Parkinson’s disease (PD) is the second most common neurodegenerative disorder worldwide, second only to Alzheimer’s disease(Reference De Lau and Breteler1). PD has a significantly higher incidence rate in men than in women(Reference Wooten, Currie and Bovbjerg2) and is associated with increasing age with a prevalence of 1 % in people aged over 60 years(Reference De Lau and Breteler1). With increased survival into older age, the number of people with PD will continue to increase in the coming years(Reference Marras and Tanner3) and, in turn, this will perpetuate an imposing social and economic burden(Reference De Lau and Breteler1).
The diagnosis of idiopathic PD is based on positive clinical findings of two or more symptoms of parkinsonism, which are bradykinesia, tremor, rigidity, and postural instability, and the absence of any obvious causative factors or indicators of atypical disease(Reference Hughes, Daniel and Kilford4). The UK Brain Bank criteria(Reference Hughes, Daniel and Kilford4) and the Movement Disorder Society (MDS) clinical diagnostic criteria(Reference Postuma, Berg and Stern5) are usually used to support the process of diagnosis. Bradykinesia, tremor, rigidity, and postural instability classically make up the motor component of PD symptoms(Reference Kalia and Lang6); however, the presence of non-motor symptoms can also support the diagnosis and in many cases have been shown to pre-date the onset of motor symptoms(Reference Chaudhuri, Healy and Schapira7). Non-motor symptoms can largely be grouped into neuropsychiatric, sleep, and autonomic dysfunction(Reference Chaudhuri, Healy and Schapira7), several of which can adversely affect nutritional status(Reference Breasail, Smith and Tenison8), prompting interest in the use of dietary strategies to manage these.
Pharmacological treatment for motor symptom control utilises dopaminergic medications to compensate for the dopamine loss in PD(Reference Koller and Rueda9); however, there are currently no disease-modifying pharmacological treatments available. Furthermore, treatment regimens must be highly individualised due to the heterogeneous nature of the disease. In the early stages, response to treatment is usually good; however, optimal symptom control becomes more difficult to achieve as PD progresses into a more complex phase(Reference Sveinbjornsdottir10).
Pathophysiology of Parkinson’s disease
PD is characterised by dopaminergic neuronal loss in the substantia nigra in the midbrain and degeneration of various brainstem nuclei(Reference Del Tredici, Rüb and De Vos11). Intracellular inclusions consisting of alpha-synuclein, ubiquitin, neurofilaments and other proteins aggregating as Lewy Bodies are the hallmark finding(Reference Le Heron, MacAskill and Mason12). The Braak hypothesis is a prevailing concept based on neuropathological studies that describes progression of Lewy Body pathology in a sequential pattern, starting in the enteric nervous system and olfactory bulb, progressing to the substantia nigra and brainstem, and subsequently the cortex(Reference Halliday, McCann and Shepherd13). This may also explain why preclinical symptoms such as anosmia, rapid eye movement sleep behaviour disorder, and constipation, often precede motor manifestations of PD by many years(Reference Chaudhuri, Healy and Schapira7).
Both environmental and genetic factors are thought to play a role in the pathogenesis of PD, and multiple risk factors within each of these categories have been identified(Reference Kalia and Lang6,Reference Ascherio and Schwarzschild14) . Monogenic forms constitute a small minority of PD cases overall, with the single most common genetic risk factor being a GBA mutation, present in ∼10 % of PD patients(Reference Ye, Robak and Yu15,Reference Smith and Schapira16) . Other autosomal recessive and autosomal dominant genetic forms of PD are caused by mutations in the Parkin and PINK1 genes and in the SNCA and LRRK2 genes, respectively(Reference Ye, Robak and Yu15).
Environmental toxins are postulated to interact with genetic factors in a complex interplay, resulting in a common final pathway to produce the pathology seen in PD(Reference Le Heron, MacAskill and Mason12). Similar to genetic factors, it is unlikely that in the majority of those affected that a single environmental factor is responsible, and the multi-hit hypothesis has been used to explain the variability in the risk of developing the disease, which is thought to be precipitated after a series of environmental insults combined with genetic predisposition(Reference Le Heron, MacAskill and Mason12). The strongest evidence for a toxin inducing Parkinsonism comes from exposure to the compound methyl-phenyl-tetrahydropyridine(Reference Langston, Ballard and Tetrud17), a compound accidentally produced during the synthesis of an opioid drug. Exposure to structurally similar compounds found in pesticides have been associated with a higher risk of developing PD in epidemiological studies(Reference Ascherio, Chen and Weisskopf18). Other industrial chemicals including trichloroethylene, which is most commonly used as a degreasing and cleaning solvent, have been similarly implicated. The mechanism of action of these toxins is inhibition of Mitochondrial-Complex-1, leading to neuronal loss(Reference Dorsey and Bloem19).
