Quote from SecondLifeGuide on May 12, 2024, 2:46 am

Introduction

As I’ve outline in previous posts, Isotretinoin has a profound effect on the gut and subsequently the gut-brain axis. Whilst both meta-analysis and case control studies have has very consistently pointed to an association between the development of Bowel Disease and prior Accutane exposure, the damage may take years to manifest.

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. [2] 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. [3] 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). [2][4]

 

Stem Cell Differentiation

Those who’re familiar with my other posts will understand that Accutane, as a derivative of Vitamin A, is a potent differentiating agent. That is, it exerts its effects by trigger the differentiation of stem cells into specialised cells. Many organs will rely on the maintenance of a progenitor pool of stem cells throughout adulthood, which are vital for tissue repair, regeneration, and normal organ functioning.

One such organ (the primary target of Accutane treatment) is the skin, which harbours a stem cell pool for the continuous renewal of the epidermis and for the repair of injuries. However other organs such as bones, intestines, brain, and cornea all also rely on the maintenance of a stem cell population and are equally subject to Accutane’s differentiating effects. Once these stem cells are differentiated, they cannot revert to stem cells and the stem cell population must replenish through a process called proliferation.

A key signalling pathway that maintains this delicate balance of stem cell differentiation and proliferation is Wnt/Beta-catenin. In the absence of beta-catenin signalling, stem cells undergo rapid differentiation, and the progenitor stem cell pool becomes depleted. This was most plainly demonstrated in 2023 study on mice, where researchers performed a beta-catenin gene ablation on adult mice and observed the effects on the intestinal tract. [5]

The loss of beta-catenin triggered the intestinal stem cell population to terminally differentiate resulting in the loss of function and ultimately death. This represents an exaggerated mechanism of action of Accutane, which suppresses beta-catenin through HOXA5 induction, resulting in the loss of intestinal stem cells. [6]

A case report of a 17-year-old who developed Inflammatory Bowel Disease (IBD) following isotretinoin treatment even posited inhibition of epithelial cell growth as a potential cause. [7] Conversely agents that activate the Wnt pathway to enhance beta-catenin, such as Lithium, have been found to increase intestinal stem cell populations. [8][9]

 

Butyrate, Lithium and HDACis

My previous posts have evidenced the important role Lithium can play in restoring healthy gut physiology following Accutane treatment, but how might Butyrate be of value? Butyrate, like lithium (or other beta-catenin inducers e.g. Valproate) can support the renewal of stem cell populations. Butyrate also shares some of the same epigenetic effects as these beta-catenin inducers, by inhibiting the de-acetylation of histone tails (HDAC) and thus increasing gene transcription. This isn’t a coincidence however, as activation of the Wnt/beta-catenin appears to be fundamental to HDAC inhibition. [10]

Studies have found that Butyrate, at the right concentration, can support the self-renewal of human embryonic stem cells (ESC). [11] Conversely, very high and very low concentrations of Butyrate could trigger differentiation in ESCs. The researchers identified Butyrate’s de-methylating and HDAC inhibiting action to be responsible for its impacts on stem cells and could be partially mimicked by typical HDAC inhibiting medication such as valproate. [12]

Notably, many of the same transcription factors Butyrate relies on for its stem cell renewing effects, such as c-Myc, Oct4 and Sox2, are all targeted for suppression by Accutane. Its important to recognise that the relationship between Butyrate and beta-catenin is complex, and has confounded researchers for years, even being referred to as the “butyrate paradox”. Whilst Butyrate is able to enhance epithelial and colonocyte proliferation, its also able to inhibit proliferation of cancerous stem cells on account of a differential effect on beta-catenin-TCF complexing. [13] Overall, the benefits of Butyrate within the beta-catenin model predominate.

https://secondlifeguide.com/2023/11/19/the-power-of-butyrate/