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Question details: 90% of serotonin goes to the gut. Could this be a possible mechanism why SSRIs cause weight gain in some people?

90% Serotonin (5-hydroxytryptamine, 5-HT) refers to where it’s made. ~90% of the body’s 5-HT is apparently made by the gastrointestinal Enterochromaffin cell, ~5% each by the myenteric (gut-associated) neurons and the brain (1, 2). However, the bulk of enterochromaffin-derived 5-HT isn’t kept locally but rather deposited into the blood circulation inside densely packed Platelet granules and how it’s delivered to distant sites is still a mystery as is whether it indeed acts as an endocrine hormone (3).

Selective serotonin reuptake inhibitor (SSRI) & Weight Gain: Not Universal, Depends On The Drug

According to a systematic literature review, SSRI’s influence on weight depends on the specific SSRI (see table below from 4).

Weight gain: Paroxetine, Citalopram, Clomipramine, Duloxetine, Escitalopram

Minimal effect: Fluvoxamine, Fluvoxamine CR (Controlled Release), Sertraline, Fluoxetine

Given 5-HT’s abundant production in the GI tract and such striking differences in how different SSRIs influence weight, it would indeed seem obvious to assess

Of three possible ways to assess how SSRIs could affect gut microbiota, i.e., study their effect on human or animal model gut microbiota or their direct effect on microbes, only the last is best studied to date.

Human Gut Microbiota Are Different Between Major depressive disorder (MDD) Patients & Healthy Controls (4 studies as of 2016). Relevance? Not Clear.

As of 2016, a handful of studies compared gut microbiota composition differences between MDD patients and healthy controls. However, none adequately addressed how SSRIs affect gut microbiota composition.

  • At least 4 different studies found fecal microbiota of MDD patients and healthy controls to be different (5, 6, 7, 8). However, with respect to what’s different there’s little consensus between these studies so not yet clear what these data imply. As for how SSRI might affect gut microbiota, only one of these studies (6) addressed that tangentially without coming to a clear conclusion so even less is known about it.
  • Two of these studies even transferred fecal microbiota samples from MDD patients and healthy controls into experimental mice (7) or rats (8) to see if animals that receive MDD fecal microbiota recapitulate depression features, as assessed in experimental animals. Apparently they recapitulated some features such as alterations in FST (forced swim test, Behavioural despair test), and Anhedonia and other anxiety-like behaviors, implying gut microbiota may have a causative role in depression.
  • A few individuals with clinically diagnosed depression including those on antidepressants were part of two linked, much larger gut microbiota studies (9, 10) attempting to build a picture of the core human gut microbiota. While one of these studies found antidepressants to be among the 13 drugs associated with gut microbiota variation, unfortunately the antidepressant in question wasn’t SSRI but rather the SNRI (Serotonin–norepinephrine reuptake inhibitor), Venlafaxine (10). In any case, those on Venlafaxine (23 women and 6 men) were a tiny proportion of the total study population of 1106, making the linkage statistically weak so this is very much preliminary data.

Direct SSRI effect on microbes: Direct & Synergistic Antimicrobial Effects On Microbial Cultures In Vitro

A number of studies reported direct antimicrobial effect of psychotropic drugs like SSRI (11, 12, 13). Majority of such studies found Sertraline to be active against bacteria, fungi and even an eukaryotic parasite, a quite surprising effect since human epidemiological data suggest Sertraline minimally affects weight.

While early speculation suggested such activity is non-specific (23), subsequent studies showed that SSRIs can also synergize with traditional antibiotics (24) and antifungals (25, 26).

SSRI may inhibit or kill microbes through their effect on the microbial Efflux (microbiology) pump, i.e., generalizable energy-dependent mechanisms that vastly different microbes use to pump out substances that are toxic for them. Efflux pump mechanisms being greatly conserved between microbes as disparate as bacteria, fungi and eukaryotic parasites suggests it may be quite difficult for them to successfully mutate molecules that SSRIs target.

On the one hand SSRIs being able to inhibit and/or kill microbes in culture indirectly suggests they could affect human gut microbiota. On the other hand bulk of such data is for Sertraline which epidemiological studies suggest has minimal effect on weight. In other words, we’re still firmly at square one as to whether and how SSRIs could affect human gut microbiota.

Bibliography

1. Gershon, Michael D., Anna B. Drakontides, and Leonard L. Ross. “Serotonin: synthesis and release from the myenteric plexus of the mouse intestine.” Science 149.3680 (1965): 197-199.

2. Gershon, Michael D., and Jan Tack. “The serotonin signaling system: from basic understanding to drug development for functional GI disorders.” Gastroenterology 132.1 (2007): 397-414. https://www.researchgate.net/pro…

3. Gershon, Michael D. “5-Hydroxytryptamine (serotonin) in the gastrointestinal tract.” Current opinion in endocrinology, diabetes, and obesity 20.1 (2013): 14. http://www.ncbi.nlm.nih.gov/pmc/…

4. Dent, Robert, et al. “Changes in body weight and psychotropic drugs: a systematic synthesis of the literature.” PLoS One 7.6 (2012): e36889. http://journals.plos.org/plosone…

5. Naseribafrouei, A., et al. “Correlation between the human fecal microbiota and depression.” Neurogastroenterology & Motility 26.8 (2014): 1155-1162. http://onlinelibrary.wiley.com/d…

6. Jiang, Haiyin, et al. “Altered fecal microbiota composition in patients with major depressive disorder.” Brain, behavior, and immunity 48 (2015): 186-194. Elsevier: Article Locator

7. Zheng, P., et al. “Gut microbiome remodeling induces depressive-like behaviors through a pathway mediated by the host’s metabolism.” Molecular psychiatry 21.6 (2016): 786-796.

