JMNP/
Articles/
2511002205
  • Open Access
  • Review

Gut Feeling: What Gut Microbes Do and Why They Matter

  • Lutfun Nahar

Received: 20 Sep 2025 | Revised: 17 Oct 2025 | Accepted: 23 Oct 2025 | Published: 07 Nov 2025

Abstract

The human gut is home to a bustling city of life. Trillions of bacteria, archaea, fungi, protozoa, and viruses live side by side. These microbial passengers help digest food, train the immune system, and produce molecules that support health far beyond the gut. Many of these species remain unknown, and much of their world is still unexplored. Natural products are chemical treasures from plants, fungi, and other natural sources. These bioactive compounds can shape the microbial community in powerful ways. Some promote helpful microbes and suppress harmful ones. Others are transformed by microbial enzymes into new molecules with stronger effects or for better absorption. This review explores the molecular conversations between gut microbes and natural products. It opens a 21-part series that explores how microbiota and natural product interactions can help prevent disease, restore balance, and guide the future of personalized medicine.

References 

  • 1.
    Thaiss, C.A.; Zmora, N.; Levy, M.; et al. The microbiome and innate immunity. Nature 2016, 535, 65–74. https://doi.org/10.1038/nature18847.
  • 2.
    Johnson, K.V.; Foster, K.R. Why does the microbiome affect behaviour? Nat. Rev. Microbiol. 2018, 16, 647–655. https://doi.org/10.1038/s41579-018-0014-3.
  • 3.
    Afzaal, M.; Saeed, F.; Anjum, F.M.; et al. Human gut microbiota in health and disease: Unveiling the relationship. Front. Microbiol. 2022, 13, 999001. https://doi.org/10.3389/fmicb.2022.999001.
  • 4.
    Lloyd-Price, J.; Abu-Ali, G.; Huttenhower, C. The healthy human microbiome. Nature 2017, 550, 61–66. https://doi.org/10.1038/nature24648.
  • 5.
    Ma, Y.Y.; Li, X.; Yu, J.T.; et al. Therapeutics for neurodegenerative diseases by targeting the gut microbiome: From bench to bedside. Transl. Neurodegener. 2024, 13, 12. https://doi.org/10.1186/s40035-024-00404-1.
  • 6.
    Gounot, J.S. Genomic catalogues of the human gut microbiome: Expanding diversity and function. Nat. Biotechnol. 2022, 40, 1780–1790. https://doi.org/10.1038/s41587-022-01356-4.
  • 7.
    Sutcliffe, I.C.; Trujillo, M.E.; Goodfellow, M. A call to arms for systematists: Revitalising the description of microbial diversity. Antonie Van Leeuwenhoek 2021, 114, 559–564. https://doi.org/10.1007/s10482-021-01539-0.
  • 8.
    Hou, K.; Wu, Z.-X.; Chen, X.-Y.; et al. Microbiota in health and diseases. Nat. Rev. Gastroenterol. Hepatol. 2022, 19, 639–657. https://doi.org/10.1038/s41575-022-00698-4.
  • 9.
    Peterson, C.T. Gut microbiota-mediated biotransformation of medicinal herb-derived natural products: A narrative review of new frontiers in drug discovery. J 2024, 7, 351–372. https://doi.org/10.3390/j7030020.
  • 10.
    Agus, A.; Clément, K.; Sokol, H. Gut microbiota-derived metabolites as central regulators in metabolic disorders. Gut 2021, 70, 1174–1182. https://doi.org/10.1136/gutjnl-2020-323071.
  • 11.
    Wang, Y.; Xu, H.; Zhou, X.; et al. Dysregulated bile acid homeostasis: Unveiling its role in metabolic diseases. Med. Rev. 2024, 4, 262–283. https://doi.org/10.1515/mr-2024-0020.
  • 12.
    Rinninella, E.; Tohumcu, E.; Raoul, P.; et al. The role of diet in shaping human gut microbiota. Best. Pract. Res. Clin. Gastroenterol. 2023, 62–63, 101828. https://doi.org/10.1016/j.bpg.2023.101828.
  • 13.
    Wu, J.; Wang, K.; Wang, X.; et al. The role of the gut microbiome and its metabolites in metabolic diseases. Protein Cell 2021, 12, 360–373. https://doi.org/10.1007/s13238-020-00814-7.
