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Paul Clayton

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The Microbiome And The Brain

Like beta software, humans are full of bugs. And like beta software too, something that you first thought of as a bug often turns out to be a feature – and maybe, even, the future. Evolution itself is an accumulation of bugs (genetic mutations), which under the right conditions became biologically useful features; and the evolutionary process that built the complexity of higher life forms like us, has left us intensely linked to our bug ancestors, the microbes, which remain inside our cells and our organs. These bugs have most definitely become a feature. Sometimes, however, that feature can revert to being a dangerous bug.

The microbiome, a kilo or two of microbes that mostly inhabit the large bowel, contains an estimated 10,000 species of microorganisms including bacteria, archaea, fungi, viruses and protists, formerly known as protozoa. Many of these microbes have not been identified, and are simply referred to as Operational Taxonomic Units, or OTU’s; they are the dark matter of the microbiome, and their role is as mysterious as their identity. But even the ‘known’ microbial universe is not really well known. There is widespread disagreement about the numbers and species that may be involved; recent work has shown that the results of microbiome analysis are highly variable, and depend on the analytical method used (1). 

We know, however, that the microbiome can be changed substantially by changing our diet. Prebiotic fibers in pulses and legumes increase the numbers of gram-positive probiotic species very considerably, and as they grow they displace and kill off gram-negative species that contribute to chronic inflammation in the gut.

The fact that prebiotic fibers have been largely removed from processed and ultra-processed foods has increased the numbers of gram-negative bacteria inside us, and this has undoubtedly played a major role in driving irritable bowel syndrome and inflammatory bowel disease to new and exciting heights. 

We know also, that we communicate with the microbiome, and vice versa (2, 3). Stress, for example, alters gastrointestinal secretions, and these lead to significant changes in the microbiome (4, 5). Conversely, changes in the microbiome have been linked to many disorders including not just inflammatory bowel disease, but also asthma, obesity and diabetes (6, 7); and most recently, changes in brain function (8).

The microbiome produces a range of volatile compounds (‘odorants’), which are increasingly suspected to influence our mood and behavior via specific receptors in the nose and other tissues (16), and may be responsible for many of the ‘gut feelings’ we have about other people or situations. Bugs also make biogenic amines such as histamine, spermine and spermidine (9), which exert a wide range of biological effects in the brain and elsewhere. They synthesize many if not all the neurotransmitters used in the brain (2, 3, 10), and contribute to plasma and perhaps brain levels of many of these; but they also communicate with the brain directly, via the vagus nerve. 

The vagus nerve runs between the brain stem and the viscera. Once thought to carry one-way traffic from the central nervous system to the gastrointestinal system, it is increasingly seen as a bi-directional super-highway that marries the two systems, for better or for worse, in sickness and in health. It is involved, somehow, in the relationship between the microbiome and behavioural disorders, sleep disorders, affective disorders, stroke, and neurodegenerative and neuro-immune diseases (10, 11).

The close relationship between brain, behavioural and bacterial circadian rhythms is absolutely fascinating (12), and is another example of our deep and complex inter-dependence; but for brevity’s sake I will leave circadian rhythms for another occasion, and focus today only on Parkinsonism.

Parkinson’s Syndrome is caused by the progressive loss of dopaminergic neurones in the substantia nigra, deep inside the brain. (A small number of patients with Parkinsonian symptoms retain their dopaminergic neurons. Their condition is called SWEDDS, their dopaminergic neurons are not dead but probably are dysfunctional, and their pathoaetiology may be completely different. They may also require different treatment.)

There is a good deal of excess capacity in the brain, as there is with most organs; and many of these neurones can die before the typical clinical symptoms of tremor and rigidity emerge. In fact, by the time that a clinical diagnosis can be made, between a third and a half of all the dopaminergic neurones have already died (13). This is one reason why the medical (pharmaceutical) treatment of Parkinsonism is so hopeless, because it is always given far too late in the disease process, and after much of the damage has already been done. Another reason is that the anti-Parkinson drugs, which mainly concentrate on supplying the neurotransmitter l-dopamine, do not attack the fundamental target; so while they can reduce symptoms, they do nothing to slow the progress of the disease.

