi, Y.; Shi, L.; Liu, Z. Dietary Methionine Restriction Alleviates Cognitive Impairment in Alzheimer’s Disease Mice via Sex-Dependent Modulation on Gut Microbiota and Tryptophan Metabolism: A Multiomics Analysis. J. Agric. Food Chem. 2025, 73, 1356–1372. [Google Scholar] [CrossRef]
- Fasina, O.B.; Li, L.; Chen, D.; Yi, M.; Xiang, L.; Qi, J. Tetradecyl 2,3-Dihydroxybenzoate Improves Cognitive Function in AD Mice by Modulating Autophagy and Inflammation Through IPA and Hsc70 Targeting. Int. J. Mol. Sci. 2024, 25, 11719. [Google Scholar] [CrossRef]
- Liu, Z.; Dai, X.; Zhang, H.; Shi, R.; Hui, Y.; Jin, X.; Zhang, W.; Wang, L.; Wang, Q.; Wang, D.; et al. Gut microbiota mediates intermittent-fasting alleviation of diabetes-induced cognitive impairment. Nat. Commun. 2020, 11, 855. [Google Scholar] [CrossRef]
- Xie, Y.; Zou, X.; Han, J.; Zhang, Z.; Feng, Z.; Ouyang, Q.; Hua, S.; Liu, Z.; Li, C.; Cai, Y.; et al. Indole-3-propionic acid alleviates ischemic brain injury in a mouse middle cerebral artery occlusion model. Exp. Neurol. 2022, 353, 114081. [Google Scholar] [CrossRef]
- Peesh, P.; Blasco-Conesa, M.P.; El Hamamy, A.; Khan, R.; Guzman, G.U.; Honarpisheh, P.; Mohan, E.C.; Goodman, G.W.; Nguyen, J.N.; Banerjee, A.; et al. Benefits of equilibrium between microbiota- and host-derived ligands of the aryl hydrocarbon receptor after stroke in aged male mice. Nat. Commun. 2025, 16, 1767. [Google Scholar] [CrossRef] [PubMed]
- Guo, S.; Yang, L.; Ding, W.; Dagnew, T.M.; Gao, Y.; Wang, W.; Wang, P.; Huang, S.; Ran, C.; Wang, C.; et al. Hippocampal Neural Dynamics and Postoperative Delirium-like Behavior in Aged Mice. Anesthesiology 2025, 143, 625–640. [Google Scholar] [CrossRef] [PubMed]
- Mao, S.; Zhang, Z.; Huang, M.; Zhang, Z.; Hong, Y.; Tan, X.; Gui, F.; Cao, Y.; Lian, F.; Chen, R. Protective effects of indole-3-propionic acid against TCP-induced hearing loss in mice by mitigating oxidative stress and promoting neutrophil recruitment. Sci. Rep. 2025, 15, 9434. [Google Scholar] [CrossRef]
- Wang, T.; Chen, B.; Luo, M.; Xie, L.; Lu, M.; Lu, X.; Zhang, S.; Wei, L.; Zhou, X.; Yao, B.; et al. Microbiota-indole 3-propionic acid-brain axis mediates abnormal synaptic pruning of hippocampal microglia and susceptibility to ASD in IUGR offspring. Microbiome 2023, 11, 245. [Google Scholar] [CrossRef]
- Jiang, J.; Wang, D.; Jiang, Y.; Yang, X.; Sun, R.; Chang, J.; Zhu, W.; Yao, P.; Song, K.; Chang, S.; et al. The gut metabolite indole-3-propionic acid activates ERK1 to restore social function and hippocampal inhibitory synaptic transmission in a 16p11.2 microdeletion mouse model. Microbiome 2024, 12, 66. [Google Scholar] [CrossRef] [PubMed]
- Rothhammer, V.; Mascanfroni, I.D.; Bunse, L.; Takenaka, M.C.; Kenison, J.E.; Mayo, L.; Chao, C.C.; Patel, B.; Yan, R.; Blain, M.; et al. Type I interferons and microbial metabolites of tryptophan modulate astrocyte activity and central nervous system inflammation via the aryl hydrocarbon receptor. Nat. Med. 2016, 22, 586–597. [Google Scholar] [CrossRef] [PubMed]
- Owumi, S.E.; Adebisi, G. Epirubicin Treatment Induces Neurobehavioral, Oxido-Inflammatory and Neurohistology Alterations in Rats: Protective Effect of the Endogenous Metabolite of Tryptophan - 3-Indolepropionic Acid. Neurochem. Res. 2023, 48, 2767–2783. [Google Scholar] [CrossRef]
- Serger, E.; Luengo-Gutierrez, L.; Chadwick, J.S.; Kong, G.; Zhou, L.; Crawford, G.; Danzi, M.C.; Myridakis, A.; Brandis, A.; Bello, A.T.; et al. The gut metabolite indole-3 propionate promotes nerve regeneration and repair. Nature 2022, 607, 585–592. [Google Scholar] [CrossRef] [PubMed]
- Zhang, G.; Lang, Z.; Yang, Q.; Nie, Y.; Wang, Z.; Gao, M.; Zhang, N.; Xu, X. UPLC-Q-TOF/MS-based plasma metabolome to identify biomarkers and time of injury in traumatic brain injured rats. Neuroreport 2021, 32, 415–422. [Google Scholar] [CrossRef]
- Huang, Y.L.; Lin, C.H.; Tsai, T.H.; Huang, C.H.; Li, J.L.; Chen, L.K.; Li, C.H.; Tsai, T.F.; Wang, P.N. Discovery of a Metabolic Signature Predisposing High Risk Patients with Mild Cognitive Impairment to Converting to Alzheimer’s Disease. Int. J. Mol. Sci. 2021, 22, 10903. [Google Scholar] [CrossRef]
- Li, X.; Chen, D.; Chen, X.; Jiang, C.; Guo, Y.; Hang, J.; Tao, L.; Li, Y.; Yu, H. Study on the correlation between serum indole-3-propionic acid levels and the progression and prognosis of acute ischemic stroke. J. Stroke Cerebrovasc. Dis. 2024, 33, 107680. [Google Scholar] [CrossRef]
- Gaetani, L.; Boscaro, F.; Pieraccini, G.; Calabresi, P.; Romani, L.; Di Filippo, M.; Zelante, T. Host and Microbial Tryptophan Metabolic Profiling in Multiple Sclerosis. Front. Immunol. 2020, 11, 157. [Google Scholar] [CrossRef]
- Le Beau, M.M.; Carver, L.A.; Espinosa, R., 3rd; Schmidt, J.V.; Bradfield, C.A. Chromosomal localization of the human AHR locus encoding the structural gene for the Ah receptor to 7p21 → p15. Cytogenet. Cell Genet. 1994, 66, 172–176. [Google Scholar] [CrossRef]
