The microbiome and Parkinson’s Disease

The gut-brain axis is a neurohumoral communication system that gives our microbiota the capacity to influence CNS function. Growing evidence suggests the gut microbiome may be different in people with Parkinson’s Disease and that features of our microbiota relate to different motor phenotypes. If these observations can be confirmed, modifying the composition of our gut bacteria could provide entirely new tools for disease prevention. 

 The commonly cited estimate is that, in the average person, bacterial cells outnumber human cells by ten to one. Sender et al (2016) have recently revised this estimate, suggesting that bacterial and human cells are present in roughly equal numbers, the great bulk of bacteria being found in the gut, and the great bulk of human cells in the hematopoietic system.1

Even if Sender et al are correct in their lower estimate, the numerical contribution made by bacteria is still astonishingly large. So too may be their functional significance. It has been suggested that our bacteria, collectively, have the status of a “newly discovered organ” or that they constitute our “second genome”.2,3

A complex symbiosis

Whether or not this is the case, the collection of bacteria – or microbiota – which we house undoubtedly represents a complex and highly evolved system composed of up to a hundred different bacterial species. It may be as much the balancebetween these species – as opposed to the dominance of any individual or group of species - that influences human health; and the activity of different players – as much as their presence – that is important. 

Manipulating our microbiota could be an entirely new approach to complex and seemingly intractable CNS disorders

For several years, there has been evidence that the composition and function of the gut microbiota relate to conditions such as obesity and irritable bowel disease.4 More recently, advances in the speed and affordability of high-throughput gene sequencing, coupled with advances in computing, have greatly increased our ability to investigate associations between the gut microbiome and other conditions, including neurodegenerative and psychiatric diseases.

The gut microbiota and their hosts have a symbiotic relationship, and a central part of this is the gut-brain axis, a two-way, neurohumoral communication system which gives the biota the capacity to influence the functioning of the CNS and hence our behavior.5 It has been suggested that the gut-brain axis enables the microbiota to modulate anxiety, mood, cognition and even pain.6 If these ideas can be substantiated, manipulation of the microbiota could become an entirely new approach to therapy for a range of complex and sometimes seemingly intractable CNS disorders.

Figure 1

Bidirectional interaction between gut microbiota and the brain.

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PD-associated differences in microbiota

Scheperjans et al sequenced the V1-V3 regions of the bacterial 16S ribosomal RNA gene to investigate the fecal microbiota of 72 patients with PD and 72 age- and sex-matched controls.7 They came to two major conclusions: first, the gut microbiome may be different in people with PD; secondly, within patients, specific features of the microbiome appear to be related to different motor phenotypes. 

Professor Shen-Yang Lim talks about Scheperjans et al study that found evidence that the gut microbiome may be different in people with PD and  may vary with motor phenotype. Others have reported a greater frequency of pro-inflammatory bacteria, but such evidence is of correlation not causation.

Prevotellaceae were 78% less abundant in the feces of PD patients than in the feces of non-PD controls. Pooling these data with information on the abundance of three other bacterial families – plus the severity of constipation - could identify PD among study participants with 86% sensitivity and 39% specificity. In relation to phenotype, a greater abundance of Enterobacteriaceae was associated with more severe postural instability and gait difficulty, as opposed to tremor-dominant PD. 

Cross-sectional studies such as the one above reveal associations between the microbiome and disease presence and phenotype. Longitudinal studies would be required to establish the temporal and potentially causative relationship between abnormalities in gut microbiota and the development of PD. However, the associations demonstrated are suggestive, and we have at least hints into the mechanisms that might underlie causation.

Brave new world of microbiota

Shannon, Keshavarzian and colleagues from Rush University Medical Center had demonstrated alpha-synuclein staining in the colon of people with early, untreated PD.8 Such evidence of alpha-synuclein aggregation was not found in specimens from non-PD controls. Nor was it present in patients with inflammatory bowel disease. This suggested to the authors that (although PD patients also have evidence of inflammation) the presence of alpha-synuclein was specific to PD and not the result of inflammation per se or of oxidative stress. We note, however, that in subsequent work not all groups have been able to replicate these findings and there is an ongoing debate about the specificity of colonic alpha-synuclein staining for PD.9, 10

They then carried out a study to investigate whether inflammatory mechanisms that give rise to alpha-synuclein misfolding – and hence PD pathology - might be the result of altered colonic microbiota.11 

Thirty-eight people with PD and 34 healthy controls contributed fecal samples and biopsy specimens of sigmoid mucosa. Levels of butyrate-producing bacteria from the genera BlautiaCoprococcus, andRoseburia, which have been putatively identified as anti-inflammatory in their effects (and which are also thought to reduce gut permeability), were less abundant in the feces of PD patients than in control feces. Proteobacteria of the genus Ralstonia, which have been suggested as pro-inflammatory, were significantly more abundant in mucosal samples from PD patients than in biopsy specimens from controls.

Altered composition of the microbiota could trigger inflammation-mediated misfolding of α-synucleinfollowed by its prion-like propagation along the vagal nerve

Several other studies have found significant differences between the gut microbiota of PD patients and that of healthy controls.12   However, there is as yet no agreement on the specific taxa that are found to be different. In the search for consistency, it may be helpful to move towards agreed protocols for patient selection, particularly in relation to disease stage and phenotype, and controlling carefully for the effects of potential confounders (such as age, diet, medications and constipation). Perhaps above all, it would be helpful to establish standardized sequencing methodology and statistical analysis.13 

Evidence that transplanting the fecal microbiome from PD patients to mice causes synucleinopathy with motor deficits brings us closer to causation. 

