Feeling Pooped? Gut Microbiome Interventions for Depression

Posted by Seona Patel on April 5, 2025 in depression, Mental Illness, Neuroscience | Leave a comment

We often think of depression as a disorder rooted in the brain—a chemical imbalance or faulty wiring. But what if the roots of depression extend far beyond and below the skull, into an unexpected place? Scientists are increasingly finding that the gut microbiome—a vast ecosystem of bacteria, viruses, and fungi living in your gut—could play a significant role in mental health. 

Depression is a mental health disorder characterized by persistent feelings of sadness, fatigue, lack of pleasure, and other related symptoms. Approximately 280 million people are affected by depression worldwide, and current treatments such as antidepressants often take 5–8 weeks to have an effect—if they do at all^1,2. For decades, depression has been studied through the lens of the brain, focusing on neurotransmitters like serotonin and dopamine that are known for their roles in mood regulation. However, recent research suggests that the gut microbiome may play a key role (Figure 1). These microbes don’t just help digest food; they produce neurotransmitters, regulate inflammation, and even communicate with the brain via the vagus nerve. In fact, the neurons and microbes in the gut produce about 90% of the body’s serotonin. Certain gut bacteria, such as Lactobacillus plantarum and Escherichia coli, can even make serotonin themselves³. Just like how signals from the brain travel down to the gut through the vagus nerve to help regulate processes such as digestion, the neurotransmitters and metabolites produced by gut microbes can activate the vagus nerve and relay signals to the brain. This two-way communication system, called the gut-brain axis, could help explain why gut health and mental health are closely linked. 

The Altered Microbiome in Depression

Recent studies have shown that the composition and quantity of microbes in the gut are different in patients with depression compared to healthy individuals. However, it is still debated which specific genus of microbes primarily causes depression and whether this actually could be boiled down to one genus. One recent study performed genomic profiling of stool samples from healthy humans and patients with mild, moderate, or severe major depressive disorder (MDD). They found that differences in microbiome diversity reflected the severity of MDD, where Bacteroides was increased in moderate and severe MDD, while Ruminococcus and Eubacterium were decreased in the severe group. Taking this research a step further, the scientists then developed a panel of microbiota markers (including 37 gut bacteria species) that allowed them to distinguish MDD patients with different severities, demonstrating a promising strategy for objectively assessing the severity of MDD⁴.

Although this study shows that changes in the gut microbiome correlate with MDD severity, it does not demonstrate that changes in microbiome diversity cause depression or vice versa. Additionally, changes in microbiome composition are not always consistent across studies, as many factors such as your diet, medications, and more impact your gut microbiome composition. This has led to recent interest in finding personalized diets or probiotics for patients based on their gut composition, though more research is needed to see if this is more effective than non-personalized treatments.   

Regardless, genomic studies like these have helped the field identify microbes that are altered in depression, and researchers are now taking this further to explore how reintroducing microbes, through probiotics or even fecal samples from healthy patients, into the gut of depressed patients could affect depression symptoms. We’ll get into the progress of this research next!

Can we improve mental health by targeting the gut?

But First, the Dark Side of Antibiotics 

Antibiotics kill bacteria—regardless of whether they are beneficial or not. They do this by targeting bacterial structures crucial to their survival, such as the cell wall, DNA replication machinery, and protein synthesis systems. But this approach often leads to dysbiosis—an imbalance or disruption in the composition of bacteria. You might have experienced this firsthand: after a course of antibiotics for surgery or infection, some people report feeling unusually fatigued or in a low mood beyond postoperative discomfort. This isn’t just a coincidence; research suggests that antibiotic-induced dysbiosis can induce inflammation as the gut barrier weakens, reduce serotonin production, and increase the risk of mental health disorders⁵. 

Recognizing the impact of antibiotics on the gut-brain axis, researchers are investigating ways to minimize harm, such as prescribing probiotics alongside antibiotics or performing fecal microbiota transplant (FMT) therapy in those at risk of mental health complications. 

Probiotics and Prebiotics

Probiotics are live bacteria that can provide health benefits when consumed, while prebiotics are dietary fibers that nourish gut bacteria. You’ve likely seen probiotics in action without realizing it–foods like yogurt, kimchi, sauerkraut, kefir, and kombucha line grocery store shelves, boasting “live and active cultures” (Figure 3). These fermented foods contain bacterial strains like Lactobacillus and Bifidobacterium, which may help maintain a balanced microbiome. Prebiotics–their less-famous counterparts–are found in fiber-rich foods like garlic, onions, bananas, and oats.

Some studies suggest that certain strains of probiotics may alleviate symptoms of depression by supporting a healthier microbiome. For example, broad-spectrum antibiotic administration induced changes in the gut microbiome composition, increased depression-like behavior, reduced social recognition, and altered neuronal firing in the hippocampus (a brain region involved in learning and memory) in mice⁶. These phenotypes were reversed following probiotic treatment with Lactobacillus casei. Additionally, the authors found that levels of bacteria in the Lachnospiraceae family were decreased in animals given antibiotics, which is also known to occur in patients with MDD. Several bacterial species within this family degrade fiber into short-chain fatty acids, which are anti-inflammatory metabolites that support the intestinal barrier. Probiotic treatment restored Lachnospiraceae levels, and higher abundance of these bacteria correlated with lower depression-like behaviors.