Effect of dietary interventions on PD disease progression, symptoms and severity; why now?
Despite decades of research, there have been no pharmacological breakthroughs in disease-modifying therapies for PD(Reference Murakami, Shiraishi and Umehara20) and the standard dopaminergic treatment for motor symptom control remains levodopa(Reference Tambasco, Romoli and Calabresi21). This has led to a shift in focus by both patients and researchers(Reference Kulcsarova, Skorvanek and Postuma22) towards non-pharmacological approaches such as diet and exercise, which are central to a person’s healthy lifestyle(Reference Wang and Shih23). While emerging evidence has demonstrated that exercise is associated with better balance and gait, functional ability and quality of life(Reference Padilha, Souza and Grossl24), the role of diet requires further attention.
The aim of the current article is to review the evidence from randomised controlled trials (RCTs) examining the effect of dietary patterns, individual foods and beverages, and nutritional supplements, including nutrients, bioactive compounds, and biotics on pre-specified outcomes. These outcomes include PD progression, motor symptoms, non-motor symptoms, specifically those affecting the gastrointestinal (GI) tract, and PD severity. PD progression and severity is commonly measured using either the Hoehn and Yahr (H&Y) scale or the MDS-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS). The H&Y scale scores a patient’s disease stage from Stage 1 where there is only minimal or no functional disability and unilateral involvement, to Stage 5 where the disability causes confinement to a bed or wheelchair(Reference Hoehn and Yahr25). The MDS-UPDRS (previously known as UPDRS) evaluates motor signs (Part III of the questionnaire), the impact of motor and non-motor symptoms on daily living (Parts I, II) and motor complications (Part IV) and is the most widely used clinical rating scale in PD(Reference Goetz, Tilley and Shaftman26). Changes in the total UPDRS score can indicate disease progression, whereas the individual scores provide indications on the disease’s severity. Motor symptoms, on the other hand, are most frequently measured via the MDS-UPDRS Part III; however, study defined motor evaluations, such as ‘on’ time, as well as proxy measures, such as functional capacity, are also valid alternatives. Finally, GI-related outcomes are measured by a host of tools, such as diaries, questionnaires and scales, such as the gastrointestinal symptom rating scale (GSRS)(Reference Kulich, Madisch and Pacini27).
Dietary patterns
Eight RCTs(Reference Rusch, Beke and Nieves28–Reference Amiri, Javanbakht and Baghbanian35) have investigated the effect of dietary patterns on PD progression and severity, as well as motor and GI symptoms (Table 1).
Table 1 Randomised controlled trials of dietary patterns in Parkinson’s disease
Abbreviations: BM, bowel movement; BSFS, Bristol stool form scale; FTT, finger tapping task; GI, gastrointestinal; GSRS, gastrointestinal symptom rating scale; KD, ketogenic diet; MedDiet, Mediterranean diet; MDS-UPDRS, Movement Disorder Society-Unified Parkinson’s disease rating scale; TUG, timed up & go.
* Only between-group analyses reported.
† Entailed receiving a handout containing the following: recommendations for increasing fibre intake, physical activity, and fluid intake (at least 6–8 cups); and laxative medication list (e.g. stool softeners, osmotic, bulk producing, etc.) with usage recommendations.
‡ The on state refers to when the patient is experiencing symptomatic control due to medication, conversely the off state refers to when medication wears off.