We might find a better target in the gut.

There is evidence for at least two possible drivers of progressive damage to neurones in the substantia nigra. One of these is viral (14). The other relates to the prion-like accumulation of a mal-folded protein called alpha-synuclein which causes neuro-inflammation and nerve damage (15), and forms clumps called Lewy bodies, a hallmark of the Parkinsonian brain. (This is similar to the accumulation of the mal-folded beta amyloid protein that forms plaques in the brain during Alzheimer’s). The viral and prionic models are not mutually exclusive. It is possible that either or both factors may play a role in any one patient, and it is also possible that the virus causes or contributes to alpha-synuclein mal-folding and accumulation. 

Both virus and alpha-synuclein, however, appear to derive from the microbiome, or tissues which are microbiome-dependent. The virus involved has been putatively identified as one that normally lives in the gut (14). Alpha-synuclein mal-folding is believed to start either in the gut or in the vagal neuronal network supplying the gut, before travelling back up the vagus nerve and into the brain. It may also start in the olfactory bulb, before travelling back into the brain via the olfactory nerve (16, 17). (Olfactory neurones are in direct contact with the nasal aka aeropharyngeal microbiome).

This would explain why the earliest signs of Parkinsonism are not the well-known signs of brain damage but a group of symptoms that occur in the gut, the olfactory system and the peripheral nervous system. These include constipation, loss of the sense of smell, orthostatic hypotension and reduced heart rate variability.

There is a rationale, therefore, for targeting the microbiome via diet. Here are ten pieces of evidence that support the prophylactic use of prebiotics and polyphenols:

  1. Chronic constipation is a well-established risk factor for Parkinsonism (18, 19). 
  2. Dysbiosis, which inevitably occurs in chronic constipation, is commonly found in Parkinsonian patients (20-22). 
  3. Dysbiosis generally causes inflammation in the gut.
  4. Alpha-synuclein is synthesised in the GALT (the gut’s immune system) as a response to gastro-intestinal infection and probably, therefore, to dysbiosis and related inflammation (23, 24).
  5. Dysbiosis causes the accumulation of mal-folded alpha-synuclein (25), via changes in polyphenol chemistry.
  6. Inflamation changes the structure of alpha-synuclein directly, making it neurotoxic (26).
  7. Dysbiosis and gut dysfunction accelerate the development of Parkinson’s in an animal model (27). 
  8. The progressive removal of prebiotic fibres from processed and ultra-processed foods in today’s diet is directly linked to increases in dysbiosis, irritable bowel disease and inflammatory bowel disease. The incidence of Parkinsonism is also increasing (28); as would be expected if dysbiosis and inflammation are indeed drivers.
  9. Severing the vagus nerve, which interrupts the neuronal transfer of alpha-synuclein from the dysbiotic gut to the brain, appears to reduce the risk of (clinical) Parkinson’s considerably (29). It does not provide 100% protection because alpha-synuclein may be able to enter the brain via alternative routes such as the circulatory system (30).
  10. Several studies find that the risk of Parkinsonism is increased in patients with inflammatory bowel disease (31-33). Full disclosure: one study reported that IBD was protective (34).

All of these pieces of evidence suggest that dysbiosis is involved in driving the earliest stages of the disease. If this is true, dietary change would be a easier and safer remedy than severing the vagus nerve!

I would recommend the regular consumption of mixed prebiotic fibres, which reduces chronic inflammation in the gut. To this I would add a blend of polyphenols which enter the small bowel (such as green tea, cocoa or berry flavonoids) and the large bowel (such as the avenanthramides found in oats); thereby adding to the local anti-inflammatory effects.. And to that I would add an omega 3 / lipophile polyphenol combination, to reduce any neuro-inflammation that might already be occurring in the brain, and especially in the substantia nigra. Finally, I would include HydroCurc, a modified form of curcumin which superior bioavailability; as curcuminoids have been shown to inhibit alpha-synuclein aggregation (35), as well as conferring potent anti-inflammatory effects.  

