Gut feelings: the relations between depression, anxiety, psychotropic drugs and the gut microbiome

Gut Microbes. 2023 Dec;15(2):2281360. doi: 10.1080/19490976.2023.2281360. Epub 2023 Nov 28.


The gut microbiome is involved in the bi-directional relationship of the gut - brain axis. As most studies of this relationship are small and do not account for use of psychotropic drugs (PTDs), we explored the relations of the gut microbiome with several internalizing disorders, while adjusting for PTDs and other relevant medications, in 7,656 Lifelines participants from the Northern Netherlands (5,522 controls and 491 participants with at least one internalizing disorder). Disorders included dysthymia, major depressive disorder (MDD), any depressive disorder (AnyDep: dysthymia or MDD), generalized anxiety disorder (GAD) and any anxiety disorder (AnyAnx: GAD, social phobia and panic disorder). Compared to controls, 17 species were associated with depressive disorders and 3 were associated with anxiety disorders. Around 90% of these associations remained significant (FDR <0.05) after adjustment for PTD use, suggesting that the disorders, not PTD use, drove these associations. Negative associations were observed for the butyrate-producing bacteria Ruminococcus bromii in participants with AnyDep and for Bifidobacterium bifidum in AnyAnx participants, along with many others. Tryptophan and glutamate synthesis modules and the 3,4-Dihydroxyphenylacetic acid synthesis module (related to dopamine metabolism) were negatively associated with MDD and/or dysthymia. After additional adjustment for functional gastrointestinal disorders and irritable bowel syndrome, these relations remained either statistically (FDR <0.05) or nominally (P < 0.05) significant. Overall, multiple bacterial species and functional modules were associated with internalizing disorders, including gut - brain relevant components, while associations to PTD use were moderate. These findings suggest that internalizing disorders rather than PTDs are associated with gut microbiome differences relative to controls.

Keywords: dysthymia; generalized anxiety disorder; gut microbiome; gut-brain axis; internalizing disorders; major depressive disorder; psychotropic drugs.

MeSH terms

  • Anxiety
  • Anxiety Disorders
  • Depression
  • Depressive Disorder, Major* / drug therapy
  • Gastrointestinal Microbiome*
  • Humans
  • Psychotropic Drugs


  • Psychotropic Drugs

Grants and funding

SB and MS are supported by EUCAN-connect, a federated FAIR platform enabling large-scale analysis of high-value cohort data connecting Europe and Canada in personalized health. RG is supported by the collaborative TIMID project (LSHM18057-SGF) financed by the PPP allowance made available by Top Sector Life Sciences & Health to Samenwerkende Gezondheidsfondsen (SGF) to stimulate public-private partnerships and co-financing by health foundations that are part of the SGF. AZ is supported by European Research Council (ERC) Starting Grant 715772, Netherlands Organization for Scientific Research (NWO) VIDI grant 016.178.056 and CardioVasculair Onderzoek Nederland (CVON) grant 2018-27. AZ and AK are supported by NWO Gravitation grant ExposomeNL 024.004.017. JF is supported by the Dutch Heart Foundation IN-CONTROL (CVON2018-27), the ERC Consolidator grant (grant agreement No. 101001678), NWO-VICI grant VI.C.202.022, the AMMODO Science Award 2023 for Biomedical Sciences from Stichting Ammodo, and the Netherlands Organ-on-Chip Initiative, an NWO Gravitation project (024.003.001) funded by the Ministry of Education, Culture and Science of the government of The Netherlands. RKW is supported by the Seerave Foundation and the Dutch Digestive Foundation (16-14). CW is supported by an ERC advanced grant (ERC-322698) and an NWO Spinoza award (NWO SPI 92-266). Sequencing of the cohort was also funded by a CVON grant (CVON 2012-03) to JF and AZ. HMvL was supported by a NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation and an NWO VENI grant (NWO-ZonMW 09150161810021).