- Gutiérrez-Vázquez, C.; Quintana, F.J. Regulation of the Immune Response by the Aryl Hydrocarbon Receptor. Immunity 2018, 48, 19–33. [Google Scholar] [CrossRef]
- Barroso, A.; Mahler, J.V.; Fonseca-Castro, P.H.; Quintana, F.J. The aryl hydrocarbon receptor and the gut-brain axis. Cell Mol. Immunol. 2021, 18, 259–268. [Google Scholar] [CrossRef]
- Iwaniak, P.; Owe-Larsson, M.; Urbańska, E.M. Microbiota, Tryptophan and Aryl Hydrocarbon Receptors as the Target Triad in Parkinson’s Disease-A Narrative Review. Int. J. Mol. Sci. 2024, 25, 2915. [Google Scholar] [CrossRef]
- Salminen, A. Activation of aryl hydrocarbon receptor (AhR) in Alzheimer’s disease: Role of tryptophan metabolites generated by gut host-microbiota. J. Mol. Med. 2023, 101, 201–222. [Google Scholar] [CrossRef] [PubMed]
- Sondermann, N.C.; Faßbender, S.; Hartung, F.; Hätälä, A.M.; Rolfes, K.M.; Vogel, C.F.A.; Haarmann-Stemmann, T. Functions of the aryl hydrocarbon receptor (AHR) beyond the canonical AHR/ARNT signaling pathway. Biochem. Pharmacol. 2023, 208, 115371. [Google Scholar] [CrossRef] [PubMed]
- Stockinger, B.; Di Meglio, P.; Gialitakis, M.; Duarte, J.H. The aryl hydrocarbon receptor: Multitasking in the immune system. Annu. Rev. Immunol. 2014, 32, 403–432. [Google Scholar] [CrossRef]
- Rothhammer, V.; Quintana, F.J. The aryl hydrocarbon receptor: An environmental sensor integrating immune responses in health and disease. Nat. Rev. Immunol. 2019, 19, 184–197. [Google Scholar] [CrossRef]
- Farooqi, A.A.; Rakhmetova, V.; Kapanova, G.; Tanbayeva, G.; Mussakhanova, A.; Abdykulova, A.; Ryskulova, A.G. Role of Ubiquitination and Epigenetics in the Regulation of AhR Signaling in Carcinogenesis and Metastasis: “Albatross around the Neck” or “Blessing in Disguise”. Cells 2023, 12, 2382. [Google Scholar] [CrossRef]
- Bessede, A.; Gargaro, M.; Pallotta, M.T.; Matino, D.; Servillo, G.; Brunacci, C.; Bicciato, S.; Mazza, E.M.; Macchiarulo, A.; Vacca, C.; et al. Aryl hydrocarbon receptor control of a disease tolerance defence pathway. Nature 2014, 511, 184–190. [Google Scholar] [CrossRef] [PubMed]
- Kimura, E.; Tohyama, C. Embryonic and Postnatal Expression of Aryl Hydrocarbon Receptor mRNA in Mouse Brain. Front. Neuroanat. 2017, 11, 4. [Google Scholar] [CrossRef] [PubMed]
- Lamas, B.; Natividad, J.M.; Sokol, H. Aryl hydrocarbon receptor and intestinal immunity. Mucosal Immunol. 2018, 11, 1024–1038. [Google Scholar] [CrossRef]
- Huang, Z.B.; Hu, Z.; Lu, C.X.; Luo, S.D.; Chen, Y.; Zhou, Z.P.; Hu, J.J.; Zhang, F.L.; Deng, F.; Liu, K.X. Gut microbiota-derived indole 3-propionic acid partially activates aryl hydrocarbon receptor to promote macrophage phagocytosis and attenuate septic injury. Front. Cell Infect. Microbiol. 2022, 12, 1015386. [Google Scholar] [CrossRef]
- Zhuang, H.; Ren, X.; Jiang, F.; Zhou, P. Indole-3-propionic acid alleviates chondrocytes inflammation and osteoarthritis via the AhR/NF-κB axis. Mol. Med. 2023, 29, 17. [Google Scholar] [CrossRef]
- Venkatesh, M.; Mukherjee, S.; Wang, H.; Li, H.; Sun, K.; Benechet, A.P.; Qiu, Z.; Maher, L.; Redinbo, M.R.; Phillips, R.S.; et al. Symbiotic bacterial metabolites regulate gastrointestinal barrier function via the xenobiotic sensor PXR and Toll-like receptor 4. Immunity 2014, 41, 296–310. [Google Scholar] [CrossRef]
- Yisireyili, M.; Takeshita, K.; Saito, S.; Murohara, T.; Niwa, T. Indole-3-propionic acid suppresses indoxyl sulfate-induced expression of fibrotic and inflammatory genes in proximal tubular cells. Nagoya J. Med. Sci. 2017, 79, 477–486. [Google Scholar] [CrossRef] [PubMed]
- Vrzalová, A.; Pečinková, P.; Illés, P.; Gurská, S.; Džubák, P.; Szotkowski, M.; Hajdúch, M.; Mani, S.; Dvořák, Z. Mixture Effects of Tryptophan Intestinal Microbial Metabolites on Aryl Hydrocarbon Receptor Activity. Int. J. Mol. Sci. 2022, 23, 10825. [Google Scholar] [CrossRef]
- Kim, S.; Li, H.; Jin, Y.; Armad, J.; Gu, H.; Mani, S.; Cui, J.Y. Maternal PBDE exposure disrupts gut microbiome and promotes hepatic proinflammatory signaling in humanized PXR-transgenic mouse offspring over time. Toxicol. Sci. 2023, 194, 209–225. [Google Scholar] [CrossRef]
- Zhang, J.; Kuehl, P.; Green, E.D.; Touchman, J.W.; Watkins, P.B.; Daly, A.; Hall, S.D.; Maurel, P.; Relling, M.; Brimer, C.; et al. The human pregnane X receptor: Genomic structure and identification and functional characterization of natural allelic variants. Pharmacogenet. Genom. 2001, 11, 555–572. [Google Scholar] [CrossRef]
- Sun, L.; Sun, Z.; Wang, Q.; Zhang, Y.; Jia, Z. Role of nuclear receptor PXR in immune cells and inflammatory diseases. Front. Immunol. 2022, 13, 969399. [Google Scholar] [CrossRef]
- Torres-Vergara, P.; Ho, Y.S.; Espinoza, F.; Nualart, F.; Escudero, C.; Penny, J. The constitutive androstane receptor and pregnane X receptor in the brain. Br. J. Pharmacol. 2020, 177, 2666–2682. [Google Scholar] [CrossRef]
- Kliewer, S.A.; Goodwin, B.; Willson, T.M. The nuclear pregnane X receptor: A key regulator of xenobiotic metabolism. Endocr. Rev. 2002, 23, 687–702. [Google Scholar] [CrossRef]