Such a nutritional combination might be an effective way of reducing risk, and would have no downside. This approach is not likely to be so useful if taken late in the disease ie once the clinical symptoms of brain damage have already appeared.

There are also genetic risk factors, and it is not yet known whether these can be modified by external inputs. But if I had a genetic risk marker such as a mutated LRRK2, PARK7, PINK1, PRKN, or SNCA gene, or there was a strong family history of Parkinsonism, I would certainly adopt the above nutritional regime. Having said that, it is precisely in the genetic risk sector that dietary modification is least likely to be effective. But it is certainly worth trying, and will in any case produce multiple health benefits.

The evidence linking aeropharyngeal dysbiosis to the nasal route of alpha-synuclein malfolding and transfer is, at the time of writing, rather less substantial. I do not yet know whether attempting to change the aeropharyngeal microbiome would be helpful. However, there is growing evidence that periodontal disease, which is highly inflammatory, increases the risk of Parkinsonism (ie 36). It may be that specific oral microbes are involved; for example, there are some bacterial species involved in perio that appear to be particularly damaging for the dopaminergic nerves involved in Parkinson’s (37). Or it may be the local generation (and therefore locally high concentrations) of inflammatory mediators produced in periodontal disease that trigger alpha-synuclein mal-folding in the olfactory bulb. Or it may be that microbes and inflammatory compounds both play a role.

If this is true, and on balance I believe it is, improved oral hygiene should be added to your anti-Parkinsonian regime. This includes toothbrush and floss, of course, but it should also involve algal fucoidans, which have been shown to reduce plaque formation (38), and thus protect against periodontal disease.

References:

1. Hugon P, Lagier JC, Colson P, Bittar F, Raoult D. Repertoire of human gut microbes. Microb Pathog. 2017 May;106:103-112.

2. Patterson E, Cryan JF, Fitzgerald GF, Ross RPDinan TGStanton C. Gut microbiota, the pharmabiotics they produce and host health. Proc Nutr Soc. 2014;73:477–789.

3. Wall R, Cryan JF, Ross RP, Fitzgerald GFDinan TG, Stanton C. Bacterial neuroactive compounds produced by psychobiotics. Adv Exp Med Biol. 2014;817:221–239.

4. MacLaren R, Radcliffe RA, Van Matre ET, Robertson CE, Ir D, Frank DN. The Acute Influence of Acid Suppression with Esomeprazole on Gastrointestinal Microbiota and Brain Gene Expression Profiles in a Murine Model of Restraint Stress. Neuroscience. 2018 Dec 15;398:206-217.

5. Maltz RM, Keirsey J, Kim SC, Mackos AR, Gharaibeh RZ, Moore CC, Xu J, Somogyi A, Bailey MT. Social Stress Affects Colonic Inflammation, the Gut Microbiome, and Short Chain Fatty Acid Levels and Receptors. J Pediatr Gastroenterol Nutr. 2018 Dec 11. doi: 10.1097/MPG.0000000000002226.

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7. Huang YJ, Marsland BJ, Bunyavanich S, et al. The microbiome in allergic disease: current understanding and future opportunities-2017. PRACTALL document of the American academy of allergy, asthma & immunology and the European academy of allergy and clinical immunology. J Allergy Clin Immunol. 2017;139:1099–1110.

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9. Pugin B, Barcik W, Westermann P, Heider A, Wawrzyniak M, Hellings P, Akdis CA, O’Mahony L. A wide diversity of bacteria from the human gut produces and degrades biogenic amines. Microb Ecol Health Dis. 2017 Jan 1;28(1):1353881.

