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By Nicole Cain, ND, MA

A recent study published in the journal, Microbiology Spectrum entitled, “Clostridioides difficile infection dysregulates brain dopamine metabolism” found a growing body of evidence linking gut microbiota composition with the development of neurological disease, anxiety in particular. 

Clostridioides difficile, otherwise referred to as clostridium difficile or C. difficile, is a pathogen that overgrows in the gut after extended antibiotic therapy. C. difficile overgrowth has long been associated with digestive disease – such as pseudomembranous colitis, toxic megacolon, and sepsis. However, emerging research suggests that C. difficile bacteria also produce metabolites capable of impacting neurotransmission and brain functionality.

The gut-brain-microbiota axis is a bidirectional highway between the brain, gut, and resident microbes. The composition of the microbes in the gut play an important role in the function of the immune system, endocrine system, and nervous system.

Researchers have found that while antibiotics are a useful treatment for eliminating certain infectious organisms, antibiotic use also results in destruction of the normal gut microbiota. In the absence of adequate amounts of healthy bacteria, opportunistic bacteria, such as C. difficile are given space and resources to proliferate. 

As a result of the change in microflora, concentrations and forms of metabolites change. In the case of C. difficile overgrowth, testing reveals increasing levels of a toxic metabolite called p-cresol. P-cresol is an organic compound that is involved in the metabolism of dopamine into noradrenaline (norepinephrine and then epinephrine). As p-cresol levels rise, dopamine conversion into adrenaline is inhibited, resulting in elevations of dopamine and low levels of epinephrine.

Unchecked elevations in dopamine results in symptoms of anxiety, paranoia, intense excitement, emotional eating, and autistic behaviors as examples. Symptoms of low noradrenaline may be associated with low blood pressure (hypotension), low blood sugar (hypoglycemia), anxiety, weakness, and depression.

In the search for integrative solutions for mental health, including and especially anxiety, research into the mechanisms by which specific microbiota impact the nervous system have opened doors into novel testing and treatment.

Based on findings from the publications on C. difficile metabolites possibly interfering with dopamine production and causing anxiety and other neurological disturbances, functional medicine testing is warranted. Organic acid testing is a particularly valuable functional assessment tool for C. difficile species, as it includes screening for four key C. difficile metabolites, including: HPHPA (3-(3-hydroxyphenyl)-3-hydroxypropionic acid), 4-Hydroxyphenylacetic acid, 3-Indoleacetic acid, and 4-Cresol.

Armed with baseline testing, integrative treatments may be employed and follow-up testing conducted in order to assess efficacy. 

A three-pronged integrative approach may include:

Replenishing beneficial bacteria: Research has suggested that certain strains of probiotic bacteria offer significant therapeutic value in mitigating the effects and symptoms associated with C. difficile. For example, a 2022 study in Archives of Microbiology demonstrated that supplementation with strains of Lactobacillus rhamnosus and Lactobacillus plantarum inhibited C. difficile growth, repaired gut tight-junctions, inhibited C. difficile toxins, and reduced inflammation in addition to a variety of other protective effects.

Direct anticlostridial agents: While the oral antibiotics metronidazole and vancomycin tend to be quite effective against C. difficile, the tradeoff is that these antibiotics can also kill off beneficial bacteria.

Research into alternative approaches to antibiotics against C. difficile is promising. According to a 2021 study published in the Journal of Global Antimicrobial Resistance, curcuminoids, a constituent of turmeric, inhibits growth of C. difficile without having any negative effect on beneficial gut bacteria. 

Spore busters: Because C. difficile can form biofilms, treatment should also include those that are effective against the bacteria in their “vegetative” or spore form. Emerging evidence suggests berberines in combination with vancomycin has a synergistic antimicrobial effect against C. difficile.

Berberine is a polyphenolic compound that can be isolated from certain herbal remedies such as Hydrastic canadensis (goldenseal), Coptis chinensis (Chinese goldthread), and Rhizoma coptidis.

Final Remarks

Integrative and holistic medicine research and treatment fills a much needed gap in medical approaches to mental healthcare. Individualization via functional medicine testing and precision-based therapies offer the potential to not only mitigate symptoms but actually improve the health of the sufferer. 

Armed with data pertaining to the mechanism by which infectious organisms, such as C. difficile, may interfere with neurological health not only raises the bar on expected treatment outcomes but provides hope for the future of healthcare as well.  

References

Cain, N. (2022). Clostridia: The Gut Infection That is Wreaking Havoc on Your Neurotransmitters. Retrieved from https://drnicolecain.com/clostridia-the-gut-brain-axis/

Cain, N. (2022) Mood, mind & microbes: State of the union. Psychology Today. Retrieved from: https://www.psychologytoday.com/us/blog/mood-mind-and-microbes/202204/mood-mind-microbes-state-the-union

Frost, L. R., Cheng, J. K. J., & Unnikrishnan, M. (2021). Clostridioides Difficile Biofilms: A Mechanism of Persistence in the Gut? PLOS Pathogens. Retrieved from: https://doi.org/10.1371/journal.ppat.1009348

Hell, M., Bernhofer, C., Stalzer, P., Kern, J., & Claassen, E. (2013). Probiotics in Clostridium Difficile Infection: Reviewing the Need for a Multistrain Probiotic. Beneficial Microbes. Retrieved from: https://doi.org/10.3920/bm2012.0049

Jeng, H. S., & Yan, T. R. (2022). Lactiplantibacillus plantarum E51 Protects Against Clostridioides Difficile-Induced Damages on Caco-2 Intestinal Barrier Functions. Archives of Microbiology. Retrieved from: https://doi.org/10.1007/s00203-022-02837-6

Lillis, C. (2022) What to Know About Epinephrine and Norepinephrine. MedicalNewsToday. Retrieved from: https://www.medicalnewstoday.com/articles/325485#deficiency

Mody, D., Athamneh, A. I., & Seleem, M. N. (2020). Curcumin: A Natural Derivative with Antibacterial Activity Against Clostridium Difficile. Journal of Global Antimicrobial Resistance. Retrieved from: https://doi.org/10.1016/j.jgar.2019.10.005

Vinithakumari, A. A., Padhi, P., Hernandez, B., Lin, S. J. H., Dunkerson-Kurzhumov, A., Showman, L., Breitzman, M., Stokes, C., Sulaiman, Y., Tangudu, C., Kuttappan, D. A., Muyyarikkandy, M. S., Willette, A. A., Phillips, G. J., Anantharam, V., Perera, A., Sponseller, B. A., Kanthasamy, A., & Mooyottu, S. (2022). Clostridioides Difficile Infection Dysregulates Brain Dopamine Metabolism. Microbiology Spectrum. Retrieved from: https://doi.org/10.1128/spectrum.00073-22

Wultańska, D., Piotrowski, M., & Pituch, H. (2020). The Effect of Berberine Chloride and/or its Combination With Vancomycin on the Growth, Biofilm Formation, and Motility of Clostridioides Difficile. European Journal of Clinical Microbiology and Infectious Diseases. Retrieved from:  https://doi.org/10.1007/s10096-020-03857-0

Nicole Cain ND, MA has degrees in clinical psychology and naturopathic medicine. She is a regular contributor for Psychology Today, has been interviewed as a mental health expert by Forbes, and is published in Salon, Well+Good and NDNR. She is currently writing a book about anxiety and can be found on Instagram @DrNicoleCain.