  • 14.
    Hu, X.; Zhang, Y.; Li, J.; et al. Polyphenol-induced gut metabotypes and their implications for host health. Food Funct. 2024, 15, 456–472. https://doi.org/10.1039/D3FO03045A.
  • 15.
    Bolte, L.A.; Vich Vila, A.; Imhann, F.; et al. Long-term dietary patterns are associated with pro-inflammatory and anti-inflammatory features of the gut microbiome. Gut 2021, 70, 1287–1298. https://doi.org/10.1136/gutjnl-2020-322670.
  • 16.
    Zeng, Q.; Feng, X.; Hu, Y.; et al. The human gut microbiota is associated with host lifestyle: A comprehensive narrative review. Front. Microbiol. 2025, 16, 1549160. https://doi.org/10.3389/fmicb.2025.1549160.
  • 17.
    Ye, X.; Li, H.; Anjum, K.; et al. Dual role of indoles derived from intestinal microbiota on human health. Front. Immunol. 2022, 13, 903526. https://doi.org/10.3389/fimmu.2022.903526.
  • 18.
    Hasan, M.N.; Li, T.; Gu, L. Gut microbiota and vagus nerve signalling in health and disease. Front. Neurosci. 2025, 19, 1523456. https://doi.org/10.3389/fnins.2025.1523456.
  • 19.
    O’Riordan, K.J.; Moloney, G.M.; Keane, L.; et al. The gut microbiota-immune-brain axis: Therapeutic implications. Cell Rep. Med. 2025, 6, 101982. https://doi.org/10.1016/j.xcrm.2025.101982.
  • 20.
    Ratsika, A.; Cruz Pereira, J.S.; Lynch, C.M.K.; et al. Microbiota-immune-brain interactions: A lifespan perspective. Curr. Opin. Neurobiol. 2023, 78, 102652. https://doi.org/10.1016/j.conb.2022.102652.
  • 21.
    Wang, Y.J.; Yeh, T.L.; Shih, M.C.; et al. Dietary polyphenols and gut microbiota interactions. Nutrients 2020, 12, 2934. https://doi.org/10.3390/nu12102934.
  • 22.
    Jin, J.; Zhang, H.; Zhang, J.; et al. Gut microbiota and natural product metabolism: Emerging mechanisms. Phytomedicine 2022, 98, 153933. https://doi.org/10.1016/j.phymed.2022.153933.
  • 23.
    Wang, L.Y.; He, L.H.; Xu, L.J.; et al. Short-chain fatty acids: Bridges between diet, gut microbiota, and health. J. Gastroenterol. Hepatol. 2024, 39, 1728–1736. https://doi.org/10.1111/jgh.16619.
  • 24.
    Du, Y. Fermentation of dietary fibers and production of SCFAs. Front. Nutr. 2022, 9, 876543. https://doi.org/10.3389/fnut.2022.876543.
  • 25.
    Kumar, J.; Rani, K.; Datt, C. Molecular link between dietary fibre, gut microbiota and health. Mol. Biol. Rep. 2020, 47, 6229–6237. https://doi.org/10.1007/s11033-020-05611-3.
  • 26.
    Martin-Gallausiaux, C.; Marinelli, L.; Blottière, H.M.; et al. SCFA: Mechanisms and functional importance in the gut. Proc. Nutr. Soc. 2021, 80, 37–49. https://doi.org/10.1017/S0029665120006916.
  • 27.
    Chambers, E.S.; Viardot, A.; Psichas, A.; et al. Effects of targeted delivery of propionate to the human colon on appetite regulation. Gut 2015, 64, 1744–1754. https://doi.org/10.1136/gutjnl-2014-307913.
  • 28.
    Yan, H.; Ajuwon, K.M. Butyrate enhances intestinal barrier function. PLoS ONE 2017, 12, e0179586. https://doi.org/10.1371/journal.pone.0179586.
  • 29.
    Vyhlídalová, B.; Krasulová, K.; Pečinková, P.; et al. Gut microbial catabolites of tryptophan as AhR ligands. Int. J. Mol. Sci. 2020, 21, 2614. https://doi.org/10.3390/ijms21072614.
