The last twenty years have seen a growing body of scientific research substantiating what many ancient cultures always knew: that the brain and the gut are intimately connected and influence each other in real-time. (1)
This fascinating relationship is bidirectional, meaning that the brain impacts the gut, and the gut, in turn, strongly influences the brain.
This new scientific understanding is revolutionizing the field of integrative medicine and opening the door to potential novel treatments that directly target the gut in order to heal a myriad of mental health disorders, including depression. Now more than ever, psychiatrists are realizing that gut health and mental health are inextricably connected.
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The Gut Microbiota Explained
Our human gut is home to trillions of microbes, 95% of which are friendly and beneficial to our existence. (2) Collectively, these microbes are known as the gut microbiota. The total genetic material contained in the gut microbiota is called the gut microbiome. The communication pathway between the gut microbiota and the central nervous system (CNS) is largely mediated by the vagus nerve and is referred to as the microbiota-gut-brain axis.
Our gut microbiota consists of a delicate balance of bacteria, archaea, fungi, protozoans, and viruses that perform many essential bodily functions, including producing vitamins, synthesizing brain neurotransmitters, digesting food, improving gut motility, and providing vital immune system support.
When pathogens disrupt the delicate balance of the gut microbiota (a condition known as gut dysbiosis), the optimal functioning of the gut is disrupted, and adverse health effects can occur, including deleterious effects on mental health.
The Gut Microbiota in Depressed Patients
Research has indicated that the gut microbiota in depressed individuals is different from that of non-depressed individuals. Namely, depressed patients tend to have a less diverse ecosystem of bacteria in their gut as well as more harmful bacteria compared to beneficial bacteria. (3)
A 2023 systematic review and meta-analysis published in the journal Translational Psychiatry found that depressed individuals had higher numbers of pro-inflammatory bacteria and fewer numbers of anti-inflammatory bacteria. (4)
A 2022 study of over 2500 human subjects found that certain bacteria, namely Sellimonas, Eggerthella, Lachnoclostridium, and Hungatella, were more prevalent in depressed people. (5)
Another systematic review published in 2022 in the journal Molecular Psychiatry also concluded that the gut microbiota composition in depressed patients was different compared to healthy controls. In this review, study subjects with either major depressive disorder, bipolar disorder, or schizophrenia were found to have lower levels of bacteria that produced helpful short-chain fatty acids (butyrate), higher levels of problematic bacteria that produced lactic acid, and higher levels of bacteria involved with glutamate and GABA metabolism. (6)
Enter Probiotics, Prebiotics, and Psychobiotics
Probiotics (good bacteria) are beneficial collections of live microorganisms that confer health benefits on the host when consumed in sufficient quantities. (7)
Prebiotics are fibrous foodstuffs that humans are unable to digest but that probiotic bacteria love to eat. Examples of prebiotics include bananas, apples, onions, and garlic.
Psychobiotics, a term coined in 2013 by researchers, refers to probiotics and prebiotics that have positive mental health effects and that can help treat psychiatric illnesses. (8)
Probiotics Help Treat Depression: Evidence-Based Research from 2021 to the Present
Over the last decade, numerous studies have provided compelling evidence supporting the role of probiotics in the treatment of depression. Here we discuss three recent studies from 2021 onwards:
A 2021 pilot study in humans with major depressive disorder found that a combination of the probiotics Lactobacillus helveticus R0052 and Bifidobacterium longum R0175 improved mood and anxiety in 4 weeks. Study subjects completed the Montgomery-Asberg Depression Rating Scale (MADRS) before and after treatment, and answers indicated that depressive symptoms had improved from a “moderate” to a “mild” rating. (9)
A 2022 double-blind, randomized controlled trial evaluated the efficacy of Bifidobacterium breve CCFM1025 in treating 45 human subjects with depression. Results showed a significant decrease in depression in one month, as measured by the Hamilton Depression Rating Scale-24 (HDRS-24). (10)
Another double-blind, placebo-controlled, randomized clinical trial published in JAMA Psychiatry in 2023 found that depressed subjects given probiotics experienced fewer depressive symptoms compared to controls. (11)
Participants in this study were given 8 billion colony-forming units (CFUs) per day of a multistrain probiotic for 8 weeks in addition to their ongoing antidepressant medication. Results showed that probiotics not only helped improve depression but were well tolerated with no serious adverse side effects – an important consideration when deciding whether to add probiotics to the standard of care for depression.
But How Exactly Do Probiotics Improve Depression?