- Hernandez, J.P.; Mota, L.C.; Baldwin, W.S. Activation of CAR and PXR by Dietary, Environmental and Occupational Chemicals Alters Drug Metabolism, Intermediary Metabolism, and Cell Proliferation. Curr. Pharmacogenom. Person. Med. 2009, 7, 81–105. [Google Scholar] [CrossRef]
- Dutta, M.; Lim, J.J.; Cui, J.Y. Pregnane X Receptor and the Gut-Liver Axis: A Recent Update. Drug Metab. Dispos. 2022, 50, 478–491. [Google Scholar] [CrossRef]
- Bautista-Olivier, C.D.; Elizondo, G. PXR as the tipping point between innate immune response, microbial infections, and drug metabolism. Biochem. Pharmacol. 2022, 202, 115147. [Google Scholar] [CrossRef] [PubMed]
- Nieves, K.M.; Hirota, S.A.; Flannigan, K.L. Xenobiotic receptors and the regulation of intestinal homeostasis: Harnessing the chemical output of the intestinal microbiota. Am. J. Physiol. Gastrointest. Liver Physiol. 2022, 322, G268–G281. [Google Scholar] [CrossRef] [PubMed]
- Frye, C.A.; Paris, J.J.; Walf, A.A.; Rusconi, J.C. Effects and Mechanisms of 3α,5α,-THP on Emotion, Motivation, and Reward Functions Involving Pregnane Xenobiotic Receptor. Front. Neurosci. 2011, 5, 136. [Google Scholar] [CrossRef] [PubMed]
- Karbownik, M.; Garcia, J.J.; Lewiński, A.; Reiter, R.J. Carcinogen-induced, free radical-mediated reduction in microsomal membrane fluidity: Reversal by indole-3-propionic acid. J. Bioenerg. Biomembr. 2001, 33, 73–78. [Google Scholar] [CrossRef]
- Karbownik, M.; Reiter, R.J.; Garcia, J.J.; Cabrera, J.; Burkhardt, S.; Osuna, C.; Lewiński, A. Indole-3-propionic acid, a melatonin-related molecule, protects hepatic microsomal membranes from iron-induced oxidative damage: Relevance to cancer reduction. J. Cell Biochem. 2001, 81, 507–513. [Google Scholar] [CrossRef]
- Karbownik, M.; Stasiak, M.; Zygmunt, A.; Zasada, K.; Lewiński, A. Protective effects of melatonin and indole-3-propionic acid against lipid peroxidation, caused by potassium bromate in the rat kidney. Cell Biochem. Funct. 2006, 24, 483–489. [Google Scholar] [CrossRef]
- Poeggeler, B.; Sambamurti, K.; Siedlak, S.L.; Perry, G.; Smith, M.A.; Pappolla, M.A. A novel endogenous indole protects rodent mitochondria and extends rotifer lifespan. PLoS ONE 2010, 5, e10206. [Google Scholar] [CrossRef]
- Qi, W.; Reiter, R.J.; Tan, D.X.; Manchester, L.C.; Siu, A.W.; Garcia, J.J. Increased levels of oxidatively damaged DNA induced by chromium(III) and H2O2: Protection by melatonin and related molecules. J. Pineal Res. 2000, 29, 54–61. [Google Scholar] [CrossRef]
- Karbownik, M.; Reiter, R.J.; Cabrera, J.; Garcia, J.J. Comparison of the protective effect of melatonin with other antioxidants in the hamster kidney model of estradiol-induced DNA damage. Mutat. Res. 2001, 474, 87–92. [Google Scholar] [CrossRef] [PubMed]
- Morzyk-Ociepa, B.; Rozycka-Sokolowska, E. X-ray and infrared spectrum on metal complexes with indolecarboxylic acids: Part, V. Catena-poly[{aqua(η2-indole-3-propionato-O,O′)zinc}-η2-:-μ-indole-3-propionato-O, O′:-O]. Vib. Spectrosc. 2007, 43, 405–414. [Google Scholar] [CrossRef]
- Owumi, S.E.; Adedara, I.A.; Oyelere, A.K. Indole-3-propionic acid mitigates chlorpyrifos-mediated neurotoxicity by modulating cholinergic and redox-regulatory systems, inflammatory stress, apoptotic responses and DNA damage in rats. Environ. Toxicol. Pharmacol. 2022, 89, 103786. [Google Scholar] [CrossRef]
- Schütz, B.; Krause, F.F.; Taudte, R.V.; Zaiss, M.M.; Luu, M.; Visekruna, A. Modulation of Host Immunity by Microbiome-Derived Indole-3-Propionic Acid and Other Bacterial Metabolites. Eur. J. Immunol. 2025, 55, e202451594. [Google Scholar] [CrossRef]
- Xu, H.; Luo, Y.; An, Y.; Wu, X. The mechanism of action of indole-3-propionic acid on bone metabolism. Food Funct. 2025, 16, 406–421. [Google Scholar] [CrossRef]
- Paeslack, N.; Mimmler, M.; Becker, S.; Gao, Z.; Khuu, M.P.; Mann, A.; Malinarich, F.; Regen, T.; Reinhardt, C. Microbiota-derived tryptophan metabolites in vascular inflammation and cardiovascular disease. Amino Acids 2022, 54, 1339–1356. [Google Scholar] [CrossRef]
- Teunis, C.; Nieuwdorp, M.; Hanssen, N. Interactions between Tryptophan Metabolism, the Gut Microbiome and the Immune System as Potential Drivers of Non-Alcoholic Fatty Liver Disease (NAFLD) and Metabolic Diseases. Metabolites 2022, 12, 514. [Google Scholar] [CrossRef] [PubMed]
- Gao, L.; Song, Y.; Zhang, F.; Zhao, Y.; Hu, H.; Feng, Y. Indolepropionic acid modulates the immune response in allergic rhinitis through the AKT/CEBPB/IL-10 signaling pathway. Mol. Med. Rep. 2025, 32, 204. [Google Scholar] [CrossRef]
- Sabarathinam, S. Deciphering the gut microbiota’s (Coprococcus and Subdoligranulum) impact on depression: Network pharmacology and molecular dynamics simulation. Pharmacol. Biochem. Behav. 2024, 241, 173805. [Google Scholar] [CrossRef]
- Lu, J.; Wang, H.; Zhang, H.; Li, J.; Li, H.; Chen, Q.; Han, D.; Liu, J.; Lv, L.; Xiong, J.; et al. Gut Metabolite Indole-3-Propionic Acid Regulates Macrophage Autophagy Through PPT1 Inhibiting Aging-Related Myocardial Fibrosis. Adv. Sci. 2025, e01070. [Google Scholar] [CrossRef]
