Objective: To determine the functional effects of disrupted intestinal microbiota in Parkinson’s disease (PD), particularly the impacts of dysbiosis on inflammation, neuroprotective hormone secretion, and gastrointestinal (GI) symptoms; and therapeutic response to prebiotic fiber.

Background: PD patients are known to have significantly disrupted intestinal microbiota,[1] however the functional significance of dysbiosis remains elusive.  Emerging evidence suggests PD dysbiosis favors pro-inflammatory bacteria at the expense of short-chain fatty acid (SCFA)-producing species.[2-4]  Here we determine the effects of this pro-inflammatory milieu on SCFA, inflammatory markers, and glucagon-like peptide 1 (GLP-1), an incretin hormone with neuroprotective effects,[5] and assess treatment response to SCFA-promoting prebiotic fiber.

Method: De novo PD patients and age-matched healthy control subjects (10 per group, mean age 64 years) underwent serum collection for quantification of SCFA, zonulin, cytokines, and postprandial GLP-1 by ELISA as previously described,[6] and stool collection for bacterial diversity, community structure, and caprotectin.  Blood and stool were recollected after 10 grams of prebiotic fiber twice daily for 10 days.  Motor symptoms were assessed by movement disorder specialists and GI symptoms by a PROMIS scale.

Results: Compared to healthy control subjects, PD patients had decreased stool abundance of SCFA-producing bacteria of genus Faecalibacterium, lower plasma SCFA, and increased pro-inflammatory stool bacteria (p<0.05 for each comparison).  These effects were exacerbated by levodopa treatment in a separate cohort of 10 patients.  We demonstrated a 2-fold reduction in SCFA-dependent postprandial GLP-1 secretion in PD.  Dietary prebiotic improved microbial composition, serum SCFA, PD-associated GI symptoms, and intestinal barrier integrity, and decreased markers of gut and systemic inflammation.

Conclusion: Here we show that PD intestinal microbiota are associated with pro-inflammatory signaling and decreased production of SCFA.  These deleterious changes improve by treatment with SCFA-promoting prebiotic dietary fiber, which also improves PD-associated GI symptoms.  We provide evidence that diminished microbial SCFA production may contribute to the PD phenotype by decreasing secretion of neuroprotective GLP-1, and have developed a novel organoid system to test this concept in our ongoing studies.

References: [1] Sampson TR, Debelius JW, Thron T, et al. Gut Microbiota Regulate Motor Deficits and Neuroinflammation in a Model of Parkinson’s Disease. Cell. 2016;doi:10.1016/j.cell.2016.11.018
[2] Lubomski M, Tan AH, Lim SY, Holmes AJ, Davis RL, Sue CM. Parkinson’s disease and the gastrointestinal microbiome. Journal of Neurology. 2019;(0123456789)doi:10.1007/s00415-019-09320-1
[3] Unger MM, Spiegel J, Dillmann KU, et al. Short chain fatty acids and gut microbiota differ between patients with Parkinson’s disease and age-matched controls. Parkinsonism and Related Disorders. 2016;doi:10.1016/j.parkreldis.2016.08.019
[4] Keshavarzian A, Engen P, Bonvegna S, Cilia R. The gut microbiome in Parkinson’s disease: A culprit or a bystander? Prog Brain Res. 2020;252:357-450. doi:10.1016/bs.pbr.2020.01.004
[5] Athauda D, Maclagan K, Skene SS, et al. Exenatide once weekly versus placebo in Parkinson’s disease: a randomised, double-blind, placebo-controlled trial. The Lancet. 2017;doi:10.1016/S0140-6736(17)31585-4
[6] Manfready RA, Engen PA, Verhagen Metman L, et al. Attenuated Postprandial GLP-1 Response in Parkinson’s Disease. Front Neurosci. 2021;15:660942. doi:10.3389/fnins.2021.660942

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MDS Abstracts - https://www.mdsabstracts.org/abstract/intestinal-microbial-dysbiosis-promotes-prebiotic-reversible-inflammation-in-parkinsons-disease/