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14. Hoenen C, Gustin A, Birck C, Kirchmeyer M, Beaume N, Felten P, Grandbarbe L, Heuschling P, Heurtaux TAlpha-Synuclein Proteins Promote Pro-Inflammatory Cascades in Microglia: Stronger Effects of the A53T Mutant. PLoS One. 2016; 11(9): e0162717.

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17. Bienenstock J, Kunze WA, Forsythe P. Disruptive physiology: olfaction and the microbiome-gut-brain axis. Biol Rev Camb Philos Soc. 2018 Feb;93(1):390-403.

18. Lin CH, Lin JW, Liu YC, Chang CH, Wu RM. Risk of Parkinson’s disease following severe constipation: a nationwide population-based cohort study. Parkinsonism Relat Disord. 2014;20:1371–5. 

19. Plouvier AO, Hameleers RJ, van den Heuvel EA, Bor HH, Olde Hartman TC, Bloem BR, van Weel C, Lagro-Janssen AL. Prodromal symptoms and early detection of Parkinson’s disease in general practice: a nested case-control study. Fam Pract. 2014;31:373–8.

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24. Stolzenberg E, Berry D, Yang, Lee EY, Kroemer A, Kaufman S, Wong GCL, Oppenheim JJ, Sen S, Fishbein T, Bax A, Harris B, Barbut D, Zasloff MA. A Role for Neuronal Alpha-Synuclein in Gastrointestinal Immunity. J Innate Immun. 2017;9(5):456-463.

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29. Svensson E, Horvath-Puho E, Thomsen RW, Djurhuus JC, Pedersen L, Borghammer P, Sorensen HT. Vagotomy and subsequent risk of Parkinson’s disease. Ann Neurol. 2015;78:522–9.

30. Matsumoto J, Stewart T, Sheng L, Li N, Bullock K, Song N, Shi M, Banks WA, Zhang J. Transmission of α-synuclein-containing erythrocyte-derived extracellular vesicles across the blood-brain barrier via adsorptive mediated transcytosis: another mechanism for initiation and progression of Parkinson’s disease? Acta Neuropathol Commun. 2017 Sep 13;5(1):71.

31. Lin JC, Lin CS, Hsu CW, Lin CL, Kao CH. Association Between Parkinson’s Disease and Inflammatory Bowel Disease: a Nationwide Taiwanese Retrospective Cohort Study. Inflamm Bowel Dis. 2016 May;22(5):1049-55.

32. Villumsen M, Aznar S, Pakkenberg B, Jess T, Brudek T. Inflammatory bowel disease increases the risk of Parkinson’s disease: a Danish nationwide cohort study 1977-2014. Gut. 2019 Jan;68(1):18-24.

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34. Camacho-Soto A, Gross A, Searles Nielsen S, Dey N, Racette BA. Inflammatory bowel disease and risk of Parkinson’s disease in Medicare beneficiaries. Parkinsonism Relat Disord. 2018 May;50:23-28.

35.Herva MEZibaee SFraser GBarker RAGoedert M, Spillantini MG. Anti-amyloid compounds inhibit α-synuclein aggregation induced by protein misfolding cyclic amplification (PMCA). J Biol Chem. 2014 Apr 25;289(17):11897-905.

36. Kaur T, Uppoor A, Naik D. Parkinson’s disease and periodontitis – the missing link? A review. Gerodontology. 2016 Dec;33(4):434-438.

37. Choi JG, Kim N, Ju IG, Eo H, Lim SM, Jang SE, Kim DH, Oh MS. Oral administration of Proteus mirabilis damages dopaminergic neurons and motor functions in mice. Sci Rep. 2018 Jan 19;8(1):1275.

38. Jun JY, Jung MJ, Jeong IH, Yamazaki K, Kawai Y, Kim BM. Antimicrobial and Antibiofilm Activities of Sulfated Polysaccharides from Marine Algae against Dental Plaque Bacteria. Mar Drugs. 2018 Aug 27;16(9). pii: E301.

This text was originally published here on On Wednesday, January 9, 2019.
This is a guest post. The opinions expressed are the writer’s own.

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