- Savitz, J. The kynurenine pathway: A finger in every pie. Mol. Psychiatry 2020, 25, 131–147. [Google Scholar] [CrossRef]
- Badawy, A.A. Kynurenine Pathway of Tryptophan Metabolism: Regulatory and Functional Aspects. Int. J. Tryptophan Res. 2017, 10, 1178646917691938. [Google Scholar] [CrossRef] [PubMed]
- Stone, T.W.; Darlington, L.G.; Badawy, A.A.; Williams, R.O. The Complex World of Kynurenic Acid: Reflections on Biological Issues and Therapeutic Strategy. Int. J. Mol. Sci. 2024, 25, 9040. [Google Scholar] [CrossRef] [PubMed]
- Sadik, A.; Somarribas Patterson, L.F.; Öztürk, S.; Mohapatra, S.R.; Panitz, V.; Secker, P.F.; Pfänder, P.; Loth, S.; Salem, H.; Prentzell, M.T.; et al. IL4I1 Is a Metabolic Immune Checkpoint that Activates the AHR and Promotes Tumor Progression. Cell 2020, 182, 1252–1270.E34. [Google Scholar] [CrossRef]
- Hughes, T.D.; Güner, O.F.; Iradukunda, E.C.; Phillips, R.S.; Bowen, J.P. The Kynurenine Pathway and Kynurenine 3-Monooxygenase Inhibitors. Molecules 2022, 27, 273. [Google Scholar] [CrossRef] [PubMed]
- Ciapała, K.; Mika, J.; Rojewska, E. The Kynurenine Pathway as a Potential Target for Neuropathic Pain Therapy Design: From Basic Research to Clinical Perspectives. Int. J. Mol. Sci. 2021, 22, 11055. [Google Scholar] [CrossRef] [PubMed]
- Tanaka, M.; Szabó, Á.; Vécsei, L. Redefining Roles: A Paradigm Shift in Tryptophan-Kynurenine Metabolism for Innovative Clinical Applications. Int. J. Mol. Sci. 2024, 25, 12767. [Google Scholar] [CrossRef]
- Pocivavsek, A.; Schwarcz, R.; Erhardt, S. Neuroactive Kynurenines as Pharmacological Targets: New Experimental Tools and Exciting Therapeutic Opportunities. Pharmacol. Rev. 2024, 76, 978–1008. [Google Scholar] [CrossRef]
- Mor, A.; Tankiewicz-Kwedlo, A.; Ciwun, M.; Lewkowicz, J.; Pawlak, D. Kynurenines as a Novel Target for the Treatment of Inflammatory Disorders. Cells 2024, 13, 1259. [Google Scholar] [CrossRef]
- Kozieł, K.; Urbanska, E.M. Kynurenine Pathway in Diabetes Mellitus-Novel Pharmacological Target? Cells 2023, 12, 460. [Google Scholar] [CrossRef]
- Alberts, C.; Owe-Larsson, M.; Urbanska, E.M. New Perspective on Anorexia Nervosa: Tryptophan-Kynurenine Pathway Hypothesis. Nutrients 2023, 15, 1030. [Google Scholar] [CrossRef]
- Sorgdrager, F.J.H.; Naudé, P.J.W.; Kema, I.P.; Nollen, E.A.; Deyn, P.P. Tryptophan Metabolism in Inflammaging: From Biomarker to Therapeutic Target. Front. Immunol. 2019, 10, 2565. [Google Scholar] [CrossRef] [PubMed]
- Liang, Y.; Xie, S.; He, Y.; Xu, M.; Qiao, X.; Zhu, Y.; Wu, W. Kynurenine Pathway Metabolites as Biomarkers in Alzheimer’s Disease. Dis. Markers 2022, 2022, 9484217. [Google Scholar] [CrossRef] [PubMed]
- Urenjak, J.; Obrenovitch, T.P. Neuroprotective potency of kynurenic acid against excitotoxicity. Neuroreport 2000, 11, 1341–1344. [Google Scholar] [CrossRef]
- Alves, L.F.; Moore, J.B.; Kell, D.B. The Biology and Biochemistry of Kynurenic Acid, a Potential Nutraceutical with Multiple Biological Effects. Int. J. Mol. Sci. 2024, 25, 9082. [Google Scholar] [CrossRef]
- Huang, F.C. Therapeutic Potential of Nutritional Aryl Hydrocarbon Receptor Ligands in Gut-Related Inflammation and Diseases. Biomedicines 2024, 12, 2912. [Google Scholar] [CrossRef]
- Bahman, F.; Choudhry, K.; Al-Rashed, F.; Al-Mulla, F.; Sindhu, S.; Ahmad, R. Aryl hydrocarbon receptor: Current perspectives on key signaling partners and immunoregulatory role in inflammatory diseases. Front. Immunol. 2024, 15, 1421346. [Google Scholar] [CrossRef] [PubMed]
- Sathyasaikumar, K.V.; Pérez de la Cruz, V.; Pineda, B.; Vázquez Cervantes, G.I.; Ramírez Ortega, D.; Donley, D.W.; Severson, P.L.; West, B.L.; Giorgini, F.; Fox, J.H.; et al. Cellular Localization of Kynurenine 3-Monooxygenase in the Brain: Challenging the Dogma. Antioxidants 2022, 11, 315. [Google Scholar] [CrossRef]
- Fukui, S.; Schwarcz, R.; Rapoport, S.I.; Takada, Y.; Smith, Q.R. Blood-brain barrier transport of kynurenines: Implications for brain synthesis and metabolism. J. Neurochem. 1991, 56, 2007–2017. [Google Scholar] [CrossRef]
- Ostapiuk, A.; Urbanska, E.M. Kynurenic acid in neurodegenerative disorders-unique neuroprotection or double-edged sword? CNS Neurosci. Ther. 2022, 28, 19–35. [Google Scholar] [CrossRef]
- Lamptey, R.N.L.; Chaulagain, B.; Trivedi, R.; Gothwal, A.; Layek, B.; Singh, J. A Review of the Common Neurodegenerative Disorders: Current Therapeutic Approaches and the Potential Role of Nanotherapeutics. Int. J. Mol. Sci. 2022, 23, 1851. [Google Scholar] [CrossRef]
- Freisem, D.; Hoenigsperger, H.; Catanese, A.; Sparrer, K.M.J. Inborn errors of canonical autophagy in neurodegenerative diseases. Hum. Mol. Genet. 2025, ddae179. [Google Scholar] [CrossRef]
- Dugger, B.N.; Dickson, D.W. Pathology of Neurodegenerative Diseases. Cold Spring Harb. Perspect. Biol. 2017, 9, a028035. [Google Scholar] [CrossRef]
- Argueti-Ostrovsky, S.; Alfahel, L.; Kahn, J.; Israelson, A. All Roads Lead to Rome: Different Molecular Players Converge to Common Toxic Pathways in Neurodegeneration. Cells 2021, 10, 2438. [Google Scholar] [CrossRef] [PubMed]