  • 30.
    Li, S. Modulation of immunity by tryptophan microbial metabolites. Front. Nutr. 2023, 10, 1209613. https://doi.org/10.3389/fnut.2023.1209613.
  • 31.
    Trabelsi, M.S.; Lestavel, S.; Staels, B.; et al. Intestinal bile acid receptors as regulators of glucose homeostasis. Proc. Nutr. Soc. 2017, 76, 192–202. https://doi.org/10.1017/S0029665116002834.
  • 32.
    Yu, H.; Nie, R.; Shen, C. The role of bile acids in regulating glucose and lipid metabolism. Endocr. J. 2023, 70, 359–374. https://doi.org/10.1507/endocrj.EJ22-0544.
  • 33.
    Sharma, A.; Sharma, G.; Im, S.H. Gut microbiota in regulatory T cell generation and function. Gut Microbes 2025, 17, 2516702. https://doi.org/10.1080/19490976.2025.2516702.
  • 34.
    Mukhopadhya, I.; Louis, P. Gut microbiota-derived SCFAs and their role in health and disease. Nat. Rev. Microbiol. 2025, 23, 215–232. https://doi.org/10.1038/s41579-025-01183-w.
  • 35.
    Li, T.H.; Liu, L.; Hou, Y.Y.; et al. C-type lectin receptor-mediated immune recognition of gut microbiota. Gastroenterol. Rep. 2019, 7, 312–321. https://doi.org/10.1093/gastro/goz028.
  • 36.
    Garabatos, N.; Santamaria, P. Gut microbial antigenic mimicry in autoimmunity. Front. Immunol. 2022, 13, 873607. https://doi.org/10.3389/fimmu.2022.873607.
  • 37.
    Shaheen, W.A.; Quraishi, M.N.; Iqbal, T.H. Gut microbiome and autoimmune disorders. Clin. Exp. Immunol. 2022, 209, 161–174. https://doi.org/10.1093/cei/uxac057.
  • 38.
    Gieryńska, M.; Szulc-Dąbrowska, L.; Struzik, J.; et al. Integrity of the intestinal barrier: The involvement of epithelial cells and microbiota. Animals 2022, 12, 145. https://doi.org/10.3390/ani12020145.
  • 39.
    Dmytriv, T.R.; Storey, K.B.; Lushchak, V.I. Intestinal barrier permeability: The influence of gut microbiota, nutrition, and exercise. Front. Physiol. 2024, 15, 1380713. https://doi.org/10.3389/fphys.2024.1380713.
  • 40.
    Schroeder, B.O. Fight them or feed them: How the intestinal mucus layer manages the gut microbiota. Gastroenterol. Rep. 2019, 7, 3–12. https://doi.org/10.1093/gastro/goy052.
  • 41.
    Di Vincenzo, F.; Del Gaudio, A.; Petito, V.; et al. Gut microbiota, intestinal permeability, and systemic inflammation: A narrative review. Intern. Emerg. Med. 2024, 19, 275–293. https://doi.org/10.1007/s11739-023-03374-w.
  • 42.
    Mayer, E.A.; Knight, R.; Mazmanian, S.K.; et al. Gut microbes and the brain: Paradigm shift in neuroscience. J. Neurosci. 2014, 34, 15490–15496. https://doi.org/10.1523/JNEUROSCI.3299-14.2014.
  • 43.
    Jameson, K.G.; Kazmi, S.A.; Ohara, T.E.; et al. Select microbial metabolites in the small intestinal lumen regulate vagal activity via receptor-mediated signalling. iScience 2024, 28, 111699. https://doi.org/10.1016/j.isci.2024.111699.
  • 44.
    Dicks, L.M.T. Gut bacteria and neurotransmitters. Microorganisms 2022, 10, 1838. https://doi.org/10.3390/microorganisms10091838.
  • 45.
    Cheng, J.; Hu, H.; Ju, Y.; et al. Gut microbiota-derived short-chain fatty acids and depression: Deep insight into biological mechanisms and potential applications. Gen. Psychiatry 2024, 37, e101374. https://doi.org/10.1136/gpsych-2023-101374.
  • 46.
    Li, T.; Hasan, M.N.; Gu, L. Bile acids regulation of cellular stress responses in liver physiology and diseases. eGastroenterology 2024, 2, e100074. https://doi.org/10.1136/egastro-2024-100074.
