1. Introduction
2. Differential Effects of Accutane and Butyrate
3. Epigenetics and Stem Cells
4. Microbiome and libido
5. Butyrate and hormones: DHT and 5AR
6. Sodium Butyrate
7. Conclusion
8. Related Articles
9. Article Summary
10. How to Increase Butyrate Producers in the Gut
11. References

Introduction

Butyrate is a short chain fatty acid, which is endogenously produced through microbial fermentation of dietary fibres in the lower intestinal tract. Short chain fatty acids (SCFAs) such as acetate, propionate and butyrate are produced by the bacteria in the colon from starch and dietary fibres. Some fermented foods contain very small quantities naturally, such as Parmesan or pecorino cheeses, and anyone familiar with the supplement Sodium Butyrate will recognise the distinctly cheesy odour.

The primary function of SCFAs is in energy metabolism, where they provide up to 70% of the energy requirement of the epithelial cells that line the colon. Although butyrate only constitutes 15% of endogenous SCFAs in the colon it is arguably the most important, capable of exerting profound effects throughout the body. [1]

Despite being only four carbons long its role in maintaining gut homeostasis is pivotal, and therefore plays an important role in the gut-brain axis. Additionally, butyrate possesses potent epigenetic effects as a histone deacetylase inhibitor. Butyrate can encourage open chromatin structure leading to enhanced gene transcription, which is pertinent for Post Accutane Syndrome.

In this post, we will delve into the known impacts of Accutane on gut health, explore how these relate to the symptoms of Post Accutane Syndrome, and consider the potential benefits of supplemental butyrate in addressing these issues. This exploration aims to illuminate the intricate connections between our gut health and overall well-being, emphasizing the significant yet often overlooked role of butyrate.

Differential Effects of Accutane and Butyrate

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 a 1.5 times risk odds ratio.

The FDA’s MedWatch have also reported 83 cases of newly developed cases of Inflammatory 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]

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.

Epigenetics and Stem Cells

A key signalling pathway that maintains this delicate balance of stem cell differentiation and proliferation is Wnt/β-catenin. In the absence of β-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 β-catenin gene ablation on adult mice and observed the effects on the intestinal tract. [5]

The loss of β-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 β-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 β-catenin, such as Lithium, have been found to increase intestinal stem cell populations. [8][9]

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 β-catenin inducers e.g. Valproate) can support the renewal of stem cell populations.

Butyrate also shares some of the same epigenetic effects as these β-catenin inducers, by inhibiting the de-acetylation of histone tails (HDAC) and thus increasing gene transcription by maintaining an open chromatin structure. This isn’t a coincidence however, as activation of the Wnt/β-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 β-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 β-catenin-TCF complexing. [13] Overall, the benefits of Butyrate within the β-catenin model predominate.

Microbiome and libido

The microbiome is intimately related to the brain, and perturbations to gut health are implicated in an array of psychiatric conditions. One such condition is hypoactive sexual desire disorder (HSDD). Sexual desire is mediated by a complex system of neurotransmitters and hormones. In particular dopamine, noradrenaline, melanocortin and oxytocin and all required to generate feelings of sexual excitement. The gut microbiome plays a key role in the production of these neurotransmitters as well as in regulating hormones.

Researchers have found a reduction in microbiome diversity and richness can lead to a loss of sexual desire. Women suffering from HSDD were found to have reduced abundance of Ruminococcaceae, a genus of bacteria which is the primary producer of endogenous butyrate. [14]

As previously mentioned, Butyrate supports gut health, but it can also directly cross the blood brain barrier to exert its effects. Ruminococcaceae, through its production of Butyrate, could therefore be implicated in HSSD pathogenesis through its direct epigenetic effect on excitatory genes in the frontal cortex. [15] Alternatively, the significance of Ruminococcaceae in HSSD could be through a secondary action on modulating neurotransmitter production in the gut.

Interestingly the researchers also identified an increased abundance of Bifidobacterium and Lactobacillus among women with HSDD. These two strains of bacteria have also been linked to the development of Ulcerative Colitis, a condition that develops with significantly greater odds in those previously treated with Accutane.

This suggests that HSDD is not only associated with a reduction of Butyrate producing bacteria, but an elevation in other strains also linked to Inflammatory Bowel Disease (IBD) pathogenesis. Poignantly, IBD is itself directly associated with a sexual dysfunction, for both psychological and biochemical reasons. [16]

Furthermore, Biopsies from Crohn’s and Ulcerative Colitis patients identified a significantly diminished proportion of Butyrate forming bacteria. [17] Supplemental sodium Butyrate has even been demonstrated to be an effective treatment Ulcerative Colitis, by restoring both a healthy gut microbiome and physiology. [18]

The connection between gut health and sexual health can be further evidenced by the differences in microbiome between those with erectile dysfunction and healthy controls.  A study of men aged between 20-40 years old with no history of other mitigating factors such as hypertension, vascular disease, or even obvious signs of gastrointestinal disease, and yet presenting with erectile dysfunction, were found to be suffering from dysbiosis.

In particular the researchers linked the increased abundance of inflammatory strains such as streptococci, as well as a general loss in flora diversity. These researchers also highlighted the importance of butyrate producing bacteria in countering this effect by reducing inflammation. [19] This supports the evidence from livestock, that Butyrate supplemented diets improved fertility parameters through an anti-inflammatory action.[20]

Butyrate and hormones: DHT and 5AR

The utility of histone deacetylase inhibition and β-catenin induction in maintaining gut health is evident – however so far, I’ve not actually addressed the primary medical application of HDAC inhibitors: mood regulation. Medications such as Valproate and Trichostatin A, which are HDAC inhibitors like Butyrate, are primarily used in the treatment of Bipolar and depressive disorder.