Mediterranean diet
Only two RCTs (Table 1) have investigated the impact of a Mediterranean dietary pattern (MedDiet) on disease progression and symptoms in PD(Reference Rusch, Beke and Nieves28,Reference Paknahad, Sheklabadi and Moravejolahkami29) . In an 8-week parallel, two-arm RCT, there was no significant improvement in constipation symptoms in response to the MedDiet and standard constipation care compared to standard constipation care alone(Reference Rusch, Beke and Nieves28). Paknahad and colleagues(Reference Paknahad, Sheklabadi and Moravejolahkami29) demonstrated a significant decrease in non-motor symptoms after 10 weeks, yet no improvement in motor signs when examined using UPDRS (Table 1). Further research is necessary in the area to confirm these findings. Since both trials provided either dietary counselling(Reference Rusch, Beke and Nieves28) or diet plans to participants(Reference Paknahad, Sheklabadi and Moravejolahkami29), further RCTs could consider removing common barriers to dietary change such as cost, acceptability and time(Reference Munt, Partridge and Allman-Farinelli36).
Ketogenic diet
Three RCTs (Table 1) assessed the impact of a ketogenic diet on outcomes of interest(Reference Phillips, Murtagh and Gilbertson30–Reference Choi, Delgado and Chen32). In a pilot 8-week RCT designed to test the plausibility, safety and efficacy of this dietary pattern, a decrease in the total MDS-UPDRS score in both the intervention and placebo groups was seen with no significant difference between the two groups(Reference Phillips, Murtagh and Gilbertson30). Whilst a significantly better non-motor score was found in those following the ketogenic dietary pattern, there was an exacerbation of tremor and rigidity and a more adverse lipid profile in the ketogenic group(Reference Phillips, Murtagh and Gilbertson30). The two other trials showed no significant difference in motor function(Reference Krikorian, Shidler and Summer31) or functional capacity(Reference Choi, Delgado and Chen32) between the ketogenic and control diet over either an 8 week(Reference Krikorian, Shidler and Summer31) or 1 week period(Reference Choi, Delgado and Chen32) (Table 1). All three RCTs were either pilot(Reference Phillips, Murtagh and Gilbertson30,Reference Krikorian, Shidler and Summer31) , or feasibility trials(Reference Choi, Delgado and Chen32) and thus further research is needed to determine the effect of a ketogenic diet on PD progression, motor symptoms, and PD severity.
Protein redistribution diet
Protein redistribution (PRD) is defined as limiting protein intake at breakfast and lunch with no quantitative restriction of protein at dinner(Reference Rusch, Flanagan and Suh37). Only three RCTs(Reference Carter, Nutt and Woodward33–Reference Amiri, Javanbakht and Baghbanian35) examined the impact of PRD in PD on the outcomes of interest (Table 1). Over 8 weeks, lowering and redistributing dietary protein intake significantly improved motor function compared to a standard protein intake(Reference Carter, Nutt and Woodward33). When a PRD diet was combined with a nicotine-rich diet for 12 weeks, motor signs were significantly improved compared to a non-nicotine control diet but there were no differences between the PRD diet + nicotine and a nicotine-only group(Reference Amiri, Javanbakht and Baghbanian35). Barichella and colleagues(Reference Barichella, Marczewska and De Notaris34) showed a significant improvement in disease severity and progression in response to 8 weeks of a PRD diet(Reference Barichella, Marczewska and De Notaris34) (Table 1). Given that amino acids derived from dietary protein are known to compete with levodopa for absorption, thus adversely affecting motor symptoms, it is unsurprising that there are no RCTs in the literature having examined the impact of PRD on other outcomes of interest for this review. Further research of the PRD is necessary, however, wherein protein intake is based on patient body weight.
Foods & beverages
Six RCTs(Reference Cilia, Laguna and Cassani38–Reference Oliveira, Iraci and Pinheiro43) have investigated the effect of individual foods and beverages on PD disease progression, severity, and motor symptoms (Table 2).
Table 2 Randomised controlled trials of foods and beverages in Parkinson’s disease
Abbreviations: 6-MWT, six-minute walking test; BBS, berg balance scale; H&Y, Hoehn and Yahr; MDS-UPDRS, Movement Disorder Society-Unified Parkinson’s disease rating scale; MP, mucuna pruriens; TUG, timed up & go.
* Only between-group analyses reported.
† The on state refers to when the patient is experiencing symptomatic control due to medication, conversely the off state refers to when medication wears off.