  • 47.
    Barrio, C.; Arias-Sánchez, S.; Martín-Monzón, I. The gut microbiota-brain axis, psychobiotics and its influence on brain and behaviour: A systematic review. Psychoneuroendocrinology 2022, 137, 105640. https://doi.org/10.1016/j.psyneuen.2021.105640.
  • 48.
    Ramadan, Y.N.; Alqifari, S.F.; Alshehri, K.; et al. Microbiome gut-brain axis: Impact on brain development and mental health. Mol. Neurobiol. 2025, 62, 10813–10833. https://doi.org/10.1007/s12035-025-04846-0.
  • 49.
    Zhao, Y.; Zhong, X.; Yan, J.; et al. Gut microbiota-derived metabolites and host signalling. Front. Microbiol. 2022, 13, 956378. https://doi.org/10.3389/fmicb.2022.956378.
  • 50.
    Feng, W.; Liu, J.; Cheng, H.; et al. Dietary compounds in modulation of gut microbiota-derived metabolites. Front. Nutr. 2022, 9, 939571. https://doi.org/10.3389/fnut.2022.939571.
  • 51.
    Kim, C.H. Immune regulation by microbiome metabolites. Immunology 2018, 154, 220–229. https://doi.org/10.1111/imm.12930.
  • 52.
    Yang, W.; Cong, Y. Gut microbiota-derived metabolites in the regulation of host immune responses and immune-related inflammatory diseases. Cell Mol. Immunol. 2021, 18, 866–877. https://doi.org/10.1038/s41423-021-00661-4.
  • 53.
    Zhao, L.; Sui, M.; Zhang, T.; et al. The interaction between ginseng and gut microbiota. Front. Nutr. 2023, 10, 1301468. https://doi.org/10.3389/fnut.2023.1301468.
  • 54.
    Zhang, Z.W.; Cong, L.; Peng, R.; et al. Transformation of berberine to its demethylated metabolites by the CYP51 enzyme in the gut microbiota. J. Pharm. Anal. 2020, 10, 600–608. https://doi.org/10.1016/j.jpha.2020.10.001.
  • 55.
    Chu, L.L.; Huy, N.Q.; Tung, N.H. Microorganisms for ginsenosides biosynthesis: Recent progress, challenges, and perspectives. Molecules 2023, 28, 1437. https://doi.org/10.3390/molecules28031437.
  • 56.
    Ornelas, A.; Dowdell, A.S.; Lee, J.S.; et al. Microbial metabolite regulation of epithelial cell-cell interactions and barrier function. Cells 2022, 11, 944. https://doi.org/10.3390/cells11060944.
  • 57.
    Lee, J.S.; Wang, R.X.; Colgan, S.P. Microbial metabolite regulation of epithelial tight junctions and barrier. In Tight Junctions; Springer: Berlin/Heidelberg, Germany, 2022; pp. 181–200. https://doi.org/10.1007/978-3-030-97204-2_8.
  • 58.
    Paudel, D.; Nair, D.V.T.; Joseph, G.; et al. Gastrointestinal microbiota-directed nutritional and therapeutic interventions for inflammatory bowel disease: Opportunities and challenges. Gastroenterol. Rep. 2024, 12, goae033. https://doi.org/10.1093/gastro/goae033.
  • 59.
    Sun, X.; Shukla, M.; Wang, W.; et al. Unlocking gut-liver-brain axis communication metabolites: Energy metabolism, immunity, and barriers. NPJ Biofilms Microbiomes 2024, 10, 61. https://doi.org/10.1038/s41522-024-00610-9.
  • 60.
    Blachier, F. Metabolism of dietary substrates by intestinal bacteria and consequences for the host intestine. In Metabolism of Alimentary Compounds by the Intestinal Microbiota and Health; Springer: Berlin/Heidelberg, Germany, 2023; pp. 45–144. https://doi.org/10.1007/978-3-031-26322-4_3.
  • 61.
    Konopelski, P.; Mogilnicka, I. Biological effects of indole-3-propionic acid, a gut microbiota-derived metabolite, and its precursor tryptophan. Int. J. Mol. Sci. 2022, 23, 1222. https://doi.org/10.3390/ijms23031222.