8. Kelly, John R., et al. “Transferring the blues: Depression-associated gut microbiota induces neurobehavioural changes in the rat.” Journal of Psychiatric Research 82 (2016): 109-118.

9. Zhernakova, Alexandra, et al. “Population-based metagenomics analysis reveals markers for gut microbiome composition and diversity.” Science 352.6285 (2016): 565-569.

10. Falony, Gwen, et al. “Population-level analysis of gut microbiome variation.” Science 352.6285 (2016): 560-564.

11. Munoz-Bellido, J. L., S. Munoz-Criado, and J. A. Garcıa-Rodrıguez. “Antimicrobial activity of psychotropic drugs: selective serotonin reuptake inhibitors.” International journal of antimicrobial agents 14.3 (2000): 177-180).

12. Samanta, Amalesh, et al. “Evaluation of in vivo and in vitro antimicrobial activities of a selective Serotonin reuptake inhibitor Sertraline Hydrochloride.” Anti-Infective Agents 10.2 (2012): 95-104. https://www.researchgate.net/pro…

13. Kalaycı, Sadık, Selami Demirci, and Fikrettin Sahin. “Antimicrobial Properties of Various Psychotropic Drugs Against Broad Range Microorganisms.” Current Psychopharmacology 3.3 (2014): 195-202. https://www.researchgate.net/pro…

14. Kaatz, Glenn W., et al. “Phenylpiperidine selective serotonin reuptake inhibitors interfere with multidrug efflux pump activity in Staphylococcus aureus.” International journal of antimicrobial agents 22.3 (2003): 254-261. https://www.researchgate.net/pro…

15. Bohnert, Jürgen A., et al. “Efflux inhibition by selective serotonin reuptake inhibitors in Escherichia coli.” Journal of antimicrobial chemotherapy 66.9 (2011): 2057-2060. Efflux inhibition by selective serotonin reuptake inhibitors in Escherichia coli

16. Lass-Flörl, C., et al. “Antifungal properties of selective serotonin reuptake inhibitors against Aspergillus species in vitro.” Journal of Antimicrobial Chemotherapy 48.6 (2001): 775-779. Antifungal properties of selective serotonin reuptake inhibitors against Aspergillus species in vitro

17. Lass-Flörl, Cornelia, et al. “Interaction of sertraline with Candida species selectively attenuates fungal virulence in vitro.” FEMS Immunology & Medical Microbiology 35.1 (2003): 11-15. http://femsim.oxfordjournals.org…

18. Rainey, Meredith M., et al. “The antidepressant sertraline targets intracellular vesiculogenic membranes in yeast.” Genetics 185.4 (2010): 1221-1233. http://www.genetics.org/content/…

19. Zhai, Bing, et al. “The antidepressant sertraline provides a promising therapeutic option for neurotropic cryptococcal infections.” Antimicrobial agents and chemotherapy 56.7 (2012): 3758-3766. The Antidepressant Sertraline Provides a Promising Therapeutic Option for Neurotropic Cryptococcal Infections

20. Treviño-Rangel, Rogelio de J., et al. “Activity of sertraline against Cryptococcus neoformans: in vitro and in vivo assays.” Medical mycology (2015): myv109.

21. Paul, Simon, Roger B. Mortimer, and Marilyn Mitchell. “Sertraline demonstrates fungicidal activity in vitro for Coccidioides immitis.” Mycology (2016): 1-3. http://www.tandfonline.com/doi/p…

22. Palit, Partha, and Nahid Ali. “Oral therapy with sertraline, a selective serotonin reuptake inhibitor, shows activity against Leishmania donovani.” Journal of antimicrobial chemotherapy 61.5 (2008): 1120-1124. Oral therapy with sertraline, a selective serotonin reuptake inhibitor, shows activity against Leishmania donovani

23. Young, T. J., et al. “Antifungal activity of selective serotonin reuptake inhibitors attributed to non-specific cytotoxicity.” Journal of Antimicrobial Chemotherapy 51.4 (2003): 1045-1047. Antifungal activity of selective serotonin reuptake inhibitors attributed to non-specific cytotoxicity

24. Ayaz, Muhammad, et al. “Sertraline enhances the activity of antimicrobial agents against pathogens of clinical relevance.” Journal of Biological Research-Thessaloniki 22.1 (2015): 1. https://www.researchgate.net/pro…

25. Nayak, Rahul, and Jianping Xu. “Effects of sertraline hydrochloride and fluconazole combinations on Cryptococcus neoformans and Cryptococcus gattii.” Mycology 1.2 (2010): 99-105. http://www.tandfonline.com/doi/p…

26. Rossato, Luana, et al. “In vitro synergistic effects of chlorpromazine and sertraline in combination with amphotericin B against Cryptococcus neoformans var. grubii.” Folia microbiologica (2016): 1-5.

https://www.quora.com/How-do-SSRIs-affect-the-microbiome/answer/Tirumalai-Kamala

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