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Add-on probiotics for inflammatory depression – A double-blind randomized placebo-controlled trial

Söderberg Veibäck, Gustav LU ; Lindahl, Jesper LU ; Suneson, Klara LU ; Tjernberg, Johanna LU ; Ståhl, Darya LU orcid ; Landberg, Rikard ; Asp, Marie LU ; Kjellberg, Amanda ; Falknäs, Fabian and Sjöberg, Klas LU orcid , et al. (2025) In Brain, Behavior, and Immunity 129. p.348-358
Abstract

Previous treatment studies have suggested an antidepressant effect of adjunctive probiotics, but more high-quality randomized controlled trials (RCTs) are needed before clinical implementation. The mechanisms underlying putative antidepressant effects of probiotics are not understood, but one possibility is that they are mediated via short-chain fatty acids (SCFAs) − neuroactive bacterial metabolites with anti-inflammatory properties. The main aim of this study was to test the adjunctive antidepressant efficacy of a Lactobacillus probiotic in depressed patients with concomitant systemic low-grade inflammation, and to test the relationship between treatment response and short-chain fatty acids (SCFAs) in blood and feces. In this 8-week... (More)

Previous treatment studies have suggested an antidepressant effect of adjunctive probiotics, but more high-quality randomized controlled trials (RCTs) are needed before clinical implementation. The mechanisms underlying putative antidepressant effects of probiotics are not understood, but one possibility is that they are mediated via short-chain fatty acids (SCFAs) − neuroactive bacterial metabolites with anti-inflammatory properties. The main aim of this study was to test the adjunctive antidepressant efficacy of a Lactobacillus probiotic in depressed patients with concomitant systemic low-grade inflammation, and to test the relationship between treatment response and short-chain fatty acids (SCFAs) in blood and feces. In this 8-week double-blind RCT, patients with major depressive disorder (MDD), BMI ≥ 25 kg/m2 and high-sensitivity C-reactive protein (hs-CRP) ≥ 1 mg/L were randomized to receive either a Limosilactobacillus reuteri (L. reuteri) probiotic supplement or placebo added to their regular and stable treatment. Primary outcomes were changes in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score and “inflammatory depressive symptoms” defined as a composite score of Patient Health Questionnaire-9 items related to sleep disturbance, energy levels, and appetite disturbance. Secondary outcomes included anxiety symptoms, anhedonia, insomnia, fatigue, and gastrointestinal symptoms. SCFAs were analyzed in blood and feces pre- and post-intervention. In a modified intention-to-treat analysis including all patients with at least one post-baseline visit (n = 75), there were no significant effects of probiotics relative to placebo on any of the primary or secondary outcomes (all p > 0.25). Lower baseline levels, and a greater treatment-associated increase, of fecal formic acid was significantly associated with a decrease in MADRS score in the probiotics group (p < 0.01). While we did not observe an overall antidepressant effect of add-on L. reuteri probiotic for overweight depressed patients with systemic low-grade inflammation, we found preliminary evidence for anti-inflammatory formic acid as a biomarker, and possibly a mediator, of treatment response.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Inflammation, Major depressive disorder, Probiotics, RCT, Short-chain fatty acids
in
Brain, Behavior, and Immunity
volume
129
pages
11 pages
publisher
Elsevier
external identifiers
  • pmid:40484149
  • scopus:105008779824
ISSN
0889-1591
DOI
10.1016/j.bbi.2025.06.002
language
English
LU publication?
yes
id
4142a56a-65cb-4c9c-a5fc-3eae32c9f5e4
date added to LUP
2025-11-04 11:40:38
date last changed
2025-11-04 11:41:33
@article{4142a56a-65cb-4c9c-a5fc-3eae32c9f5e4,
  abstract     = {{<p>Previous treatment studies have suggested an antidepressant effect of adjunctive probiotics, but more high-quality randomized controlled trials (RCTs) are needed before clinical implementation. The mechanisms underlying putative antidepressant effects of probiotics are not understood, but one possibility is that they are mediated via short-chain fatty acids (SCFAs) − neuroactive bacterial metabolites with anti-inflammatory properties. The main aim of this study was to test the adjunctive antidepressant efficacy of a Lactobacillus probiotic in depressed patients with concomitant systemic low-grade inflammation, and to test the relationship between treatment response and short-chain fatty acids (SCFAs) in blood and feces. In this 8-week double-blind RCT, patients with major depressive disorder (MDD), BMI ≥ 25 kg/m<sup>2</sup> and high-sensitivity C-reactive protein (hs-CRP) ≥ 1 mg/L were randomized to receive either a Limosilactobacillus reuteri (L. reuteri) probiotic supplement or placebo added to their regular and stable treatment. Primary outcomes were changes in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score and “inflammatory depressive symptoms” defined as a composite score of Patient Health Questionnaire-9 items related to sleep disturbance, energy levels, and appetite disturbance. Secondary outcomes included anxiety symptoms, anhedonia, insomnia, fatigue, and gastrointestinal symptoms. SCFAs were analyzed in blood and feces pre- and post-intervention. In a modified intention-to-treat analysis including all patients with at least one post-baseline visit (n = 75), there were no significant effects of probiotics relative to placebo on any of the primary or secondary outcomes (all p &gt; 0.25). Lower baseline levels, and a greater treatment-associated increase, of fecal formic acid was significantly associated with a decrease in MADRS score in the probiotics group (p &lt; 0.01). While we did not observe an overall antidepressant effect of add-on L. reuteri probiotic for overweight depressed patients with systemic low-grade inflammation, we found preliminary evidence for anti-inflammatory formic acid as a biomarker, and possibly a mediator, of treatment response.</p>}},
  author       = {{Söderberg Veibäck, Gustav and Lindahl, Jesper and Suneson, Klara and Tjernberg, Johanna and Ståhl, Darya and Landberg, Rikard and Asp, Marie and Kjellberg, Amanda and Falknäs, Fabian and Sjöberg, Klas and Lavebratt, Catharina and Wolkowitz, Owen M. and Lindqvist, Daniel}},
  issn         = {{0889-1591}},
  keywords     = {{Inflammation; Major depressive disorder; Probiotics; RCT; Short-chain fatty acids}},
  language     = {{eng}},
  pages        = {{348--358}},
  publisher    = {{Elsevier}},
  series       = {{Brain, Behavior, and Immunity}},
  title        = {{Add-on probiotics for inflammatory depression – A double-blind randomized placebo-controlled trial}},
  url          = {{http://dx.doi.org/10.1016/j.bbi.2025.06.002}},
  doi          = {{10.1016/j.bbi.2025.06.002}},
  volume       = {{129}},
  year         = {{2025}},
}