“All disease begins in the gut”
– Hippocrates
Two weeks ago, an 11-year-old boy was sick with pharyngitis, commonly known as a sore throat. He then experiences a sudden onset of violent outbursts and separation anxiety, followed by the development of obsessions, compulsions, motor and vocal tics, irritability, and insomnia1. What could possibly encompass this peculiar combination of physical and psychiatric symptoms?
What is PANDAS?
Hippocrates once stated that “all disease begins in the gut”. Although this quote may seem like an overstatement, it should not be easily dismissed. The story of this young boy describes a typical case of PANDAS, or Pediatric Auto-immune Neuropsychiatric Disorder Associated with Streptococcal infections. PANDAS is a rare auto-immune disease that is relatively new and less commonly known. It is characterized by the sudden onset of symptoms related to obsessive-compulsive and tic disorders, temporally linked to an infection of group A beta-hemolytic streptococci (GAS) (Fig.1)2.
Although the term “GAS” may not instantaneously ring a bell, these bacteria are quite ubiquitous and are the main culprit for many bacterial infections in children. Upon exposure, these foreign intruders will disturb an individual’s normal flora and seek refuge on the skin or in the throat, as in the case of strep throat. Majority of infections result in minor symptoms; however, in some prepubescent children, a GAS infection can trigger an auto-immune response. This reaction occurs when the immune system detects and targets the GAS invaders but also mistakenly attacks normal healthy brain tissue due to similarities in molecular structure. This precipitated attack on the brain is believed to lead to the sudden onset of neuropsychiatric symptoms present in PANDAS3.
Gut-brain axis and a state of dysbiosis
As the role of the immune system in PANDAS is quite evident and 70-80% of immune cells exist in the gut, it is safe to suggest that there is a unique interplay between the community of microorganisms that live in the gut (microbiota) and the immune system4. These gut microorganisms are capable of regulating brain function and behavior through immune-mediated pathways via the microbiota-gut-brain (MGB) axis. In short, the MGB axis refers to the bidirectional communication between the gut and the brain5. Factors such as stress, infection, and diet can alter the stability of the gut composition and lead to dysbiosis, or an imbalance in the gut’s microbial communities6. There has been extensive research into the involvement of the MGB axis in various neuropsychiatric disorders, such as depression, but its role in the pathophysiology of PANDAS was only a recent discovery.
A 2018 study by Quagliariello et al. found that streptococcal infections wreak havoc on the gut’s microbial communities by selecting for pro-inflammatory bacterial strains7 (Fig.2). These pathogenic species trigger immune response activation that may lead to neuronal inflammation (Pathway 1). In addition, the gut composition displayed a lower level of protective species, which normally helps to strengthen the gut barrier and maintain a state of homeostasis. So not only is the immune system over-activated, but the permeability of the gut mucosa is heightened. This increased permeability allows bacterial pathogens and toxic metabolites to leak out of the gut and into the bloodstream, eventually crossing the blood brain barrier (BBB) and contributing to neuroinflammation (Pathway 2). This imbalance between the “good guys” and the “bad guys” exacerbates the path to dysbiosis by fostering an inflammatory intestinal environment, and this flow of toxicity travels upstream to the brain to initiate the onset of OCD- and tic-like symptoms in these patients. Simply put, “leaky gut → leaky brain”.
Fig.2: A simplified model of the microbiota gut-brain axis. (1) Higher levels of pathogenic species trigger an auto-immune response. (2) Fewer protective species increase gut permeability, allowing toxins to leak out and cross the blood-brain barrier. Image produced in BioRender.
Healing the gut to heal the brain
Although first-line treatment of antibiotic therapy is almost necessary to take on an active GAS infection, it does not guarantee the eradication of symptoms, nor prevent relapse. Antibiotics do help to alleviate certain symptoms, such as anxiety and irritability in our model patient, but its efficacy weans off upon discontinuation. Patients might continue to experience flare-ups following viral infections and are left to deal with a waxing and waning of symptoms. Rather than relying on a round of antibiotics every time symptoms flare up, the goal should instead be to stabilize the gut and strengthen the immune system to make patients less susceptible to future infections. As our microbiota are quite flexible and easily influenced by diet and environment, they make for a promising target for treatment.