- Godoy, J.A.; Rios, J.A.; Picón-Pagès, P.; Herrera-Fernández, V.; Swaby, B.; Crepin, G.; Vicente, R.; Fernández-Fernández, J.M.; Muñoz, F.J. Mitostasis, Calcium and Free Radicals in Health, Aging and Neurodegeneration. Biomolecules 2021, 11, 1012. [Google Scholar] [CrossRef] [PubMed]
- Garg, G.; Trisal, A.; Singh, A.K. Unlocking the therapeutic potential of gut microbiota for preventing and treating aging-related neurological disorders. Neuroscience 2025, 572, 190–203. [Google Scholar] [CrossRef]
- Park, K.J.; Gao, Y. Gut-brain axis and neurodegeneration: Mechanisms and therapeutic potentials. Front. Neurosci. 2024, 18, 1481390. [Google Scholar] [CrossRef]
- Morshedi, D.; Rezaei-Ghaleh, N.; Ebrahim-Habibi, A.; Ahmadian, S.; Nemat-Gorgani, M. Inhibition of amyloid fibrillation of lysozyme by indole derivatives--possible mechanism of action. FEBS J. 2007, 274, 6415–6425. [Google Scholar] [CrossRef] [PubMed]
- Hao, Z.; Ji, R.; Su, Y.; Wang, H.; Yang, W.; Zhang, S.; Liu, Y.; Ma, S.; Guan, F.; Cui, Y. Indole-3-Propionic Acid Attenuates Neuroinflammation and Cognitive Deficits by Inhibiting the RAGE-JAK2-STAT3 Signaling Pathway. J. Agric. Food Chem. 2025, 73, 5208–5222. [Google Scholar] [CrossRef]
- Prasad, K. AGE-RAGE stress: A changing landscape in pathology and treatment of Alzheimer’s disease. Mol. Cell Biochem. 2019, 459, 95–112. [Google Scholar] [CrossRef] [PubMed]
- Wang, L.; Zhao, D.; Wang, H.; Wang, L.; Liu, X.; Zhang, H. FPS-ZM1 inhibits LPS-induced microglial inflammation by suppressing JAK/STAT signaling pathway. Int. Immunopharmacol. 2021, 100, 108117. [Google Scholar] [CrossRef] [PubMed]
- Scheltens, P.; De Strooper, B.; Kivipelto, M.; Holstege, H.; Chételat, G.; Teunissen, C.E.; Cummings, J.; van der Flier, W.M. Alzheimer’s disease. Lancet 2021, 397, 1577–1590. [Google Scholar] [CrossRef] [PubMed]
- Rostagno, A.A. Pathogenesis of Alzheimer’s Disease. Int. J. Mol. Sci. 2022, 24, 107. [Google Scholar] [CrossRef] [PubMed]
- D’Alessandro, M.C.B.; Kanaan, S.; Geller, M.; Praticò, D.; Daher, J.P.L. Mitochondrial dysfunction in Alzheimer’s disease. Ageing Res. Rev. 2025, 107, 102713. [Google Scholar] [CrossRef]
- Daly, T.; Kepp, K.P.; Imbimbo, B.P. Are lecanemab and donanemab disease-modifying therapies? Alzheimers Dement. 2024, 20, 6659–6661. [Google Scholar] [CrossRef]
- Dragicevic, N.; Copes, N.; O’Neal-Moffitt, G.; Jin, J.; Buzzeo, R.; Mamcarz, M.; Tan, J.; Cao, C.; Olcese, J.M.; Arendash, G.W.; et al. Melatonin treatment restores mitochondrial function in Alzheimer’s mice: A mitochondrial protective role of melatonin membrane receptor signaling. J. Pineal Res. 2011, 51, 75–86. [Google Scholar] [CrossRef]
- Loganathan, C.; Kandasamy, S.; Sakayanathan, P.; Ameen, F.; Iruthayaraj, A.; Thayumanavan, P. Amalgamation of experimental strategies, computational simulation, and computer-assisted-theoretical analysis to decipher the interaction of newly synthesized plumbagin-indole-3-propionic ester with cholinesterases. J. Biomol. Struct. Dyn. 2025, 1–16. [Google Scholar] [CrossRef]
- Sidhambaram, J.; Sakayanathan, P.; Loganathan, C.; Iruthayaraj, A.; Thayumanavan, P. Esterified Indole-3-propionic Acid: A Novel Inhibitor against Cholinesterase Identified through Experimental and Computational Approaches. ACS Omega 2025, 10, 9073–9087. [Google Scholar] [CrossRef]
- Bendheim, P.E.; Poeggeler, B.; Neria, E.; Ziv, V.; Pappolla, M.A.; Chain, D.G. Development of indole-3-propionic acid (OXIGON) for Alzheimer’s disease. J. Mol. Neurosci. 2002, 19, 213–217. [Google Scholar] [CrossRef]
- Poeggeler, B.; Miravalle, L.; Zagorski, M.G.; Wisniewski, T.; Chyan, Y.J.; Zhang, Y.; Shao, H.; Bryant-Thomas, T.; Vidal, R.; Frangione, B.; et al. Melatonin reverses the profibrillogenic activity of apolipoprotein E4 on the Alzheimer amyloid Abeta peptide. Biochemistry 2001, 40, 14995–15001. [Google Scholar] [CrossRef]
- Pappolla, M.A.; Matsubara, E.; Vidal, R.; Pacheco-Quinto, J.; Poeggeler, B.; Zagorski, M.; Sambamurti, K. Melatonin Treatment Enhances Aβ Lymphatic Clearance in a Transgenic Mouse Model of Amyloidosis. Curr. Alzheimer Res. 2018, 15, 637–642. [Google Scholar] [CrossRef] [PubMed]
- Rynkowska, A.; Stępniak, J.; Karbownik-Lewińska, M. Melatonin and Indole-3-Propionic Acid Reduce Oxidative Damage to Membrane Lipids Induced by High Iron Concentrations in Porcine Skin. Membranes 2021, 11, 571. [Google Scholar] [CrossRef] [PubMed]
- Iwan, P.; Stepniak, J.; Karbownik-Lewinska, M. Cumulative Protective Effect of Melatonin and Indole-3-Propionic Acid against KIO3-Induced Lipid Peroxidation in Porcine Thyroid. Toxics 2021, 9, 89. [Google Scholar] [CrossRef] [PubMed]
- Tysnes, O.B.; Storstein, A. Epidemiology of Parkinson’s disease. J. Neural Transm. 2017, 124, 901–905. [Google Scholar] [CrossRef]
- Volpicelli-Daley, L.A.; Luk, K.C.; Patel, T.P.; Tanik, S.A.; Riddle, D.M.; Stieber, A.; Meaney, D.F.; Trojanowski, J.Q.; Lee, V.M. Exogenous α-synuclein fibrils induce Lewy body pathology leading to synaptic dysfunction and neuron death. Neuron 2011, 72, 57–71. [Google Scholar] [CrossRef]