While human research is still limited, smaller clinical trials hint that specific probiotic blends, or even a diet rich in prebiotics, could complement traditional depression treatments. One 2022 study tested high-dose probiotic supplementation as an add-on to standard depression treatment in MDD patients⁷. They found that probiotic treatment containing several strains within the Streptococcus, Bifidobacterium, Lactobacillus, and Bulgaricus genera improved depressive symptoms  (55% remission rate vs. 40% in those given a placebo), though effects were strongest in patients who were more compliant with taking the probiotics daily. Treatment also modulated gut microbiota composition and reduced neural responses to negative emotional stimuli in brain regions such as the putamen, which is involved in emotional processing. These results suggest that probiotics may offer a novel approach to managing depression through promoting gut health.

Prebiotics, while less studied, appear to support these effects by fueling the growth of gut microbes. Pre-biotic fibers such as inulin (found in garlic and bananas) promote the growth of Bifidobacterium, which is often reduced in patients with MDD⁸. However, results from clinical trials in MDD patients given prebiotics have not demonstrated as much promise as probiotics, as longer term trials are needed to pinpoint optimal doses, individual variability in treatment response, and the synergy between prebiotics, probiotics, and antidepressants⁹. 

Fecal Microbiota Transplantation (FMT)

FMT – the transfer of processed stool from a healthy donor into a patient’s intestines – might sound hard to stomach (pun intended) compared to simply taking probiotic pills. But when we consider how much more bacterial diversity is in a stool sample compared to a bottle of probiotics, it starts to make sense why doctors are exploring this for tough cases. While probiotics introduce specific strains, FMT aims to completely rebuild the gut microbiome composition, like replanting an entire forest rather than just adding a few new trees. 

Currently used for severe gut infections like C. difficile (Figure 4), FMT is now being studied for MDD due to its ability to restore microbiome diversity. Several studies have explored whether the gut microbiota from patients with MDD is involved in the development of MDD^10,11,12. In order to test this, scientists performed FMT from patients with MDD into the intestine of rats to determine whether this would induce depression-like behaviors in the rat. In one study, they found that FMT from depressed patients into rats resulted in these previously healthy rats developing classic symptoms of depression, such as losing interest in sweet treats they normally enjoyed (anhedonia), becoming more anxious in open spaces, and showing changes in serotonin metabolism¹¹. The results of these studies provide evidence that the gut microbiome might play a causal role in the development of depression, at least in rodents.

A few small studies have looked into the efficacy of FMT as a therapeutic intervention for MDD in humans. One case study report on a 79-year-old female patient with depression who discontinued her medication and underwent FMT from her healthy grandson reported improved cognitive function and depression symptoms within 4 weeks of FMT, and she remained in remission almost a year later¹³. Another 2023 pilot study aimed to assess whether FMT is safe and feasible for MDD, which is critical to assess before larger-scale clinical trials are performed¹⁴. This study found no serious adverse outcomes to FMT, indicating that it is a safe option, and larger-scale studies are needed to see if FMT could improve symptoms of MDD.  

Conclusion

The idea that our mental well-being is influenced by trillions of microbes in our gut may sound like science fiction, but ongoing research is providing more evidence to support this. In people with depression, the gut microbiome often exhibits reduced diversity and an imbalance of beneficial and harmful bacteria. These changes can amplify inflammation, alter neurotransmitter production, and disrupt the gut-brain axis. While microbiome-based therapies are still in the early stages, the evidence is compelling: a healthy gut might mean a healthier mind. Future treatments and areas of research include personalized probiotics, microbiome testing for depression risk and severity, and psychobiotics–drugs designed to target gut-brain pathways. 

So the next time you feel off, remember: your brain isn’t the only thing controlling your mood. Your gut might have a say, too! 

References

1. World. (2023, March 31). Depressive disorder (depression). Who.int; World Health Organization: WHO. https://www.who.int/news-room/fact-sheets/detail/depression

2. Henssler, J. (2018, April 3). Trajectories of Acute Antidepressant Efficacy: How Long to Wait for Response? A Systematic Review and Meta-Analysis of Long-Term, Placebo-Controlled Acute Treatment Trials. Psychiatrist.com; The Journal of Clinical Psychiatry. https://www.psychiatrist.com/jcp/extending-antidepressant-treatment-how-long-to-wait-for-response/

3. Strandwitz, P. (2018). Neurotransmitter modulation by the gut microbiota. Brain Research, 1693, 128–133. https://doi.org/10.1016/j.brainres.2018.03.015

4. Hu, X., Li, Y., Wu, J., Zhang, H., Huang, Y., Tan, X., Wen, L., Zhou, X., Xie, P., Oluwatayo Israel Olasunkanmi, Zhou, J., Sun, Z., Liu, M., Zhang, G., Yang, J., Zheng, P., & Xie, P. (2023). Changes of gut microbiota reflect the severity of major depressive disorder: a cross sectional study. Translational Psychiatry, 13(1). https://doi.org/10.1038/s41398-023-02436-z