So not only is the immune system over-activated, but the permeability of the gut mucosa is heightened.
In a large sample study investigating different treatments for PANDAS, more than half of the families reported positive health outcomes after treatment with probiotics, omega3, and vitamin D8. These alternative approaches were thought to improve mood through mechanisms involving re-flourishing the gut, increasing microbial diversity, reducing gut permeability, and strengthening immunity. In another PANDAS case study, a patient reported an improvement of symptoms and the eventual removal of diagnosis after following a specific nutritional protocol9. This diet focused on nutrient-rich foods to heal the leaky gut and introduced probiotics to replace pathogens in the gut with beneficial microbes. These types of alternative nutritional protocols are becoming more prevalent as practitioners observe, and scientists report the beneficial effects of maintaining a healthy gut microbiome.
Though the case that has been described exemplifies when things go awry, it serves to educate us about the importance of balancing a healthy gut and its diverse microbiota, even for healthy individuals. Whereas dysbiosis is linked to aversive symptoms, or even lead to the onset of disorders, homeostasis encourages alleviation, and in many cases, prevention.
Simply put, leaky gut -> leaky brain.
So, where do you stand? This high-speed, two-way street between the gut and the brain is a fascinating field of research. PANDAS is just one example used to portray the significance of the MGB axis in neuropsychiatry. As first mentioned by Hippocrates, this gut-brain relationship has long been realized, but we are now unravelling the scientific mechanisms to back up his statement. What other diseases could be linked to, or ameliorated, by the gut? Researchers should be following their “gut feeling” and start looking in the right places.
About the writer
Maya Allister is a second-year neuroscience master student at the VU. She recently completed an internship on the effects of mindfulness on the functional brain network of MS patients. Previously she worked with a PANDAS-specialist who focused on the gut-brain connection, motivating her to write this article.
Further reading
1. Frankovich J, Thienemann M, Rana S, Chang K. Five youth with pediatric acute-onset neuropsychiatric syndrome of differing etiologies. Journal of Child and Adolescent Psychopharmacology. 2015;25(1):31-37. doi:10.1089/cap.2014.0056
2. Swedo SE, Leonard HL, Garvey M, et al. Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections. FOCUS. 2004;2(3):496-506. doi:10.1176/foc.2.3.496
3. Orlovska S, Vestergaard CH, Bech BH, Nordentoft M, Vestergaard M, Benros ME. Association of streptococcal throat infection with mental disorders. JAMA Psychiatry. 2017;74(7):740. doi:10.1001/jamapsychiatry.2017.0995
4. Wiertsema SP, van Bergenhenegouwen J, Garssen J, Knippels LM. The interplay between the gut microbiome and the immune system in the context of infectious diseases throughout life and the role of Nutrition in Optimizing Treatment Strategies. Nutrients. 2021;13(3):886. doi:10.3390/nu13030886
5. Dinan TG, Cryan JF. Microbes, immunity, and behavior: Psychoneuroimmunology meets the microbiome. Neuropsychopharmacology. 2016;42(1):178-192. doi:10.1038/npp.2016.103
6. Kim Y-K, Shin C. The microbiota-gut-brain axis in neuropsychiatric disorders: Pathophysiological mechanisms and novel treatments. Current Neuropharmacology. 2018;16(5):559-573. doi:10.2174/1570159×15666170915141036
7. Quagliariello A, Del Chierico F, Russo A, et al. Gut microbiota profiling and gut–brain crosstalk in children affected by pediatric acute-onset neuropsychiatric syndrome and pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections. Frontiers in Microbiology. 2018;9. doi:10.3389/fmicb.2018.00675
Image credits: Cover photo from GettyImages; Figure 1 from the CDC’s Public Health Image Library; Figure 2 was created by the writer using BioRender.