Gut-brain Short-circuit

The gut-brain connection is increasingly well-documented. From autism (1) to emotional well-being (2), multiple aspects of personality (3), disorders of affect and anxiety (4) and neurodegenerative diseases such as Parkinsonism (5) and perhaps Alzheimer’s (6), it is abundantly clear that the bugs in our gut have major short- and long-term effects on our brains, and our artificially insular construct of self.

Further evidence for the microbes in ‘me’ comes from the weird world of bariatric surgery. 

A relatively successful surgical procedure in terms of achieving weight loss in the morbidly obese, it has long been associated with post-operative personality and mood changes (ie 7, 8) and, of course, the surprisingly common ‘bariatric divorce’ (ie 9). Very recently, a new avenue of research has opened up; an association has been found between bariatric surgery and an increased risk of epilepsy (10), predominantly focal epilepsy (11). 

The fact that this association held after major confounders had been filtered out, occurred with different kinds of bariatric surgery and was maintained after other epileptogenic insults (ie stroke), suggests that surgery was indeed causative. And it is to do, I think, with the relationship between diet and seizure threshold.

Bariatric surgery works primarily by enforcing reduced food intake, which is not in itself a bad thing. However, when you scan the pre- and post-surgery diets recommended by mainstream institutions (ie 12) you see they are generally low volume, low calorie, low carb and almost devoid of prebiotic fibers. The colonic microbiota must therefore shift away from gram-positive saccharolytic microbes, which produce butyrate, towards proteolytic and bile-resistant species (ie 13, 14) which are predominantly gram-negative and intrinsically pro-inflammatory (ie 15).

Butyrate, a short chain fatty acid with pronounced anti-inflammatory effects in the gut, central nervous system and other tissues (16-18), is intimately involved in epilepsy. By inhibiting the enzyme histone deacetylase it increases the acetylation of histones (and other proteins), an epigenetic mechanism which results in improved neuronal energetics, health and survival (19), significant anti-ageing effects (20-22), reduced neuroinflammation (22) and distinct anti-epilepsy benefits (23-25).

Conversely, intestinal inflammation reduces the effectiveness of antiepileptic drugs (26, 27), lowering the seizure threshold and making seizures more likely. 

Diet-induced microbiotal shift leading to reduced butyrate synthesis therefore emerges as a plausible link between bariatric surgery and clinical epilepsy.

The studies cited above are mostly pre-clinical, but there is clinical evidence as well. A pro-inflammatory (dysbiotic) microbiota has been linked to drug-resistant epilepsy (28, 29), and has been found to predict the onset of epilepsy in children (30).

There is an apparent paradox here.

The diet best known to raise the seizure threshold is not the high fiber diet but the low fiber ketogenic diet, low calorie versions of which have also been shown to be helpful in multiple sclerosis (31) and Alzheimer’s (32). The ketogenic diet has a significant impact on the microbiota (33), and reduces butyrate-producing saccharolytic species such as bifidobacteria dramatically (33, 34). 

But there is a work-around. During ketosis, the liver produces the ketone bodies acetoacetate, acetone – and butyrate. And here is another; the ketogenic diet reduces the population of intestinal pro-inflammatory Th17 cells (33), pro-inflammatory Group 3 innate lymphoid cells (35), the production of pro-inflammatory mediators (33), and therefore neuro-inflammation (36).

What does this mean in practical terms? 

Dietary or any other factors which cause intestinal inflammation are likely to drive neuroinflammation (27-38) and neuroinflammation appears to be a significant driver for epilepsy (37). On the balance of evidence, and given the importance of the gram-positive saccharolytic species, a ketogenic diet with added prebiotic fibers might produce additive or supra-additive benefits in terms of seizure control and gut health. I would add omega 3 HUFA’s (38) with a pinch of polyphenols for luck (39), in the form of Balance Oil.

One key component of epilepsy is oxidative/nitrosative stress (OXNOS), which overlaps with neuroinflammation (40). OXNOS is also a driver in Parkinson’s Disease (41), which gives me the opportunity to refer back to my favourite Parkinsonian patient. The one whose irreversible condition reversed (42). 

After 3 years of extensive pharmaconutritional program, which amongst other things reduces OXNOS (43, 44) and neuro-inflammation (42, 45) and recreates a pre-transitional anti-inflammatory microbiota (46-51), his anosmia, the first symptom to emerge and the last to fade, has finally disappeared. He can once again smell the coffee, fresh sawdust (he is an expert wood worker) and the rising panic of his neurology consultant, a prominent fellow whose pharmaceutical expertise has left him staring at shadows of shadows on the cave wall. 

With every such joyous case the limitations of the currently hegemonic medical model become clearer, and the need for reform more urgent.

Finally, the gut-brain connection can go wrong in both directions. There appears to be a reverse kind of gut-brain short-circuit, namely abdominal or autonomic epilepsy. Although the condition is not well understood, it has been suggested that epileptic activity in the hypothalamus might trigger gastrointestinal symptoms via the vagus nerve. It is rare, mostly affects children and responds reasonably well to anticonvulsants (52). 

While this is yet another condition that likely responds to appropriate pharmaco-nutritional intervention, children in particular should be provided with rapid relief of pain and suffering. I can bore for Britain about nutritional issues, but there will always be a role for pharmaceuticals. While their effects are generally limited to the suppression of symptoms, their rapid onset of action is clinically important.

Next week: How to take a hit, and keep a clear head.

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