The generic explanation for their efficacy is that they increase brain derived neurotrophic factor (BDNF), which improves neuronal plasticity, regeneration, and survival. However recent research has begun to point to an effect on 5-alpha-reduced neurosteroids. 5-alpha-reductase is an enzyme that metabolises a range of hormones and neurosteroids, but most notably testosterone into the more potent androgen Dihydrotestosterone (DHT).

DHT is central to the progression of androgenic alopecia and is suppressed by the hair loss medication Finasteride. [21] 5-alpha-reductase and DHT are also implicated in acne pathogenesis and undergo suppression by Accutane treatment, potentially constituting one its therapeutic targets. [22] Whilst suppressing 5-alpha-reductase might be beneficial in treating balding or acne, it can also leave patients suffering from depression and a crushed libido. [23]

Neurosteroid metabolites of 5-alpha-redcuctase such as Allopregnanolone, THDOC and Androstanediol all play crucial roles in supporting mood and brain health and appear to be subject to augmentation by HDAC inhibition. HDAC inhibitors such as Valproate and Butyrate can stimulate glial cell production, which are the nonneuronal cells that support healthy neuron physiology and are induced by 5-alpha-reduced neurosteroids. [24]

The effect of Sodium Butyrate on glial cell induction and BDNF was completely mitigated by Finasteride treatment, implying that its effect was potentially mediated by 5-alpha-reduced neurosteroids. [25] Butyrate has further hormonal effects mediated through its epigenetic action.

Treatment with Butyrate can enhance ovarian steroidogenesis, and mRNA levels of genes associated with steroidogenesis such as steroidogenic acute regulatory (StAR) protein and PPAR-γ. [26] ChIP-qPCR analysis identified the increased acetylation of the H3K9 as the relevant pathway. This is notable given that both StAR and PPAR-γ are subject to suppression Accutane. [27]

Conclusion

In this post I’ve identified Butyrate as a potential target for remediating both sexual and gastrointestinal symptoms of Post Accutane Syndrome. I’ve shown that Butyrate has hypomethylating action, which I’ve identified in previous posts as being key in remediating the lasting adverse effects of Accutane treatment.

I’ve also shown that Accutane treatment can trigger Irritable Bowel Diseases such as Ulcerative colitis, and that treatment with Butyrate can normalise the differences in Microbiota and gut physiology seen in these conditions. I’ve also shown that the specific dysbiosis associated with IBD are also implicated in suppressed libido and mood, and the loss of Butyrate generating bacteria is central explaining these effects. Butyrate can be obtained directly from supplements such as Sodium Butyrate, or by increasing dietary consumption of certain foods such as legumes.

Article Summary

• Butyrate and SCFAs: Butyrate is a short-chain fatty acid produced through the fermentation of dietary fibers in the colon, along with other SCFAs like acetate and propionate. It plays a significant role in energy metabolism, especially for the cells lining the colon.
• Butyrate’s Importance: Despite constituting only 15% of SCFAs in the colon, butyrate has significant systemic effects, influencing gut homeostasis, gut-brain axis function, and epigenetic regulation through histone deacetylase inhibition (HDAC).
• Butyrate and Accutane: Accutane (Isotretinoin) affects gut health, which can lead to bowel diseases like ulcerative colitis (UC) and inflammatory bowel disease (IBD). Studies suggest an increased risk of UC and IBD after Accutane treatment.
• Accutane’s Effect on Stem Cells: Accutane influences stem cell differentiation by affecting the Wnt/β-catenin signaling pathway. This can deplete stem cells needed for tissue repair, leading to various side effects, including intestinal damage.
• Butyrate’s Role in Stem Cell Renewal: Butyrate supports stem cell renewal, similar to lithium and valproate, through HDAC inhibition and Wnt pathway activation. However, its effects on β-catenin are complex, referred to as the “butyrate paradox.”
• Microbiome and Sexual Health: A reduction in butyrate-producing bacteria, like Ruminococcaceae, is linked to conditions such as hypoactive sexual desire disorder (HSDD). Butyrate’s role in supporting gut health may also affect neurotransmitter production and sexual function.
• Butyrate and Mood Disorders: Butyrate’s HDAC inhibition can improve neuronal plasticity and mood by increasing brain-derived neurotrophic factor (BDNF) and supporting glial cell production. It may also influence 5-alpha-reduced neurosteroids, important for mood regulation and libido.
• Butyrate in Hormonal Regulation: Butyrate can enhance steroidogenesis in the ovaries, promoting gene transcription linked to hormone production. This has potential therapeutic implications, particularly as Accutane suppresses related pathways.

How to Increase Butyrate Producers in the Gut

The most effective substrate for encouraging the activity of Butyrate is resistant starch when it escapes digestion. These starches are then fermented by butyrate producing bacteria such as Ruminococcaceae. Increasing dietary sources of Butyrate can significantly elevate both Butyrate concentrations, and Butyrate producing bacteria.

For example, one study of 174 university students found that supplementing certain dietary starches could dramatically increase short-chain fatty acid (SCFA) production, as well as increase the relative abundance of butyrate-producing bacteria.