Mucuna pruriens
Mucuna pruriens (MP) is a tropical legume that contains natural levodopa, which is a precursor to dopamine and therefore a compound that may offer symptomatic motor relief in PD. The effect of MP on the outcomes of interest has been investigated in three RCTs(Reference Cilia, Laguna and Cassani38–Reference Katzenschlager, Evans and Manson40). Both Katzenschlager et al. (Reference Katzenschlager, Evans and Manson40) and Cilia et al. (Reference Cilia, Laguna and Cassani39) reported that when administered as a single dose, MP was effective in controlling motor symptoms, motor fluctuations and medication-induced side effects for up to 4 h after intake. Furthermore, the overall tolerability profile was promising, with reported adverse events being mild and tending to be less frequent when compared to levodopa medication (Table 2). However, both RCTs investigated the patients’ response to a single MP dose, which, while important to assess safety and efficacy, is not representative of real life, where regular levodopa/carbidopa is often required. As a result, Cilia et al. (Reference Cilia, Laguna and Cassani38) undertook an 8-week RCT, which showed MP supplementation was as effective as levodopa/carbidopa therapy in improving disease severity, as well as motor and non-motor symptoms. Caution must be exercised when interpreting the results of the trials by Cilia and colleagues(Reference Cilia, Laguna and Cassani38,Reference Cilia, Laguna and Cassani39) as both were non-inferiority rather than superiority trials. Another point to emphasise is that the two RCTs by Cilia and colleagues(Reference Cilia, Laguna and Cassani38,Reference Cilia, Laguna and Cassani39) studied the same cohort of participants (Table 2). Thus, while the findings provide complementary evidence on different lengths of MP supplementation, their generalisability to the wider population remains uncertain. Finally, adverse events were frequently reported following the 8-week consumption of MP, with 50 % of participants enrolled in the treatment arm dropping out half-way through the study(Reference Cilia, Laguna and Cassani38) (Table 2). The lack of decarboxylase inhibitors, such as carbidopa or benserazide, which are usually combined with levodopa in commercial preparations, results in less efficient utilisation of levodopa in MP and, hence, more side effects. This further limits MP’s clinical use and calls for further research on the optimal dosage, timing, and population for MP therapy.
Taken together, while MP supplementation seems to be a promising alternative treatment for PD, especially in low-income settings due to the limited levodopa access and the low cost of MP, future large-scale trials, optimised in their trial design and supplementation regime are required(Reference Cilia, Laguna and Cassani38).
Dark chocolate, liquorice root extract and grape juice
Three trials investigated the effects of either dark chocolate, liquorice root extract or grape juice on PD progression, motor function, functional capacity, and severity(Reference Wolz, Schleiffer and Klingelhöfer41–Reference Oliveira, Iraci and Pinheiro43) (Table 2). Wolz et al. (Reference Wolz, Schleiffer and Klingelhöfer41) did not demonstrate a significant benefit following a single-dose consumption of dark chocolate on motor function or PD severity. However, due to the single-serving nature, future RCTs assessing regular intake of chocolate could further explore the bioactivity of cacao-derived compounds in PD. It is also important to emphasise that although the assessed outcomes were similar between groups, motor function significantly improved in the intervention group compared to baseline (Table 2). It is therefore possible that these changes would have resulted in between-group differences following chronic consumption of dark chocolate.
When liquorice extract was investigated, Petramfar et al. (Reference Petramfar, Hajari and Yousefi42) demonstrated its potential benefit over 6 months on PD severity and progression, where they found a lower total UPDRS score and part II and III UPDRS domains compared to a group consuming placebo. Future trials with adequately powered sample sizes, determined a priori, would be of interest to confirm these preliminary findings.
In combination with exercise, grape juice was investigated(Reference Oliveira, Iraci and Pinheiro43) and there was no improvement in functional capacity beyond that achieved by exercise alone over 4 weeks. However, since functional capacity measurements were secondary endpoints (Table 2), the RCT might have lacked the necessary power to detect statistical differences between the intervention and control groups. Furthermore, it is possible that 4-weeks of grape juice supplementation is not of sufficient duration for its potential ergogenic effect to influence functional capacity.
Overall, all three RCTs differed in the food or beverage that they provided (chocolate, liquorice extract and grape juice), thereby restricting their comparability (Table 2). The current lack of additional clinical trials on each food and beverage, further limits the external validity of the study findings. Clearly, as none of the included RCTs were able to demonstrate sufficient evidence of the intervention’s efficacy relative to the employed control, future studies are warranted to measure the impact of each of these food and beverages on the outcomes included within this review, as well and additional PD-specific endpoints, such as non-motor symptoms and quality of life.