Animal studies have also provided evidence supporting the importance of the gut-brain axis in PD. Transgenic mice that overexpress human alpha-synuclein are susceptible to microglial activation, PD-like motor dysfunction and brain pathology. However, while this disease process develops in animals with a typical microbiota, it does not occur in germ-free animals.14 It therefore appears that the gut microbiome is centrally involved. Giving germ-free mice microbial metabolites restores their susceptibility to neuroinflammation and motor symptoms. And, perhaps most remarkably, the development of motor dysfunction is enhanced by the transplantation into the animals of gut microbiota from patients with PD. 

Remarkably, motor dysfunction is enhanced when germ-free animals are given gut microbiota from patients with PD

Microbiome-directed therapeutics

Thoughts about how to modify the microbiome have centered on

  • the use of probiotics, ie  microbes that may have helpful effects, for example in inhibiting inflammatory processes
  • prebiotics, which are non-digested foods that promote the growth of beneficial microbiota
  • and the transplantation of fecal microbiota. 

Barichella et al carried out a double-blind, randomized controlled trial of the use of probiotics (in fermented milk) and prebiotic fiber to treat constipation in 120 patients with PD.15 Compared with controls taking placebo, patients having the pre- and probiotic treatment had a significantly greater increase in the number of complete bowel movements. This positive finding is supported by interim analysis of data from another controlled trial of probiotics in PD patients with constipation being conducted at the University of Malaya. 

Fecal microbiota transplantation (FMT) has been successful in treating recurrent infection with Clostridium difficile infection, and there are early indications it may also be helpful in obesity and inflammatory bowel disease.16 Intriguingly, ingestion of fecal matter as a means of treating food poisoning and diarrhea is a technique that seems to have been first used 1,700 years ago in China.17  Whether it will have a future as long as its past, and whether that future will encompass therapy for PD, remains to be seen.

Acknowledgements

We would like to thank Lundbeck Institute Campus Editorial Board member Professor Shen-Yang Lim (MBBS MD FRACP, Division of Neurology, Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia,) for sharing his expertise and insights surrounding the microbiome in Parkinson’s disease and for providing feedback in the development of this article.

Referencias
  1. Sender R, Fuchs S, Milo R. Revised estimates for the number of human and bacteria cells in the body. PLoS Biol. 2016; 14(8): e1002533. 
  2. Tremlett H, Bauer KC, Appel-Cresswell S et al. The gut microbiome in human neurological disease: A review. Ann Neurol. 2017;81(3):369-382.                      
  3. Dinan TG, Cryan JF. Gut feelings on Parkinson’s and depression. Cerebrum. 2017 Mar-Apr; 2017: cer-04-17.
  4. Fraher MH, O'Toole PW, Quigley EM. Techniques used to characterize the gut microbiota: a guide for the clinician. Nat Rev Gastroenterol Hepatol. 2012;9(6):312-22. 
  5. Collins SM, Surette M, Bercik P.The interplay between the intestinal microbiota and the brain. Nat Rev Microbiol. 2012;10(11):735-42. 
  6. Cryan JF, Dinan TG. Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour. Nat Rev Neurosci. 2012;13(10):701-12.
  7. Scheperjans F, Aho V, Pereira PA et al. Gut microbiota are related to Parkinson's disease and clinical phenotype. Mov Disord. 2015;30(3):350-8.
  8. Shannon KM, Keshavarzian A, Mutlu E, et al. Alpha-synuclein in colonic submucosa in early untreated Parkinson's disease. Mov Disord. 2012;27(6):709-15.
  9. Lionnet A, Leclair-Visonneau L, Neunlist M, et al. Does Parkinson's disease start in the gut? Acta Neuropathol 2018; 135(1): 1-12.

  10. Lubomski M, Tan AH, Lim SY, et al. Parkinson's disease and the gastrointestinal microbiome. J Neurol. 2019.

  11. Keshavarzian A, Green SJ, Engen PA et al. Colonic bacterial composition in Parkinson's disease. Mov Disord. 2015;30(10):1351-60. 
  12. Scheperjans F. Gut microbiota, 1013new pieces in the Parkinson's disease puzzle. Curr Opin Neurol. 2016;29(6):773-780.
  13. Goodrich JK, Di Rienzi SC, Poole AC et al. Conducting a microbiome study. Cell. 2014;158(2):250-262.
  14. Sampson TR, Debelius JW, Thron T et al. Gut Microbiota Regulate Motor Deficits and Neuroinflammation in a Model of Parkinson's Disease. Cell. 2016;167(6):1469-1480.
  15. Barichella M, Pacchetti C, Bolliri C et al. Probiotics and prebiotic fiber for constipation associated with Parkinson disease: An RCT. Neurology. 2016;87(12):1274-80.  
  16. Gupta S, Allen-Vercoe E, Petrof EO. Fecal microbiota transplantation: in perspective. Therap Adv Gastroenterol. 2016 Mar; 9(2): 229–239.
  17. Zhang F, Cui B, He X et al. Microbiota transplantation: concept, methodology and strategy for its modernization. Protein Cell. 2018; 9(5): 462–473.
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