The Gut-Brain Axis: How the Microbiota Affects Mood

"The gut is the second brain" is a popular phrase. Behind it lies concrete biology: the enteric nervous system contains between 200 and 600 million neurons, and approximately 100 trillion microorganisms inhabiting the gastrointestinal tract constantly send signals to the central nervous system. The field has been named the microbiome-gut-brain axis, and 2024-2025 brought a notable harvest of systematic reviews.

How Does the Gut Communicate with the Brain?

A review in Frontiers in Immunology (Zhu et al., 2025) describes three parallel communication channels. The first is neural: the vagus nerve (cranial nerve X) transmits signals from the gut to the brainstem via the nucleus of the solitary tract. It is through this channel that the strain Lactobacillus rhamnosus reduced anxious and depressive behavior in mice in experiments — an effect that completely disappeared after surgical severing of the nerve (vagotomy).

The second channel is endocrine. Gut bacteria influence the hypothalamic-pituitary-adrenal (HPA) axis and gut hormone production through metabolites. Short-chain fatty acids (SCFAs) — acetate, propionate, and butyrate — cross the blood-brain barrier and interact with GPR41 and GPR43 receptors, influencing mood and cognitive function. Reduced butyrate levels correlate with depressive symptoms.

The third channel is immune. Dysbiosis disrupts the integrity of the gut barrier, and bacterial lipopolysaccharides enter the bloodstream, triggering systemic inflammation. The cytokines TNF-alpha, IL-1, and IL-6 cross the blood-brain barrier and alter neurotransmitter metabolism, including serotonin and dopamine.

90% of Serotonin Is Not in the Brain

One of the most surprising figures in gut neurobiology: according to the review by Mehta et al. in Cureus (2025), more than 90% of all serotonin in the body is produced by enterochromaffin cells in the gut using the enzyme tryptophan hydroxylase 1. This serotonin regulates motility, pain sensitivity, and secretion.

Gut serotonin cannot directly cross the blood-brain barrier — the molecule is too large. But through afferent fibers of the vagus nerve, it participates in signal transmission to the brain. In parallel, a number of gut bacteria — Lactobacilli and Bifidobacteria — produce GABA and acetylcholine; Bacillus and Serratia produce dopamine precursors.

What Does Dysbiosis Do to Mood?

A systematic review of 24 case-control studies (Cao et al., BMC Psychiatry, 2025) found consistent patterns in patients with depression: reduced levels of Faecalibacterium and Coprococcus — bacteria that produce butyrate and propionate — and elevated levels of pro-inflammatory Enterobacteriaceae. In anxiety, the picture is similar: elevated Bacteroidetes and Fusobacterium, reduced butyrate producers.

The relationship is bidirectional. Chronic stress through cortisol itself destroys colonies of Lactobacilli and Bifidobacteria, triggering dysbiosis, which in turn amplifies inflammation and anxiety. A review in Molecular Neurobiology (2025) adds: germ-free mice (born and raised without a microbiota) had "dramatically impaired" microglial maturation in the brain — which was restored after SCFA administration.

Do Probiotics Work?

A number of randomized clinical trials recorded significant reductions in depression scale scores with probiotics based on Lactobacillus and Bifidobacterium (Zhu et al., 2025). However, the conditions for success are specific: the dose must exceed 10x10^9 CFU (colony-forming units), and the course must last at least 8 weeks. Short courses and low doses consistently produce no result.

Synbiotics (probiotics plus prebiotics together) showed superiority over each component separately in a number of trials. The Mediterranean diet, rich in fiber and polyphenols, increases the population of Bifidobacterium and stimulates SCFA production. Fecal microbiota transplantation (FMT) showed improvement in patients with depression comorbid with irritable bowel syndrome, but carries risks of pathogen transmission and is not yet standardized.

The main caveat of the research: most clinical trials are small in size and were conducted primarily in China (20 of the 24 studies in the Cao et al. review), which limits the generalizability of the results. The individual composition of the microbiota makes uniform recommendations difficult.