Nutrients & bioactives
Currently, 23 RCTs(Reference Suzuki, Yoshioka and Hashimoto44–Reference Li, Wang and Yu66) have been conducted investigating the effects of nutrients and bioactive compounds on disease severity and progression, and motor symptoms (Table 3).
Table 3 Randomised controlled trials of nutrients and bioactive compounds in Parkinson’s disease
Abbreviations: ABC, activities-specific balance confidence; APDM, analysis of postural dynamics and movement; CoQ10, coenzyme Q10; H&Y, Hoehn and Yahr; IU, international unit; MDS-UPDRS, Movement Disorder Society-Unified Parkinson’s disease rating scale; n-3, omega-3; RAPID, rapid assessment of postural instability in Parkinson’s disease; SOT, sensory organisation test; TUG, timed up & go.
* Only between-group analyses reported.
† Food supplement formula containing 4950 mg n-3 fatty acids, 4950 mg omega-6 (n-6) fatty acids, 0·6 mg vitamin A, 782 mg tocopherols.
Vitamin D
Vitamin D is known to exhibit neuroprotective effects via reducing oxidative stress through autophagy, thereby making it a potentially promising treatment(Reference Hafiz67). Four RCTs(Reference Suzuki, Yoshioka and Hashimoto44–Reference Bytowska, Korewo-Labelle and Berezka47) examined the effects of Vitamin D on disease progression, motor function and functional capacity, yielding conflicting results (Table 3). In patients with varying pre-trial concentrations of vitamin D there was a significantly decreased rate of disease progression when measured by both H&Y and UPDRS total score in 113 participants after 12 months of 1200 IU/d of vitamin D(Reference Suzuki, Yoshioka and Hashimoto44). In a RCT with a similar sized cohort which examined the duration of dyskinetic episodes per day, no effects were seen; however, this RCT was over the shorter time span of 3 months and supplemented with the lower daily dose of 1000 IU /d(Reference Habibi, Anamoradi and Shahidi46) (Table 3). When calcium was added to a high dose of 10 000 IU/d of Vitamin D by Hiller et al. (Reference Hiller, Murchison and Lobb45), there were no difference in functional capacity and motor function outcomes after 16 weeks; however, the power calculation was performed on the sensory organisation test(Reference Hiller, Murchison and Lobb45). Additionally, in PD patients who had deep brain stimulation, dosing using BMI-adjusted vitamin D demonstrated no improvements in functional capacity outcomes after 12 weeks(Reference Bytowska, Korewo-Labelle and Berezka47). The BMI-adjusted method of dosing seems most appropriate with recent literature suggesting that individuals with a high BMI may have an altered response to supplementation of vitamin D(Reference Tobias, Luttmann-Gibson and Mora68). Future trials should be adequately powered to investigate the role of BMI-adjusted vitamin D supplementation across functional and disease progression outcomes.
Vitamin E & n-3 fatty acids
In the 1987 DATATOP trial(48), 800 PD participants were randomised to vitamin E or placebo for 24 months and results demonstrated no slowing of disease progression, nor any improvement in disease severity and motor symptoms. The negative results of this trial might have contributed to the movement away from using vitamin E as a standalone supplement in future intervention trials. Omega-3 (n-3) has been combined with vitamin E and has shown promise in improving motor function as measured by UPDRS (Table 3). Four RCTs(Reference da Silva, Munhoz and Alvarez49,Reference Taghizadeh, Tamtaji and Dadgostar51–Reference Pantzaris, Loukaides and Paraskevis53) have investigated this over time periods ranging from 12 weeks to 30 months, with three reporting positive findings; however, Pantzaris et al. (Reference Pantzaris, Loukaides and Paraskevis53) supplemented n-3 and vitamin E with omega-6 (n-6) making it difficult to distinguish which of these supplemental fatty acids may have been responsible for the positive effect (Table 3). Interestingly, a 6-month supplementation of n-3 alone elicited no change in motor scores(Reference Pomponi, Loria and Salvati50), making it possible that n-3 & vitamin E may have synergistic or complementary effects; however, further research is needed in this area. Overall, vitamin E and n-3, when combined, have generally demonstrated promising findings on disease progression, symptoms and disease severity outcomes.
