SCFAs may improve Parkinson's disease

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Diet plays an important role in Parkinson's disease

Parkinson’s disease is one of the most common progressive systemic neurodegenerative disorders, affecting millions of people worldwide. Despite intensive research, the cause of neurodegeneration is not fully understood, so the current state of research assumes a multifactorial etiology. In addition to sporadic forms of genetic predisposition, environmental factors, including diet, play a crucial role. Gastrointestinal symptoms are often the first nonmotor symptoms in Parkinson’s disease, in addition to olfactory dysfunction, which in most cases occur years to decades before the first motor symptoms, i.e., rigor, tremor, and akinesis. enter image description here Parkinson’s disease incidence rates are rising, it has been linked to the shift in the consumption of Western-style diets since the 1980s'. Growing evidence supports the idea that microbial dysbiosis and a proinflammatory intestinal environment are central components of the pathogenesis of Parkinson’s disease. It's some time that on online forums (the "grey literature") Parkinson's patients say that using butyric acid greatly improved their symptoms. Butiric acid is one of the height SCFAs. Short-chain fatty acids are a major group of metabolites involved in the microbiome-gut interaction and are produced through the anaerobic fermentation of dietary fibers. SCFAs have been investigated as having a possibly positive effect on several neurodegenerative diseases. As for any powerful nutrient, SCFAs may have uncomfortable side effects.

In Parkinson’s disease patients, the levels of SCFA-producing bacteria and fecal SCFAs are significantly reduced.

In a recent study investigating the potential therapeutic effect of propionate, the authors observed a putative neuroprotective effect in addition to immune regulation. Consumption of prebiotic fibers has recently been tested in a small cohort of Parkinson’s disease patients over 10 days. However, SCFA supplementation in Parkinson’s disease patients over a prolonged period has not yet been evaluated. In this pre-print article, the authors conducted an impressive clinical study over 6 months to investigate direct supplementation of the SCFAs propionate and butyric acid (butyric acid) and the prebiotic 2′-fucosyllactose. This study was supported by BASF Nutrition & Health Division.

There were three arms: * propionate+butyric acid capsules (butyric acid: 2550 mg; propionate: 1260 mg) with 2400 mg placebo, * 3250 mg 2' fucosyllactose capsules with 3200 mg placebo * 3250 mg 2' fucosyllactose capsules with 3810 mg propionate+butyric acid capsules daily for up to 6 months in combination with existing PD-specific therapy. 2'-fucosyllactose is an oligosaccharide. It is the most prevalent human milk oligosaccharide (HMO) naturally in human breast milk. 2'-fucosyllactose protects against infectious diseases, it also stimulates the growth of specific bifidobacteria. 2' fucosyllactose is known to protect against Campylobacter jejuni, Salmonella enterica serotype Typhimurium, Helicobacter pylori, etc. The capsules were provided by BASF.

The primary endpoints of this study were the impact on microbiome diversity and composition as well as changes in SCFA concentration in stool and serum. The secondary endpoints were the effect on the clinical parameters defined by The Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS III), levodopa equivalent daily dose (LEDD), PANDA, and olfactory score.

The study was performed from November 2019 to August 2020. This clinical trial was registered in the German Clinical Trials Register (DRKS; registration number DRKS00027061). A total of 72 participants were randomized and assigned to one treatment group upon recruitment.

Individual subjects were seen at the outpatient clinic every 3 months after initiation of supplementation and underwent a complete neurological assessment performed by a certified neurologist.

Improved clinical outcome upon 6 months supplementation in Parkinson’s disease patients.

Supplementation was generally well tolerated. All three interventions (treatments) globally led to a decrease (so an improvement in Parkinson's disease symptoms) in MDS-UPDRS III scores and LEDD over 6 months. This means that the patient's motor function improved, and they needed less medication. Yet in every intervention group, there were few patients with unchanged or increasing MDS-UPDRS III scores over time. Each group on average improved by seven points on MDS-UPDRS III scores, amazingly the improvement was more pronounced for patients who had high scores (patients who were in worst conditions). Yet an improvement of seven points on a scale which has 260 points is very minor.

Improvement in the sense of smell (olfaction) was only observed in the group that received 2' fucosyllactose and the combination group (2' fucosyllactose+butyric acid+propionate).

Cognitive function globally improved in all groups, as indicated by positive results in the PANDA test.

To gain insight into the mechanisms underlying successful SCFA intervention, the authors combined all 3 intervention groups and stratified them into responders (R: MDS-UPDRS III V2 < MDS-UPDRS III baseline) and nonresponders (NR: MDS259 UPDRS III V2 ≥ MDS-UPDRS III baseline). The scientists then selected the 20% of patients with the lowest and highest front numbers and sorted them into two clusters. These clusters included patients with the best/worst responses to intervention.

Scientist's analysis revealed that Streptococcus sp001556435 and Agathobacter rectalis contributed to the prediction of nonresponders, whereas SFEL01 sp004557245 had a significant impact on the prediction of responders. Agathobacter rectalis is a SCFA-producing bacterium.

In summary, SCFA supplementation may be a promising disease-modifying strategy in Parkinson’s disease, hence, a follow-up phase III clinical trial to investigate the therapeutic potential of SCFAs in Parkinson’s disease is warranted. Yet it's hard to see how a so minor improvement would lead to a market agreement. Another question is how this improvement scales with time, does it persist, does it improve further, or on the contrary, does this effect disappear?

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