- Riederer, P.; Nagatsu, T.; Youdim, M.B.H.; Wulf, M.; Dijkstra, J.M.; Sian-Huelsmann, J. Lewy bodies, iron, inflammation and neuromelanin: Pathological aspects underlying Parkinson’s disease. J. Neural Transm. 2023, 130, 627–646. [Google Scholar] [CrossRef]
- Gao, Q.; Zhou, Y.; Chen, Y.; Hu, W.; Jin, W.; Zhou, C.; Yuan, H.; Li, J.; Lin, Z.; Lin, W. Role of iron in brain development, aging, and neurodegenerative diseases. Ann. Med. 2025, 57, 2472871. [Google Scholar] [CrossRef]
- Subramaniam, S.R.; Chesselet, M.F. Mitochondrial dysfunction and oxidative stress in Parkinson’s disease. Prog. Neurobiol. 2013, 106–107, 17–32. [Google Scholar] [CrossRef]
- Simon, D.K.; Tanner, C.M.; Brundin, P. Parkinson Disease Epidemiology, Pathology, Genetics, and Pathophysiology. Clin. Geriatr. Med. 2020, 36, 1–12. [Google Scholar] [CrossRef]
- Horvath, I.; Mohamed, K.A.; Kumar, R.; Wittung-Stafshede, P. Amyloids of α-Synuclein Promote Chemical Transformations of Neuronal Cell Metabolites. Int. J. Mol. Sci. 2023, 24, 12849. [Google Scholar] [CrossRef]
- Armstrong, M.J.; Okun, M.S. Diagnosis and Treatment of Parkinson Disease: A Review. JAMA 2020, 323, 548–560. [Google Scholar] [CrossRef]
- Zhu, M.; Liu, X.; Ye, Y.; Yan, X.; Cheng, Y.; Zhao, L.; Chen, F.; Ling, Z. Gut Microbiota: A Novel Therapeutic Target for Parkinson’s Disease. Front. Immunol. 2022, 13, 937555. [Google Scholar] [CrossRef]
- Li, S.; Zhao, X.; Lin, F.; Ni, X.; Liu, X.; Kong, C.; Yao, X.; Mo, Y.; Dai, Q.; Wang, J. Gut Flora Mediates the Rapid Tolerance of Electroacupuncture on Ischemic Stroke by Activating Melatonin Receptor through Regulating Indole-3-Propionic Acid. Am. J. Chin. Med. 2022, 50, 979–1006. [Google Scholar] [CrossRef]
- Mangalam, A.; Poisson, L.; Nemutlu, E.; Datta, I.; Denic, A.; Dzeja, P.; Rodriguez, M.; Rattan, R.; Giri, S. Profile of Circulatory Metabolites in a Relapsing-remitting Animal Model of Multiple Sclerosis using Global Metabolomics. J. Clin. Cell Immunol. 2013, 4, 1000150. [Google Scholar] [CrossRef]
- Candeias, L.P.; Folkes, L.K.; Porssa, M.; Parrick, J.; Wardman, P. Enhancement of lipid peroxidation by indole-3-acetic acid and derivatives: Substituent effects. Free Radic. Res. 1995, 23, 403–418. [Google Scholar] [CrossRef] [PubMed]
- Haupt, J.; Keminer, O.; Neser, C.; Windshügel, B.; Wiltzsch, V.; Schmidt, J.R.; Pliushcheuskaya, P.; Künze, G.; Scholz, U.; Müller, C.; et al. Novel aryl hydrocarbon receptor agonists as potential anti-inflammatory therapeutics: Identification and validation through drug repurposing. Biochem. Pharmacol. 2025, 240, 117066. [Google Scholar] [CrossRef] [PubMed]
- Janiga-MacNelly, A.; Vrazel, M.; Roat, A.E.; Fernandez-Luna, M.T.; Lavado, R. Exploring the biological impact of bacteria-derived indole compounds on human cell health: Cytotoxicity and cell proliferation across six cell lines. Toxicol. Rep. 2025, 14, 101883. [Google Scholar] [CrossRef] [PubMed]
- Wei, Y.; Zhang, D.; Pan, J.; Gong, D.; Zhang, G. Elucidating the Interaction of Indole-3-Propionic Acid and Calf Thymus DNA: Multispectroscopic and Computational Modeling Approaches. Foods 2024, 13, 1878. [Google Scholar] [CrossRef]
- Salminen, A. Aryl hydrocarbon receptor (AhR) reveals evidence of antagonistic pleiotropy in the regulation of the aging process. Cell Mol. Life Sci. 2022, 79, 489. [Google Scholar] [CrossRef] [PubMed]
- Wei, G.Z.; Martin, K.A.; Xing, P.Y.; Agrawal, R.; Whiley, L.; Wood, T.K.; Hejndorf, S.; Ng, Y.Z.; Low, J.Z.Y.; Rossant, J.; et al. Tryptophan-metabolizing gut microbes regulate adult neurogenesis via the aryl hydrocarbon receptor. Proc. Natl. Acad. Sci. USA 2021, 118, e2021091118. [Google Scholar] [CrossRef]
- Eckers, A.; Jakob, S.; Heiss, C.; Haarmann-Stemmann, T.; Goy, C.; Brinkmann, V.; Cortese-Krott, M.M.; Sansone, R.; Esser, C.; Ale-Agha, N.; et al. The aryl hydrocarbon receptor promotes aging phenotypes across species. Sci. Rep. 2016, 6, 19618. [Google Scholar] [CrossRef]
- Andersson, P.; McGuire, J.; Rubio, C.; Gradin, K.; Whitelaw, M.L.; Pettersson, S.; Hanberg, A.; Poellinger, L. A constitutively active dioxin/aryl hydrocarbon receptor induces stomach tumors. Proc. Natl. Acad. Sci. USA 2002, 99, 9990–9995. [Google Scholar] [CrossRef] [PubMed]
- Sári, Z.; Mikó, E.; Kovács, T.; Jankó, L.; Csonka, T.; Lente, G.; Sebő, É.; Tóth, J.; Tóth, D.; Árkosy, P.; et al. Indolepropionic Acid, a Metabolite of the Microbiome, Has Cytostatic Properties in Breast Cancer by Activating AHR and PXR Receptors and Inducing Oxidative Stress. Cancers 2020, 12, 2411. [Google Scholar] [CrossRef] [PubMed]
- A Phase 1, Randomized, Double-blind, Placebo-controlled, Multicenter, Single and Multiple Ascending Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Oral VP 20629 in Adult Subjects with Friedreich’s Ataxia; 2013. Available online: https://clinicaltrials.gov/study/NCT01898884 (accessed on 14 July 2025).