B vitamins
There are limited RCT data available examining the effect of B vitamins individually or in combination on the outcomes of interest. Only vitamins B3, B9 and B12 have been investigated, and there is no conclusive evidence that B vitamins significantly improve motor function(Reference Chong, Wakade and Seamon56–Reference Lee, Kim and Kim59) (Table 3). One of the RCTs(Reference Wakade, Chong and Seamon57) which showed no improvement after 12 weeks excluded an outlier and the majority of participants were Caucasian men, potentially adversely affecting the results. Furthermore, approximately 18 % of participants were taking Vitamin D3 or other multivitamins which could have contributed towards the findings. Two trials assessed the impact of nicotinamide ribosome (vitamin B3) on disease progression. Berven et al. (Reference Berven, Kverneng and Sheard55) intervened for 4 weeks with 3000 mg/d, whilst Brakedal and colleagues(Reference Brakedal, Dölle and Riemer54) implemented a 30-day supplementation regime of 1000 mg/d. Whilst the former trial demonstrated a significant decrease in disease progression(Reference Berven, Kverneng and Sheard55), there was no significant effect in the latter(Reference Brakedal, Dölle and Riemer54). This discrepancy in findings is likely a result of the different doses and length of supplementation used between the two trials (Table 3). Although sample sizes were also different between the two RCTs, with 20 and 30 participants randomised respectively, the absence of formal sample size calculations in either study bars further interpretation regarding the studies’ statistical power(Reference Brakedal, Dölle and Riemer54,Reference Berven, Kverneng and Sheard55) .
Coenzyme Q10
In animal models, coenzyme Q10 has shown neuroprotective effects, reducing the death of dopaminergic neurons(Reference Park, Park and Park69). Accordingly, a total of 7 RCTs investigated the effects of coenzyme Q10 on motor function in humans(Reference Shults, Oakes and Kieburtz60–Reference Li, Wang and Yu66), with 6 of these also examining disease severity and progression. Trials of large and small sample sizes and varying doses have all yielded the same negative result where there was no improvement in motor function as assessed by UPDRS part III (Table 3). However, scores of the other parts of the UPDRS including non-motor sections of daily living and motor complications decreased enough to show a positive difference in total UPDRS score in 3 of 6 trials(Reference Shults, Oakes and Kieburtz60,63,Reference Yoritaka, Kawajiri and Yamamoto65) but only 1 of 3(Reference Storch, Jost and Vieregge62) showed decreases in H&Y stage (Table 3). Trials by NINDS NET-PD(63) and Beal et al. (Reference Beal, Oakes and Shoulson64) examined the effect of Coenzyme Q10 and used similar methodology where PD patients were recruited following a diagnosis within 5 years of randomisation and aimed to prevent increases in severity after at least 12 months of supplementation. Severity was measured by an increase in total UPDRS and time to initiating levodopa treatment. These trials showed conflicting results where Beal et al. (Reference Beal, Oakes and Shoulson64) showed no difference in progression compared to a placebo whereas NINDS NET-PD investigators showed the increase in total UPDRS score fell below a prespecified futile line (Table 3). While both trials were similar in design and used the same dose of coenzyme Q10, the former randomised more than twice the number of participants (525 v. 213). It is therefore conceivable that the larger sample size in the trial by Beal et al. (Reference Beal, Oakes and Shoulson64) provided the statistical power necessary to meet the futility criterion, thereby supporting their conclusion that further investigation into coenzyme Q10 is unwarranted.
Biotics
There are currently 11 RCTs that have investigated the effects of probiotics(Reference Zali, Hajyani and Salari70–Reference Yang, He and Xu77) and synbiotics(Reference Ibrahim, Ali and Manaf78–Reference Magistrelli, Contaldi and Visciglia80) on disease severity and progression, constipation syndrome and motor function (Table 4).
Table 4 Randomised controlled trials of biotics in Parkinson’s disease
Abbreviations: BM, bowel movement; BSFS, Bristol stool form scale; CBM, complete bowel movement; CFU, colony forming units; FOS, fructo-oligosaccharides; GI, gastrointestinal; GQ, Garrigues questionnaire; GSRS, gastrointestinal symptom rating scale; GTT, gut transit time; H&Y, Hoehn and Yahr; MDS-UPDRS, Movement Disorder Society-Unified Parkinson’s disease rating scale; NMSQ, non-motor symptoms questionnaire; PACQoL, patient assessment of constipation quality of life; PACSYM, patient assessment of constipation symptom; SBM, spontaneous bowel movement.
