Leaky gut associated with depressive disorders: New insights into microbiota-induced epigenetic changes

Major depressive disorder (MDD) is a leading cause of disability in millions of people worldwide. Importantly, the gut microbiome may contribute to stress-related responses in patients experiencing depression.

A recent study in the journal Genes assessed how a leaky gut may lead to depressive disorders through changes in metabolites derived from the gut microbiota.

Study: Microbiota-Induced Epigenetic Alterations in Depressive Disorders Are Targets for Nutritional and Probiotic Therapies. Image Credit: RAJ CREATIONSZ / Shutterstock.com

Leaky gut, depressive disorders, and metabolites

The intestinal epithelial barrier prevents many toxins and pathogens from entering the lumen. However, certain events such as stress can facilitate intestinal leakage, increasing the risk of gastrointestinal anomalies and depressive disorders. Other environmental factors such as pollution and the consumption of food product residues such as pesticides can also disturb gut permeability and alter the gut microbiome.

Among the short-chain fatty acids (SCFA), butyrate is key to maintaining proper gastrointestinal health. Previous studies have shown that any disruption of butyrate-mediated gut-blood barrier integrity can lead to depressive disorders.

Depression, maternal diet, and environmental contaminants

Maternal diet during pregnancy is important for the neurological development of the offspring through changes in the gut microbiome. Unhealthy modern diets can lead to maternal dysbiosis and subsequently reduce the presence of butyrate-producing bacteria such as Firmicutes phylum. It can reduce levels of neuroactive metabolites in breast milk, thereby increasing anxiety- and depression-like behaviors in the offspring.

Exposure to chemicals such as pesticides can also lead to depressive disorders, as they can cause abnormalities in the gut microbiome. Furthermore, some pesticides, such as glyphosate, can affect neurodevelopment and neuroplasticity by crossing the placental barrier.

Probiotics and fecal microbiota transplantation (FMT) for depressive disorders

FMT involves transplanting stool into a recipient’s gastrointestinal tract from a healthy individual. FMT has been shown to be effective in experimentally induced models of depressive disorders. In fact, a recent study on human subjects revealed that the effectiveness of FMT in alleviating MDD may be due to the abundance of SCFA-producing bacteria such as Butyrivibrio and Faecalibacterium in the gastrointestinal tract.

Probiotics use epigenetic mechanisms to modulate the host’s immune response and maintain intestinal homeostasis. In mouse models, Clostridium butyricum has been used to alleviate depression-like behaviors due to its ability to secrete high levels of butyrate, a powerful anti-inflammatory agent and epigenetic modifier.

Polyphenols, herbal medicines, antipsychotics, and antidepressant medicines

By altering the structure and distribution of the bacterial community, herbal medicines, and polyphenols act as viable candidates for alleviating depression-like behaviors. For example, crocetin, an antidepressant compound found in saffron, increases levels of Turicibacter, Alistipes, and Romboutsia, which can alleviate depression-like behaviors.

Research has shown that antipsychotic drugs alleviate depressive disorders by replenishing butyrate-producing bacteria levels. Also, psychotropic drugs can trigger antidepressant effects by modulating the composition and function of gut bacteria. Antidepressants, such as tricyclic antidepressants and selective serotonin reuptake inhibitors, also affect intestinal permeability, microbiome composition, and gastrointestinal function.

The role of antibiotics and gut microbiota-related vitamins

Antibiotics have been shown to alleviate depression-like behaviors by facilitating the growth of beneficial bacteria. Lactobacilli and Bifidobacteria. One study demonstrated the beneficial effects of minocycline in reducing inflammation and alleviating depression-like phenotypes, which were attributed to the abundance of Lachnospiraceae and Clostridiales Family XIII, both of which facilitate butyrate production.

A lack of vitamins produced by the gut microbiome is also associated with certain neurological diseases such as depression. These vitamins may include thiamine (vitamin B1), niacin (vitamin B3), vitamin K, and folate.

The pathogenesis of mental health disorders can be linked to the inability to synthesize vitamins, which can be caused by gut dysbiosis. Previous studies have shown that maternal deficiency of vitamins B6, B9, and B12 can lead to anxiety/depression-like behaviors and developmental delays in offspring through changes in epigenetic.

Challenges in translating gut microbiome research into the treatment of depressive disorders

Medicines targeting the microbiome may present many therapeutic opportunities for improving mental health. However, further research is needed to better understand how bioactive metabolites of gut microorganisms influence human physiology during depression.

Another challenge is the heterogeneity in the composition of the microbiome in different human populations and geographic regions around the world. Future studies should be conducted in diverse populations and at different developmental stages to address this issue.

Journal reference:

  • Nohesara, S., Abdolmaleky, HM, Zhou, J., & Thiagalingam, S. (2023) Microbiota-Induced Epigenetic Alterations in Depressive Disorders Are Targets for Nutritional and Probiotic Therapies. Genes 14(12); 2217. doi:10.3390/genes14122217

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