Probiotics experiment- VSL#3. Gut dysbiosis and cancer, epilepsy.

I am currently on day 5 of a 30 day experiment using myself as a human guinea pig to test these high potency probiotics from Visibiome.

I first heard about this product from Dr. Rhonda Patrick and I trust her judgement. She stated how Visibiome contains 8 strains of live bacteria in concentrations of 450 billion bacteria per packet and I had this confirmed by the company that produces it. 

Why is this so important?

This is impressive as many probiotics only contain about 100 million bacteria (often dead as they should ideally be kept cold). I decided to investigate further and try these probiotics myself to see if I may benefit so I contacted the sister company based in the U.K. (Vivomaxx). 

The gut micro biome. You are only 10% organically human. (9)

Let's begin...

I received them promptly in pill l form, placed in an ice packed package. I chose the capsules because the carbohydrate content is negligible so should not interfere with my ketogenic diet to manage my epilepsy. I could experience some 'turbulence' as I adjust to it, which may or may not result in increased seizure activity temporarily. I have no idea, but I'm prepared for anything. So far so good.

The formulation used in these products is said to be the same as VSL#3, a probiotic that has been the subject of over 60 human clinical trials as a medical food in the dietary management of gastrointestinal and liver disorders.

From reading about the capsules, I found that they contain 112 billion bacteria per tiny capsule, and you can take up to 4 a day! It is said that these quantities are necessary to properly colonise the gut, which contains up to 10-100 billion bacteria/ml of faeces material. Optimal conolisation is achieved in 2-3 weeks so I have personally chosen to do this for 30 days, consistent with some interesting studies I have read. More information on the product can be found here: 

https://www.vivomixx.co.uk/faq.php 

I became interested further by studies suggesting novel mechanisms of action accounting for deficiencies of the endocannabinoid system (which is implicated in several chronic conditions) to regulate inflammation. It has also been established that endocannabinoid signalling is a key regulator of synaptic neurotransission throughout the brain (7), allowing for improvements in seizure control if you are able to target the appropriate receptors.

'The endocannabinoid system plays an important role in regulating inflammation in several chronic or anomalous gut inflammatory diseases. In vivo and ex vivo studies showed that 30 days treatment with a probiotic mix activated the endocannabinoid system in zebrafish.' (4)

The endocannabinoid system controls a variety of gastrointestinal functions. (10)

I decided to attempt to replicate this protocol in similar fashion, for 30 days. Obviously I am not a zebrafish, but I know that they are commonly used in research as they posess a similar genetic structure to humans. They share 70 percent of genes with us and 84 percent of genes known to be associated with human disease have a zebrafish counterpart. (5)

Orthologue genes shared between the zebrafish, human, mouse and chicken genomes, using orthology relationships from Ensembl Compara 63. (1)

Back to the experiment:

I began with just 1 capsule in case I experienced any gastrointestinal disturbance and from day 3, I had begun to take 2 capsules with food as I seem to tolerate it well. 

My main curiosity with this experiment in general, is to see how taking these probiotics may affect my epilepsy- positively, negatively, or no change. Personally I'm not sure if there will be any difference, but my general health may be improved. I will have a stool sample analysed after the experiment.

I also suffered a brain haemorrhage as a result of the tumour and have had brain surgery so it was interesting to find research on how the gut micro biome becomes altered as part of the inflammatory response, impacting both short and long term recovery. The simplest explanation I found came from this study on the inflammatory response to stroke in the Journal of Neuroscience. (12) A brain haemorrhage is not too dissimilar to a stroke, especially if the blood brain barrier integrity has been further affected by having had brain surgery. I still have invisible disabilities as a result of the assault on this area of my brain and I am able to control it to a large degree with diet and lifestyle adjustments but I am always looking to improve this.

Schematic showing how stroke alters gut microbiota,
which primes the immune system to exert further damage. (6)

I realise that the gut and brain have a complex, fascinating connection through these trillions of bacteria, that is only just starting to be understood at a higher level. This is exciting and provides us with so many opportunities to learn more and investigate all posibilities. 