Research suggests that probiotics exert their salutary effects on mental health by influencing numerous interrelated body systems:
Proposed Mechanisms of Action
1. Anti-Inflammatory Effects: Both systemic inflammation as well as neuroinflammation have been linked to depression. Probiotics help ameliorate inflammation by modulating the immune response and reducing levels of pro-inflammatory cytokines, such as TNF-alpha, IL-1, and IL-6. (12)
2. Increasing Neurotransmitter Levels: Probiotics increase the production of helpful neurotransmitters such as serotonin, gamma-aminobutyric acid (GABA), and dopamine. (13) These neurotransmitters play a critical role in mental health. Certain strains of probiotics, including Lactobacillus and Bifidobacterium, have been shown to produce these neurotransmitters, explaining one way probiotics likely improve depressive symptoms.
3. Strengthening the gut barrier: A "leaky gut" can lead to systemic inflammation as well as neuroinflammation, contributing to depressive symptoms and low mood. Probiotics work to combat leaky gut by fortifying the intestinal mucosal barrier and reducing intestinal permeability, thereby keeping harmful pathogens out of the bloodstream. (14)
4. Regulation of the Stress Response: The hypothalamic-pituitary-adrenal (HPA) axis plays a crucial role in the body's response to stress. Dysregulation of the HPA axis is commonly observed in individuals with depression. Probiotics, specifically Lactobacillus and Bifidobacterium species, have been shown to normalize HPA axis activity by reducing cortisol levels. (15)
5. Enhancing Neurogenesis and Neuroplasticity: Emerging research in animal models suggests that multi-strain probiotics may contribute to the formation of new neurons in the hippocampus and improve neuroplasticity in the brain, thus contributing to potential anti-depressant effects. (16)
Recommending Probiotics to Depressed Patients: The Latest Clinical Guidelines
In 2022, The World Journal of Biological Psychiatry published global clinical guidelines for treating psychiatric disorders using nutraceuticals and phytoceuticals.
The guidelines included a “provisional recommendation” for the use of probiotics as adjunctive therapy in the treatment of depression. The authors defined a “provisional recommendation” as “a level of evidence with mainly positive data from either meta-analyses or meta-reviews or two randomized-controlled trials of good or average quality, with robust, acceptable, or fair safety/tolerability.” (17)
Specifically, the clinical statement regarding probiotics stated:
Probiotic strains (e.g., Lactobacillus and Bifidobacterium spp.) at doses of 1–10 billion units per day are Provisionally Recommended for Adjunctive use and Weakly Recommended for Monotherapy use in MDD (Major Depressive Disorder)
The guidelines go on to mention that the most studied probiotics in the treatment of depression are:
- Lactobacillus and
- Bifidobacterium
However, the authors also mention that there is still no consensus on exactly which specific strains are most beneficial in the treatment of depression.
Implementing Probiotics in Clinical Practice: Key Points to Consider
As we synthesize the research and decide on the best path forward for our patients, here are some key points to keep in mind:
- An abundance of research clearly indicates that probiotics have a beneficial impact on depression and mental health. A 2023 umbrella meta-analysis—umbrella meta-analyses are widely considered the best scientific evidence available—concluded that probiotics significantly reduced depressive symptoms in humans and suggested that administering a dosage of > 10 × 109 CFU for more than 8 weeks conferred the highest chance of positive results. (18)
- Probiotics are generally considered safe with minimal side effects
- Given current evidence, probiotic supplements can be prescribed as adjunctive treatment when treating depression in adults. This means that they can be used in addition to standard medications, not in place of them.
- Multi-strain mixtures containing Lactobacillus and Bifidobacterium spp. have robust evidence supporting their anti-depressant properties. Clinical evidence suggests that using probiotic supplements for at least 8-10 weeks, at doses of at least 10 billion colony-forming units per day, increases the likelihood of experiencing positive mental health benefits.
- While probiotics are generally well-tolerated, clinicians should exercise caution when recommending probiotics to vulnerable populations, such as the elderly, the immunocompromised, pregnant women, and children.
- In addition to probiotic supplements, clinicians can encourage patients to consume probiotic-rich foods, such as cultured buttermilk, cottage cheese, apple cider vinegar, and olives.
- Psychoeducation on the gut-brain connection can help patients understand the reasoning behind our recommendations and can go a long way to improving adherence.
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Key Takeaways
In summary, as we continue to uncover the intricacies of the gut-brain connection, incorporating probiotics into our depression treatment protocols represents a holistic, evidence-based approach to mental health care. As psychiatrists and mental health professionals, we’re uniquely positioned to help our patients understand the important connection between mental health and gut health. By embracing a more integrative, mind-body approach to depression treatment, we offer our patients the best likelihood of getting better - both mentally and physically.
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