1. Introduction
2. Accutane & IBS
3. The Role of β-catenin
4. How does Lithium help?
5. Article Summary
6. References

Introduction

The gut is the colloquial term for the gastrointestinal tract, the long winding system of the intestines that’s responsible for the absorption of nutrients and the eventual expulsion of waste. Whilst there may not be an immediately obvious connection between the gut and brain health, the two systems are in fact deeply intertwined.

The term “gut-brain axis” has become increasingly popularised. The relationship between the two organs is a two-way street. Emotional states and thoughts can trigger changes in digestion, but perhaps less well known is the influence the state of the gut has in turn on emotions.

The key to unpicking this complex relationship is the microbiome. The microbiome is the community of trillions of microorganisms that preside within the intestinal tract, including bacteria, viruses, and fungi. Whilst this may sound concerning, they actually play a symbiotic role with their host organism (you!). They help to break down macronutrients like carbohydrates into short-chain fatty acids, they synthesise vitamins, they regulate immune response and much more.

Accutane & IBS

The potential health ramifications of disrupting the health of the gut (dysbiosis) are broad and complex, and so it should be of concern that Isotretinoin (Accutane) is known to have profound effects on the gut. A 2011 case control study found that ulcerative colitis (UC) was strongly associated with prior isotretinoin exposure, with a 4.4 times greater risk compared to control. The same researchers didn’t however find an association with Crohn’s disease. [1]

Ulcerative colitis is chronic condition of inflammation of the colon, with primary symptoms of abdominal pain and diarrhoea, but during flare-ups symptoms may include eye irritation, painful joints and even bone degradation.

The risk of developing UC dramatically increased with Isotretinoin dose, with each additional 20mg dose contributing an 1.5 times risk odds ratio. The FDA’s MedWatch have also reported 83 cases of newly developed cases of Irritable Bowel Disease (IBD) following exposure to Isotretinoin. [2] Whilst there is much clinical literature pointing to an association between the development of bowel and isotretinoin use, the association is complicated by the latency between Isotretinoin treatment and first diagnosis of bowel disease.

The average latency period in one study was found to be around 3 years, and using the Bradford Hill criteria which uses temporality as a measure of causation the researchers were able to dismiss any association (a decision that has come under some criticism). [1][3]

The Role of β-catenin

Now that I have presented sufficient evidence to suggest there is reasonable concern of developing bowel disease following Isotretinoin treatment, I’ll now present some mechanistic explanations and how they may help to characterise the condition of Post Accutane Syndrome (PAS) more broadly.

Literature directly relevant to this end is much sparser, given the controversy in even establishing a causal link. However, when I employ the framework I have developed over previous posts (that being the disruption to the Wnt/β-catenin pathway) the relationship between bowel disease and Isotretinoin suddenly comes into light.

If you want an understanding of this framework, then refer to previous posts. In short, the Wnt/β-catenin pathway regulates growth and cell proliferation, as well as immunity via the T-cell factor (TCF). One of the mechanisms of Accutane is the suppression of β-catenin signalling by enhancing the destruction-complex that binds β-catenin in the nucleus in a variety of tissues throughout the body. It does this through disruption of the PI3K/Akt pathway which upregulates GSK3 (one of the kinases that composes the destruction complex).

As you can imagine, suppressing β-catenin in this way leads to a decrease in cell proliferation in these effected tissues. This is one of the mechanisms that drives Isotretinoin’s proapoptotic (cell death) effects. The tissues effected in this manner range from hair follicles to cancer cells. [4][5]

How does Lithium help?

Dysregulation of GSK3 and β-catenin has a direct impact on brain health, with enhanced GSK3 leading to inflammation in the brain and memory deficits. Medications that inhibit GSK3 (such as lithium) have beneficial effects on cognition and mood. [6] It’s now becoming clear that dysregulation of GSK3 can have an indirect effect on brain health via the microbiome-gut-brain axis.

Gut dysbiosis as result of decreased diversity and microbiome health leads can health drive neurodegenerative diseases such as Alzheimer’s disease. These changes in microbiome lead to increased intestinal barrier permeability and ultimately exposed the brain to inflammatory cytokines. [7]

Probiotics have been proposed as a therapy to reverse gut dysbiosis by inhibiting the action of GSK3. [8] Probiotics and Short-Chain-Fatty-Acids (SCFAs) can enhance the action of PI3K/Akt in suppressing GSK3 through pathways including upregulation of the IGF1 receptor and free fatty acid receptor FFA2. [9]

Changes in gut composition might also have further influence on brain health by influencing epigenetics. A 2021 study in rats found a direct relationship between microbiome diversity and cognitive performance. Further analysis found that changes in microbiome were influencing hippocampal methylation status, driving the changes in cognitive performance. [10]

In previous posts I’ve presented Lithium as an ‘anti-Accutane’ medication that exerts a directly opposing mechanism of action to Isotretinoin. Whilst Isotretinoin enhances the destruction complex by upregulating GSK3 leading to suppressed β-catenin, Lithium suppresses GSK3 and increases β-catenin action. This GSK3 suppression Lithium may explain why Lithium has been found to dramatically increase the richness and diversity of the microbiome.

This cuts a striking contrast against other psychotropic medications such as SSRIs which were found to have anti-microbial effects (particularly Fluoxetine and Escitalopram), which may have relevancy to a condition related to PAS called Post Serotonin Sexual Dysfunction. [11]

A more recent study in 2022 further confirmed this effect and found that Lithium Carbonate was able to alleviate colon inflammation by up-regulating short-chain fatty acid bacteria, with potential application in treating colitis. With the science in the field is still in its infancy, I have demonstrated there is good reason to believe that Accutane drives detrimental changes to gut that can be remediated by treatment with Lithium.

Article Summary

• Gut and brain connection: The gut (gastrointestinal tract) and the brain are deeply interconnected, influencing each other via the gut-brain axis. Emotional states can impact digestion, and gut health affects emotions.
• Microbiome’s role: The gut microbiome, composed of trillions of microorganisms, plays a crucial role in digestion, nutrient absorption, immune response, and overall health. Disruption in the microbiome (dysbiosis) can lead to various health issues.
• Isotretinoin (Accutane) effects: Accutane, a drug commonly used for acne, has been linked to gut health issues, particularly with an increased risk of developing ulcerative colitis (UC). A study found a 4.4 times greater risk of UC with prior Accutane use, but no association with Crohn’s disease. The risk of UC increases with higher doses of Accutane, and FDA reports suggest potential links between the drug and other bowel diseases, such as irritable bowel disease (IBD).
• Mechanistic explanation: Accutane disrupts the Wnt/β-catenin pathway, which regulates cell growth and immune responses. This disruption affects various tissues in the body, contributing to Accutane’s side effects, such as decreased cell proliferation and increased cell death.
• Impact on brain health: Dysregulation of β-catenin and GSK3 (an enzyme in the pathway) has negative effects on brain health, potentially contributing to inflammation and memory deficits. Gut dysbiosis can also affect brain health, increasing the risk of neurodegenerative diseases.
• Probiotic therapy: Probiotics and short-chain fatty acids (SCFAs) may help reverse gut dysbiosis by inhibiting GSK3, improving gut and brain health. Lithium, a drug that suppresses GSK3, shows promise in improving gut microbiome diversity and may be useful in treating conditions like colitis.
• Lithium as a potential remedy: Lithium has opposing mechanisms to Accutane, enhancing β-catenin activity and promoting microbiome health, suggesting its potential as a treatment to counteract Accutane’s negative effects.

References