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

ABSTRACT

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:

• gut-brain axis
• gut microbiome
• internalizing disorders
• major depressive disorder
• dysthymia
• generalized anxiety disorder
• psychotropic drugs

Acknowledgments

We would like to acknowledge and thank the late Marten Hofker who had the great wisdom and vision to initiate the Lifelines DAG3/Dutch Microbiome Project. The authors wish to acknowledge the services of the Lifelines Cohort Study, the contributing research centers delivering data to Lifelines and all the study participants. The Lifelines Biobank initiative has been made possible by subsidy from the Dutch Ministry of Health, Welfare and Sport; the Dutch Ministry of Economic Affairs; the University Medical Center Groningen (UMCG); the University of Groningen (UG) and the Northern Provinces of the Netherlands. We would like to thank the Genomic Coordination Center (UMCG and UG) for their support and for providing access to their Peregrine, Calculon, Boxy and Gearshift high performance computing clusters. Metagenomics library preparation and sequencing was done at Novogene. We also thank K. Mc Intyre for English and content editing.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Author contribution

SB performed the analyses in this study, with assistance from AK, and drafted the manuscript. AK implemented statistical methods for association analyses. RG designed and implemented the metagenomic data analysis pipelines. JCS constructed gut – brain module tables. AVV, MFBG, SAS, MAYK, VC and LAB were involved in the extraction and cleaning of phenotypic data and other statistical analysis for the Dutch Microbiome Cohort. AZ, RKW, JF and CW conceived, coordinated and supported the Dutch Microbiome Cohort study. AZ, AK and HMvL conceived, coordinated and supported the current study. HMvL contributed to data collection regarding internalizing disorders. All authors critically revised and approved the manuscript.

Data availability statement

Scripts used for data analysis can be found at:

https://github.com/GRONINGEN-MICROBIOME-CENTRE/DMP and https://github.com/GRONINGEN-MICROBIOME-CENTRE/DMP_MentalHeath

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/19490976.2023.2281360

Additional information

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).