The gut brain connection is facilitated via the vagus nerve, which is very important to note for individuals with epilepsy. The vagus nerves are a pair of nerves running from the brain throughout the body to send electrical messages around all physiological systems. The central nervous system can become spontaneously overstimulated with epilepsy, but it is possible to attempt to regulate these electrical impulses with Vagal Nerve Stimulation or with microbial and/or nutritional stimuli.

'...distinct microbial and nutritional stimuli activate the vagus and the nature of the signals transmitted to the brain that lead to differential changes in the neurochemistry of the brain and behaviour.' (2)

Vagal Nerve Stimulation (VNS) device (13)

I am now probably a little too aware of how every thought we have and every action we make impacts on gut health in profound ways as a 2 way feedback system between the gut and brain via the vagus nerve.

It is interesting to think how many individuals suffering with drug resistant epilepsy will attempt to put an end to their suffering with Vagal Nerve Stimulation (VNS), by which a small electrical device similar to a pacemaker is implanted under the skin to the left vagus nerve in the next with the aim of reducing seizure activity. Its pretty invasive and only appears to give significant, but partial relief at best, with a review stating that of those who responded (54%), there was a reduction in seizure frequency of around 45-63%. (3)

This is significant, but frustration will remain for these patients, especially the non responders. I wonder if we could find kinder solutions to this complex electrical circuitry that makes up our brain and central nervous system through modulation of the gut microbiome. Could probiotics help us to find some kind of solution here for non responders and perhaps even in combination with VNS for the responders?


Gut dysbiosis and cancer:

As a secondary aim of my investigation, I would like to learn more about the clear association between gut dysbiosis and a number of cancers (17), focusing on the brain and central nervous system of course.

I have recently transitioned into a more 'mediterranean' style ketogenic diet so that the probiotics have more of a variety of prebiotics to feed off. I have also increased amounts of ginger and turmeric in my diet, which should help, theoretically at least. 

I still have ghee because it is high in butyric acid, a short chain fatty acid which the microbes love. It is at a high concentration in this food, but is also produced in the intestines by bacteria that ferment non-digestible carbohydrates. (8) I feel it would be helpful for people to remember this fact when discussing carnivorous ketogenic diet ('zero carb') approaches. It has been suggested that high levels of dietary fat decrease levels of butyric acid, but this information would shed some doubt on these findings when viewed in different contexts.- how much fat, what source, what is 'high fat', what is carb/fat ratio, etc. 

I knew early on that the ketogenic diet acts partly by shifting the gut microbiome to result in favourable changes in the gut and brain chemistry, and I attempted to optimise this effect in creative ways when I was on a 'zero carb' ketogenic diet- eg. entomophagy (insect fibre), adding specific supplements, digestive enzymes.

I read an interesting study recently revealing how the ketogenic diet is able to mitigate symptoms of epilepsy at least partly by correcting an imbalanced gut microbiota in epileptic infants. (15)

I also looked at effects of how other fasting mimicking diets, including intermittent fasting and time restricted feeding, will also alter the composition of microbiota, specifically in relation to cancer, but this was harder to find. Maybe we are still learning.  

How we might determine the composition of the microbiota in patients with cancer compared to healthy volunteers. (16)

My conclusion is that, in light of the data, from what we know and what we have yet to understand, it would not be unfeasible to suggest that taking probiotics at appropriate times may help to reduce risk of recurrence of a high grade glioma. I understand (in basic terms), the close relationship between the vagus nerve and microbiome-brain-gut-axis communication and so this may have an additional or stand alone benefit for epilepsy management and improved quality of life. Its fascinating stuff.- most of the more interesting research I found is on colon cancer, but there are obvious potential applications for a host of other cancers. Its a new area to look into, we can't make any definitive conclusions, but I'm looking forward to learning more.

