"Microbes against the blues": caring for your intestinal flora can help with depression and anxiety

A new review article in Nature has distilled what we’ve learned about the gut-brain axis in recent years and made a simple point: mood and microbiota are linked—so much so that large clinical trials of probiotics and other “psychobiotic” interventions are on the horizon. From stool donors (FMT) to strain-specific capsules and diet programs, there are several approaches; the question is no longer “does it work?” but rather who, in what, and through what means.

Background of the study

Depression and anxiety disorders remain the leading causes of disability, and standard approaches - psychotherapy and pharmacotherapy - do not help everyone and often provide an incomplete answer. Against this background, the idea of the "gut-brain axis" has gained strength in recent years: the microbiota forms metabolites, modulates immunity and, through the vagus nerve and hormonal axes, influences stress reactions and neurotransmitter systems. The connection does not seem exotic: in animals, microbiota transplantation changes behavior, and in humans, the composition and function of the microbial community correlates with the severity of symptoms.

Three classes of interventions are emerging in the clinic. The broadest tool is nutrition, with an emphasis on whole foods, fiber, and polyphenols: this is the prebiotic “fuel carrier” for beneficial microbes and a relatively safe base. A more targeted tool is probiotics/“psychobiotics”: strains that can influence inflammation, neurotransmitter synthesis and metabolism, and the stress axis. And finally, the “total reset” is microbiota transplantation (FMT), which is already showing encouraging signs in small trials in resistant depression, but requires strict safety and selection protocols.

At the same time, science is still unraveling the causality and mechanisms. “Healthy microbiota” may look different in different people, and the clinical effect is often determined not so much by the taxonomic composition as by the function of the community - what molecules it produces. Therefore, multiomic panels (metabolites, cytokines, stress hormones) and patient stratification are promising: who is suitable for a diet as a basis, who - adjuvant probiotics, and who needs more radical interventions.

The main limitations are also clear: small samples, heterogeneous protocols, lack of strain and dose standardization, limited reproducibility of biomarkers. The next step is large randomized studies with parallel mechanisms to establish which interventions and for which subgroups of patients actually improve outcomes - both as stand-alone mood modulators and as an add-on to standard therapy.

What research has already shown

• Microbiota transplant (FMT)
  Early small trials in patients with treatment-resistant depression are showing encouraging signs, with some participants reporting rapid and significant improvement, although the effect varies between individuals. Several RCTs are currently underway for depression, bipolar disorder, OCD, and ADHD.
• Probiotics as an adjunct to therapy
  A meta-analysis of 7 RCTs found that probiotics improve symptoms when added to standard treatment, but do not work alone. In a pilot RCT in people with incomplete responses to antidepressants, supplementation with a multi-strain probiotic for 8 weeks produced greater reductions in depression and anxiety than placebo.
• Diet as a 'broad key'
  Mediterranean-style diet interventions reduced depressive symptoms; the logic is simple: dietary fiber and polyphenols are 'fuel' for microbes (prebiotics), which restructures the ecosystem on a broad front.

How Microbes "Talk" to the Brain

Animal studies have already linked microbiota and depressive-anxious phenotypes; a correlative base is accumulating in humans. There are several communication channels, and they operate simultaneously:

• Immune system: microbes “calibrate” inflammation and cytokine levels.
• HPA (hypothalamic-pituitary-adrenal) axis: influence on stress responses and cortisol.
• Vagus nerve: a direct "wire" from the enteric nervous system to the brain.
• Microbial metabolites: short-chain fatty acids can penetrate the BBB, while others can alter the synthesis of neurotransmitters and growth factors.

Important: composition is not everything. Even if the flora composition changes slightly, the functions (what molecules are produced) can shift significantly; therefore, scientists are moving to multiomics: joint analysis of genes, proteins, metabolites and immune markers.

What works better - "total reboot" or spot strains?

• FMT provides a "hard reset," but it's hard to know which microbes were doing the trick.
• Psychobiotics are potentially targeted: in one trial, a strain of Bacillus (which produces dopamine and norepinephrine) could add to the effects of SSRIs, which act more through serotonin. This mechanistic complementarity is one reason to consider probiotics as an adjuvant rather than a replacement for therapy.

Where are the bottlenecks (and why it's too early to run for the capsules)

• Small samples and noisy biomarkers. In a number of studies, neither cytokines nor BDNF changed - the signal is drowned in variability; large RCTs with mechanisms are needed.
• There is no "single healthy microbiota." Different people have different "norms," and functions are often "duplicated" by different species, making standardization difficult.
• Money and motivation. Probiotics are difficult to patent, the margin is lower than pharma - large mechanistic RCTs are difficult to finance without government support and philanthropy.

What this could mean for the clinic in the coming years

• Patient stratification: multiomic panels (microbial metabolites, immune and hormonal markers) will help predict response to antidepressants and psychobiotics and select combinations.
• Diet as a base, psychobiotics as a booster: food changes the ecosystem broadly, capsules - locally; together they can work better than separately.
• Combination regimens: the idea of "antidepressant + dopamine/norepinephrine blocking strain" looks promising in anxious depression, where SSRIs are often "weaker".

What to Keep in Mind Right Now (According to Researchers)

• We need large RCTs that simultaneously collect mechanistic data (immune markers, neurotransmitters, metabolites, neuroimaging).
• Microbiota management is not a substitute for therapy. The best quality of evidence today is for adjuvant approaches (diet/probiotics plus standard care).
• Personalization is inevitable: effects depend on the initial microbial profile, lifestyle and genetics.

Authors' comment

The authors of the Nature article are cautiously optimistic: the gut-brain connection has already outgrown the exotic stage, but before it can be used in everyday clinical practice, it needs a more rigid, mechanistic foundation. Their key messages:

• Not a "happiness pill", but a modulator. Microbiota is one of the levers that influence depression and anxiety, but not a replacement for psychotherapy and pharmacotherapy. The maximum benefit is expected in the adjuvant format (diet/psychobiotics plus standard care).
• From composition to function. The focus shifts from "who lives in the gut" to "what does it do": metabolites, immune and hormonal circuits, activation of the vagus nerve. This requires multi-omic panels and parallel collection of mechanisms in RCTs.
• Personalization is inevitable. There is no “one healthy microbiota”; response to diet, probiotics, or FMT depends on the baseline microbial profile, lifestyle, and genetics. A move to stratified and even N-of-1 protocols is likely.
• Probiotics as a booster, not a solo. In meta-analyses, the best signal is when strains are added to therapy (e.g., complementing serotonergic antidepressants with effects on dopamine/norepinephrine or inflammation).
• FMT - only under strict rules. There is potential, but it is a "heavy" tool with requirements for safety and donor selection; FMT's place is in large RCTs, not in free use.
• Regulation and money are a real barrier. Live drugs are difficult to patent and standardize; without government funding and clear rules for Live Biotherapeutic Products, progress can be slow.
• Communication with the patient is critical. It is necessary to set expectations correctly: improvements are possible, but modest and not for everyone; independent cancellation of standard therapy is a risk.

Conclusion

The connection between gut microbes and mental health is no longer exotic, but a promising direction for clinical research. For now, the most realistic scenarios are diet + probiotics as a supplement to treatment, with subsequent personalization based on multiomics data. The next step is large mechanistic RCTs that will tell which microbes and in which situations help bring depression and anxiety into remission.

Source: Simon Makin. Why nurturing the gut microbiota could resolve depression and anxiety. Nature (Outlook), August 18, 2025. doi:https://doi.org/10.1038/d41586-025-02633-4