  • 62.
    Su, D.; Ağagündüz, D.; Cemali, Ö.; et al. Interaction between natural products and gut microbiota. Curr. Pharmacol. Rep. 2023, 9, 7–31. https://doi.org/10.1007/s40495-022-00309-5.
  • 63.
    Li, C.; Yao, J.; Yang, C.; et al. Gut microbiota-derived short-chain fatty acids act as mediators of the gut-liver-brain axis. Metab. Brain Dis. 2025, 40, 122. https://doi.org/10.1007/s11011-025-01554-5.
  • 64.
    Zhu, S.; Jiang, Y.; Xu, K.; et al. The progress of gut microbiome research related to brain disorders. J. Neuroinflamm. 2020, 17, Article 25. https://doi.org/10.1186/s12974-020-1705-z.
  • 65.
    Wahlström, A.; Sayin, S.I.; Marschall, H.U.; et al. Intestinal crosstalk between bile acids and microbiota and its impact on host metabolism. Cell Metab. 2016, 24, 41–50. https://doi.org/10.1016/j.cmet.2016.05.005.
  • 66.
    Sharp, C.; Foster, K.R. Host control and the evolution of cooperation in host microbiomes. Nat. Commun. 2022, 13, 3567. https://doi.org/10.1038/s41467-022-30971-8.
  • 67.
    Zhang, X.; Li, L.; Butcher, J.; et al. Advancing functional and translational microbiome research using meta-omics approaches. Microbiome 2019, 7, 154. https://doi.org/10.1186/s40168-019-0767-6.
  • 68.
    Brown, A.J.; Goldsworthy, S.M.; Barnes, A.A.; et al. The orphan G protein-coupled receptors GPR41 and GPR43 are activated by propionate and other short-chain carboxylic acids. J. Biol. Chem. 2003, 278, 11312–11319. https://doi.org/10.1074/jbc.M211609200.
  • 69.
    Ariaeenejad, S.; Gharechahi, J.; Foroozandeh Shahraki, M.; et al. Precision enzyme discovery through targeted mining of metagenomic data. Nat. Prod. Bioprospecting 2024, 14, 7. https://doi.org/10.1007/s13659-023-00426-8.
  • 70.
    Zielinski, J.M.; Luke, J.J.; Guglietta, S.; et al. High-throughput multi-omics approaches for clinical trial evaluation and drug discovery. Front. Immunol. 2021, 12, 590742. https://doi.org/10.3389/fimmu.2021.590742.
  • 71.
    Liu, Z.; Ma, A.; Mathé, E.; et al. Network analyses in microbiome based on high-throughput multi-omics data. Brief. Bioinform. 2021, 22, 1639–1655. https://doi.org/10.1093/bib/bbaa005.
  • 72.
    Grieneisen, L.; Blekhman, R.; Archie, E. How longitudinal data can contribute to understanding host genetic effects on the gut microbiome. Gut Microbes 2023, 15, 2178797. https://doi.org/10.1080/19490976.2023.2178797.
  • 73.
    Novak, V.; Andeer, P.F.; King, E.; et al. Breaking the reproducibility barrier with standardized protocols for microbiome research. PLoS Biol. 2025, 23, e3003358. https://doi.org/10.1371/journal.pbio.3003358.
  • 74.
    Peleg, M. Microbial dose-response curves and disinfection efficacy models revisited. Food Biophys. 2020, 15, 289–303. https://doi.org/10.1007/s12393-020-09249-6.
  • 75.
    Sudar, M.; Findrik Blažević, Z. Enzyme cascade kinetic modelling. In Enzyme Cascade Design and Modelling; Springer: Cham, Switzerland, 2021; pp. 91–108. https://doi.org/10.1007/978-3-030-65718-5_6.
Share this article:
Download PDF
DOI
10.53941/jmnp.2025.100022
Issue
Volume 2, Issue 4
How to Cite
Nahar, L. Gut Feeling: What Gut Microbes Do and Why They Matter. Journal of Medicinal Natural Products 2025, 2 (4), 100022. https://doi.org/10.53941/jmnp.2025.100022.
RIS
BibTex
Copyright & License
article copyright Image
Copyright (c) 2025 by the authors.