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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.


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