- Indole-3-PROpionic Acid Clinical Trials—A Pilot Study (iPROACT-Pilot). 2024. Available online: https://clinicaltrials.gov/study/NCT06674018 (accessed on 14 July 2025).
- Restoration of Impaired Microbiota-Mediated Aryl Hydrocarbon Receptor Signaling in Celiac Disease by Oral Tryptophan Supplementation: An Exploratory, Pilot Trial. 2022. Available online: https://clinicaltrials.gov/study/NCT05576038 (accessed on 14 July 2025).
Subjects | Model | Experimental Paradigm | Outcome | Ref. |
---|---|---|---|---|
In vitro studies | ||||
Primary hippocampal neurons; neuroblastoma cells | AD model-exposure to Aβ. | 1 µM IPA for 24 h. | IPA inhibited Aβ-induced lipid peroxidation, prevented neuronal death. | [35] |
Neuroblastoma cells; mouse brain endothelial cells | Neurodegeneration model-induced. | IPA-derived and 5MICA-derived hydrazone hybrids tested at up to 200 μM. | IPA derivatives protected neurons against oxidative stress, inhibited MAO-B, and preserved BBB integrity—supporting their neuroprotective potential. | [36] |
Enteric glial cells | PD model-rotenone (600 nM, 72 h). | IPA at 0.1 μM co-administered with rotenone. | IPA inhibited IL13Rα1/JAK1/STAT6 signaling. | [37] |
BV2 microglial cells and SH-SY5Y neuronal cells | LPS-induced inflammation. | 5 μM IPA for 6 h. | IPA reduced release of TNF-α. | [33] |
Hippocampal HT-22 neurons | H2O2-induced oxidative stress. | pretreatment with or without GPR30 antagonist of G15 for 2 h, incubation with IPA (250 and 500 µm) for 24 h. | IPA alleviated neurodegeneration upregulation of AMPK/SIRT1 pathway, and neuronal apoptosis. | [38] |
Rat brain microvascular endothelial cells | BBB model. | pretreatment with 2 mM IPA in DMSO for 2 h before OGD. | IPA reduced oxidative stress, MMP activity, and apoptosis; effect mediated via activation of PXR and inhibition of NF-κB signaling. | [39] |
hCMEC/D3 endothelial cells | BBB model. | IPA 1 µM for 24 h + Ox-LDL 50 µg/mL for 12 h. | IPA preserved BBB integrity, improved endothelial function, and exerted protective effects via FFAR3 activation. | [21] |
Astrocytes | Release of gliotransmitters which impact cell viability. | IPA 0.001–0.1 mM for 10 min; pre-treatment 24 h. | No effect on ATP and glutamate release from astrocytic cells. | [40] |
Astrocytes | LPS-induced cytotoxicity. | IPA (50 μM) or butyrate before LPS (1 μg/mL) stimulation. | IPA decreased LPS-evoked increases in MCP-1, IL-12, IL-13, and TNF-α levels. | [41] |
Neuroblastoma cells | PD model-Pael-R and α-synuclein overexpression in tunicamycin-induced apoptosis model. | 0.1–1 mM IPA treatment. | IPA suppressed protein aggregation, reduced ER stress, and protected neurons from apoptosis. | [42] |
In vivo studies | ||||
APP/PS1 transgenic mice | AD model. | Oral gavage; indole + IAA + IPA at 20 mg/kg/day for 4 weeks. | IPA (with other indoles) activated AhR, inhibited NF-κB/NLRP3 signaling, reduced release of proinflammatory cytokines and neurodegeneration. | [43] |
5xFAD transgenic mice | AD model. | Clostridium sporogenes (1 × 1010 CFU/day) + xylan (1% w/w) orally, for 30 days. | Improved cognition and memory, reduced Aβ pathology, enhanced synaptic structure, increased IPA levels and IPA-producing bacteria; reduced neuroinflammation, restored gut barrier integrity. | [44] |
APP/PS1 male mice | AD model. | 16-week methionine-restricted diet (0.17% w/w). | Increased serum IPA, improved cognition, reduced neuronal damage. IPA activated PPARα signaling and enhanced gut barrier integrity. | [45] |
mice | AD model-high-fat diet induced. | ABG-001 administered orally at 50 mg/kg/day for 30 days. | ABG-001 increased IPA, IPA targeted heat shock cognate 70 pathway (Hsc70/PKM2/HK2/LC3 and FOXO3a/SIRT1); reduced neuroinflammation. | [46] |
C57BL/6J mice | Diabetes-induced cognitive impairment. | IPA administered orally (10 mg/kg/day for 28 days). | IPA improved cognitive function, and reduced neuroinflammation. | [47] |
Mice | Age-related neurodegeneration model (d-galactose). | 0.5% CMC-Na dissolved in 0.9% NaCl in oral gavage, galactose s.c. 300 mg/kg−1 d- 1×/day for 8 weeks, 50 mg kg−1 IPA. | IPA alleviated neurodegeneration by reducing oxidative stress, inflammation, and neuronal apoptosis. | [38] |
C57BL/6J mice | PD model-rotenone (30 mg/kg, i.g., 4 weeks). | IPA orally at 25, 50, or 100 mg/kg/day for 6 weeks. | IPA reduced EGC gliosis, neuroinflammation, and intestinal/brain barrier damage. | [37] |
C57BL/6 mice | MCAO model of ischemic stroke. | IPA intragastrically administration at 400 μg/20 g/day during MCAO. | IPA restored gut microbiota composition, enhanced intestinal barrier integrity, modulated Treg/Th17 balance, reduced neuroinflammation and infarct size, and improved neurological function. | [48] |
Wild-type and germ-free mice | MCAO model of ischemic stroke. | IPA (50 mg/kg/day, oral gavage) given for 14 days post-stroke. | IPA treatment reduced neuroinflammation, improved neurological function, and rebalanced AHR ligand pools derived from host (kynurenine pathway) and microbiota (tryptophan catabolites). | [49] |
Aged C57BL/6 mice | Postoperative delirium-like behavior induced by anesthesia/surgery. | IPA (0.0625 mmol/kg) in 0.9% NaCl:ethanol (v/v 10:1) injected 2×/day at | IPA modulated aberrant hippocampal neural activity and reduced delirium-like behavior in aged mice. | [50] |