5. Dinan, K., & Dinan, T. (2022). Antibiotics and mental health: The good, the bad and the ugly. Journal of Internal Medicine, 292(6), 858–869. https://doi.org/10.1111/joim.13543

6. Guida, F., Turco, F., Iannotta, M., De Gregorio, D., Palumbo, I., Sarnelli, G., Furiano, A., Napolitano, F., Boccella, S., Luongo, L., Mazzitelli, M., Usiello, A., De Filippis, F., Iannotti, F. A., Piscitelli, F., Ercolini, D., de Novellis, V., Di Marzo, V., Cuomo, R., & Maione, S. (2018). Antibiotic-induced microbiota perturbation causes gut endocannabinoidome changes, hippocampal neuroglial reorganization and depression in mice. Brain, Behavior, and Immunity, 67, 230–245. https://doi.org/10.1016/j.bbi.2017.09.001

7. Schaub, A.-C., Schneider, E., Vazquez-Castellanos, J. F., Schweinfurth, N., Kettelhack, C., Doll, J. P. K., Yamanbaeva, G., Mählmann, L., Brand, S., Beglinger, C., Borgwardt, S., Raes, J., Schmidt, A., & Lang, U. E. (2022). Clinical, gut microbial and neural effects of a probiotic add-on therapy in depressed patients: a randomized controlled trial. Translational Psychiatry, 12(1). https://doi.org/10.1038/s41398-022-01977-z

8. Bouhnik, Y., Raskine, L., Champion, K., Andrieux, C., Penven, S., Jacobs, H., & Simoneau, G. (2007). Prolonged administration of low-dose inulin stimulates the growth of bifidobacteria in humans. Nutrition Research, 27(4), 187–193. https://doi.org/10.1016/j.nutres.2007.01.013

9. Zhang, Q., Chen, B., Zhang, J., Dong, J., Ma, J., Zhang, Y., Jin, K., & Lu, J. (2023). Effect of prebiotics, probiotics, synbiotics on depression: results from a meta-analysis. BMC Psychiatry, 23(1). https://doi.org/10.1186/s12888-023-04963-x

10. Zheng, P., Zeng, B., Zhou, C., Liu, M., Fang, Z., Xu, X., Zeng, L., Chen, J., Fan, S., Du, X., Zhang, X., Yang, D., Yang, Y., Meng, H., Li, W., Melgiri, N. D., Licinio, J., Wei, H., & Xie, P. (2016). Gut microbiome remodeling induces depressive-like behaviors through a pathway mediated by the host’s metabolism. Molecular Psychiatry, 21(6), 786–796. https://doi.org/10.1038/mp.2016.44

11. Kelly, J. R., Borre, Y., O’ Brien, C., Patterson, E., El Aidy, S., Deane, J., Kennedy, P. J., Beers, S., Scott, K., Moloney, G., Hoban, A. E., Scott, L., Fitzgerald, P., Ross, P., Stanton, C., Clarke, G., Cryan, J. F., & Dinan, T. G. (2016). Transferring the blues: Depression-associated gut microbiota induces neurobehavioural changes in the rat. Journal of Psychiatric Research, 82, 109–118. https://doi.org/10.1016/j.jpsychires.2016.07.019

12. Knudsen, J. K., Michaelsen, T. Y., Caspar Bundgaard-Nielsen, Nielsen, R. E., Hjerrild, S., Leutscher, P., Wegener, G., & Sørensen, S. (2021). Faecal microbiota transplantation from patients with depression or healthy individuals into rats modulates mood-related behaviour. Scientific Reports, 11(1). https://doi.org/10.1038/s41598-021-01248-9

13.  Cai, T., Shi, X., Yuan, L., Tang, D., & Wang, F. (2019). Fecal microbiota transplantation in an elderly patient with mental depression. International Psychogeriatrics, 31(10), 1525–1526. https://doi.org/10.1017/s1041610219000115

14. Green, J. E., Berk, M., Mohebbi, M., Loughman, A., McGuinness, A. J., Castle, D., Chatterton, M. L., Perez, J., Strandwitz, P., Athan, E., Hair, C., Nierenberg, A. A., Cryan, J. F., & Jacka, F. (2023). Feasibility, Acceptability, and Safety of Faecal Microbiota Transplantation in the Treatment of Major Depressive Disorder: A Pilot Randomized Controlled Trial. The Canadian Journal of Psychiatry, 68(5), 315–326. https://doi.org/10.1177/07067437221150508

15. Liang, S., Wu, X., Hu, X., Wang, T., & Jin, F. (2018). Recognizing Depression from the Microbiota–Gut–Brain Axis. International Journal of Molecular Sciences, 19(6), 1592–1592. https://doi.org/10.3390/ijms19061592

16. Ju, W. (2025).  4.1 The Gut Microbiome and its Impact on the Brain – Neuroscience: Canadian 1st Edition Open Textbook. http://neuroscience.openetext.utoronto.ca/chapter/chapter-1-the-gut-microbiome-and-its-impact-on-the-brain/