References:

1. Collins, J. E., White, S., Searle, S. M. & Stemple, D. L. Incorporating RNA-seq data into the zebrafish Ensembl genebuild. Genome Res. 22, 2067–2078 (2012)

2. Forsythe, P., Bienenstock, J. and Kunze, W.A., 2014. Vagal pathways for microbiome-brain-gut axis communication. In Microbial Endocrinology: The Microbiota-Gut-Brain Axis in Health and Disease (pp. 115-133). Springer New York.

3. García-Pallero, M.A., García-Navarrete, E., Torres, C.V., Pastor, J., Navas, M. and Sola, R.G., 2017. Effectiveness of vagal nerve stimulation in medication-resistant epilepsy. Comparison between patients with and without medication changes. Acta neurochirurgica, 159(1), pp.131-136.

4. Gioacchini, G., Rossi, G. and Carnevali, O., 2017. Host-probiotic interaction: new insight into the role of the endocannabinoid system by in vivo and ex vivo approaches. Scientific Reports, 7.

5. Howe, K., Clark, M.D., Torroja, C.F., Torrance, J., Berthelot, C., Muffato, M., Collins, J.E., Humphray, S., McLaren, K., Matthews, L. and McLaren, S., 2013. The zebrafish reference genome sequence and its relationship to the human genome. Nature, 496(7446), p.498.

6. Lewis, T. (2016) Stroke Alters Gut Microbiome, Impacting Recovery. The Scientist Magazine. From URL: http://www.the-scientist.com/?articles.view/articleNo/46557/title/Stroke-Alters-Gut-Microbiome--Impacting-Recovery/ Accesed online, 07 Oct 2017.

7. Ludányi, A., et al., 2008. Downregulation of the CB1 cannabinoid receptor and related molecular elements of the endocannabinoid system in epileptic human hippocampus. Journal of Neuroscience, 28(12), pp.2976-2990.

8. Maness, L.R., 2016. The Effect of Butyric Acid on GLUT4 and IRS1 Expression in Human Preadipocytes in vitro.

9. NeuroscienceNews.com image adapted from The Sociable Scientist. http://thesociablescientist.com  

10. Pinto, L., Capasso, R., Di Carlo, G. and Izzo, A.A., 2002. Endocannabinoids and the gut. Prostaglandins, Leukotrienes and Essential Fatty Acids (PLEFA), 66(2-3), pp.333-341.

11. Schwabe, R.F. and Jobin, C., 2013. The microbiome and cancer. Nature Reviews Cancer, 13(11), pp.800-812.

12. Singh, V. et al., “Microbiota dysbiosis controls the neuroinflammatory response after stroke,” The Journal of Neuroscience, doi:10.1523/jneurosci, 2016.

13. Vagus nerve stimulation. Epilepsy Society. from URL: https://www.epilepsysociety.org.uk/vagus-nerve-stimulation#.WdaI0a2ZM_U Accessed online, 07 Oct 2017.

14. Vivomixx. from URL: https://www.vivomixx.co.uk/faq.php Accessed online, 07 Oct 2017.(12)

15. Xie, G., Zhou, Q., Qiu, C.Z., Dai, W.K., Wang, H.P., Li, Y.H., Liao, J.X., Lu, X.G., Lin, S.F., Ye, J.H. and Ma, Z.Y., 2017. Ketogenic diet poses a significant effect on imbalanced gut microbiota in infants with refractory epilepsy. World Journal of Gastroenterology, 23(33), p.6164.

16. Zitvogel, L., Daillère, R., Roberti, M.P., Routy, B. and Kroemer, G., 2017. Anticancer effects of the microbiome and its products. Nat Rev Microbiol, 15, pp.465-78.

17. Zitvogel, L., Galluzzi, L., Viaud, S., Vétizou, M., Daillère, R., Merad, M. and Kroemer, G., 2015. Cancer and the gut microbiota: an unexpected link. Science translational medicine, 7(271), pp.271ps1-271ps1.