C57BL/6 mice | Sensorineural hearing loss induced by TCP exposure. | 40 mg/kg of IPA orally for 21 days. | IPA preserved hearing and cochlear structure, reduced oxidative stress, and activated immune defense via neutrophil and IFN-γ signaling. | [51] |
Rats | Intrauterine growth retardation model of autism spectrum disorder. | IPA orally administered at 20 mg/kg/day for 4 weeks starting at postnatal week 4. | IPA ameliorated autism-related behaviors, normalized microglial synaptic pruning, reversed NFκB upregulation, and upregulated synaptic markers PSD95 and SYN. | [52] |
Mice with 16p11.2 deletion | Autism spectrum disorder model. | Oral IPA (20 mg/kg/day) or vehicle from postnatal day 42 for 2 weeks, followed by behavioral testing. | 16p11.2 mice exhibited altered gut microbiota and reduced IPA levels; IPA supplementation improved memory and social behavior and restored inhibitory signaling in the hippocampus. | [53] |
C57BL/6 mice | BBB function. | IPA 100 mg/kg/day orally for 12 weeks (in vivo); dietary Trp supplementation (0.1%/0.5%). | IPA preserved BBB integrity, improved endothelial function, and exerted protective effects via FFAR3 activation. | [21] |
Neonatal Sprague-Dawley rats | rBMEC cells | IPA (15 mg/kg, IP) 2×/day (2 days before ligation of the common carotid artery, and a after operation and hypoxia). | IPA preserved BBB integrity by reducing inflammation, oxidative stress, MMP activity, and apoptosis; effect mediated via activation of PXR and inhibition of NF-κB signaling. | [39] |
C57BL/6J, Ifnar1−/−, IL-27ra−/−, GFAP-Cre, and AhRfl/fl mice | Experimental EAE model of MS. | IPA administered via oral gavage at 400 μg/20 g body weight/day daily from day 22 after induction of EAE. | Administration of IPA alleviated EAE symptoms in AhR-dependent way. | [54] |
Female rats | Neurotoxicity induced by epirubicin. | Co-administration of IPA at 20 or 40 mg/kg/day orally for 28 days. | IPA protected against epirubicin-induced neurotoxicity by modulating oxidative and inflammatory pathways. | [55] |
Sprague–Dawley rats | Trp pathway. | Oral IPA at 200 mg/kg; subchronic feeding at 100 mg/day or 350 mg/day for 7 days. | IPA increased brain and plasma levels of IPA and KYNA; Subchronic feeding raised plasma IPA ~19–27× and brain IPA ~2–3×. | [34] |
Male C57BL/6 mice | Sciatic crush model of peripheral nerve injury. | Oral gavage or i.p. injection of IPA; 10 or 20 mg kg−1 per day. | IPA production by Clostridium sporogenes was required for efficient axonal regeneration; IPA delivery after sciatic injury accelerated sensory function recovery. | [56] |
Sprague–Dawley rats | Traumatic brain injury model. | Serum IPA level determination | IPA serum levels initially exhibited a downward trend; after 3 days, the trend was reversed. | [57] |
Patients | Controls | Outcome | Ref. |
---|---|---|---|
Mild cognitive impairment patients who proceeded to AD (n = 19). | Patients with stable mild cognitive impairment (n = 29). | An insignificant increasing trend of plasma IPA from stable mild cognitive impairment to AD. | [58] |
Patients with PD (n = 56). | Age- and sex-matched healthy participants (n = 43). | Higher IPA levels in the plasma of PD patients compared to controls (1.26 vs. 0.83 μM); no correlation of IPA with cognitive and motor status scores of the patients. | [27] |
Patients with stroke (n = 60). | Age-matched controls without stroke (n = 64). | Decreased serum IPA from 1 to 7 days after stroke. | [49] |
Patients with acute cerebral infarction (n = 197). | Participants from a community-based stroke screening program (n = 53). | Low serum IPA served as an independent predictor of acute stroke and poor prognosis. | [59] |
Patients with premanifest (n = 52) and early symptomatic (n = 102) HD. | Healthy controls (n = 140). | Decreased plasma IPA levels in both groups: 138.5 ng/mL (premanifest HD) and 107.7 ng/mL (early symptomatic HD) vs. control (191.1 ng/mL). | [25] |
Patients with relapsing–remitting multiple sclerosis (n = 47). | Healthy controls (n = 43). | EDSS scores were significantly correlated with the urine concentration of IPA (r = 0.5, p < 0.001). | [60] |
Healthy elderly individuals (≥65 years of age) receiving probiotics (n = 32). | Healthy elderly individuals (≥65 years of age) receiving placebo (n = 31). | Elevated IPA levels were positively associated with serum BDNF levels in the probiotics group (r = 0.28, p < 0.05). | [33] |
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Owe-Larsson, M.; Drobek, D.; Iwaniak, P.; Kloc, R.; Urbanska, E.M.; Chwil, M. Microbiota-Derived Tryptophan Metabolite Indole-3-Propionic Acid-Emerging Role in Neuroprotection. Molecules 2025, 30, 3628. https://doi.org/10.3390/molecules30173628
Owe-Larsson M, Drobek D, Iwaniak P, Kloc R, Urbanska EM, Chwil M. Microbiota-Derived Tryptophan Metabolite Indole-3-Propionic Acid-Emerging Role in Neuroprotection. Molecules. 2025; 30(17):3628. https://doi.org/10.3390/molecules30173628
Chicago/Turabian StyleOwe-Larsson, Maja, Dominik Drobek, Paulina Iwaniak, Renata Kloc, Ewa M. Urbanska, and Mirosława Chwil. 2025. "Microbiota-Derived Tryptophan Metabolite Indole-3-Propionic Acid-Emerging Role in Neuroprotection" Molecules 30, no. 17: 3628. https://doi.org/10.3390/molecules30173628
APA StyleOwe-Larsson, M., Drobek, D., Iwaniak, P., Kloc, R., Urbanska, E. M., & Chwil, M. (2025). Microbiota-Derived Tryptophan Metabolite Indole-3-Propionic Acid-Emerging Role in Neuroprotection. Molecules, 30(17), 3628. https://doi.org/10.3390/molecules30173628