* Only between-group analyses reported.
† Capsules containing Lactobacillus acidophilus, Lactobacillus rhamnosus, Lactobacillus reuteri, Lactobacillus paracasei, Bifidobacterium longum, Bacillus coagulans.
‡ Capsules containing Lactobacillus acidophilus, Lactobacillus gasseri, Lactobacillus reuteri, Lactobacillus rhamnosus, Bifidobacterium bifidum, Bifidobacterium longum, Enterococcus faecalis, Enterococcus faecium.
§ Capsules containing Lactobacillus plantarum, Lactobacillus casei, Lactobacillus acidophilus, Lactobacillus bulgaricus, Bifidobacterium infantis, Bifidobacterium longum, Bifidobacterium breve and Streptococcus thermophilus.
|| Capsules containing Bacillus licheniformis, Lactobacillus acidophilus, Bifidobacterium longum, Enterococcus faecalis.
¶ Powder (‘Probio-M8’) containing Bifidobacterium animalis subsp. Lactis.
** Capsules containing Lactobacillus acidophilus, Bifidobacterium bifidum, Lactobacillus reuteri and Lactobacillus fermentum.
†† Capsules containing Lactobaillus acidophilus, Bifidobacterium infantis.
‡‡ Fermented Milk containing Lacticaseibacillus paracasei strain Shirota.
§§ Sachets composed of probiotics (Lactobacillus acidophilus, Lactobacillus casei, Lactobacillus lactis, Bifidobacterium infantis, Bifidobacterium longum) and prebiotics (fructo-oliogosaccharides & lactose).
|||| Fermented milk composed of probiotics (Streptococcus salivarius subsp. thermophilus, Enterococcus faecium, Lactobacillus rhamnosus GG, Lactobacillus acidophilus, Lactobacillus plantarum, Lactobacillus paracasei, Lactobacillus delbrueckii subsp. bulgaricus, Bifidobacterium breve, Bifidobacterium animalis subsp. lactis and prebiotics (fibre and fructo-oliogosaccharides).
¶¶ Composed of probiotics (Bifidobacterium animalis subsp. lactis BS01, Bifidobacterium longum 03, Bifidobacterium adolescentis BA02) and prebiotics (fructo-oligosaccharides & maltodextrin).
Probiotics
Probiotics are live microorganisms that confer a health benefit to the host when administered in adequate amounts(Reference Hill, Guarner and Reid81). Three trials investigated the impact of probiotics on disease progression measured using either the UPDRS total score or the H&Y scale. Yang et al. (Reference Yang, He and Xu77) showed no improvement in disease progression after 12 weeks, whereas the trial by Zali et al. (Reference Zali, Hajyani and Salari70) found a significant decrease in total UPDRS score compared to a placebo following 12 weeks of probiotic capsules. However, this trial included vitamin D as a co-treatment with probiotics (Table 4); it is therefore unclear which supplement was responsible for the difference seen, or whether the combination of supplements had complementary effects(Reference Zali, Hajyani and Salari70). Furthermore, the probiotic capsules of the latter trial included different species to those present in the other RCT. For instance, it is known that Bacillus coagulans produces digestive enzymes which might have helped alleviate gastrointestinal symptoms(Reference Cao, Yu and Liu82). Additionally, Tamtaji et al. (Reference Tamtaji, Taghizadeh and Daneshvar Kakhaki75), who had similar probiotic species in their capsules, albeit it not identical to Zali et al. (Reference Zali, Hajyani and Salari70), also observed a decrease in total UPDRS score following 12 weeks of supplementation after 60 participants were randomised (Table 4).
In relation to motor function, the evidence remains unclear with variability in trial results. Three trials(Reference Ghalandari, Assarzadegan and Habibi72,Reference Sun, Zhao and Liu74,Reference Yang, He and Xu77) reported no change in UPDRS part III and one(Reference Zali, Hajyani and Salari70) reported significant improvements (Table 4). The heterogeneity in the findings could possibly be explained by variation in the intervention provided, since vitamin D was given with probiotics in one trial(Reference Zali, Hajyani and Salari70). It is unknown if the observed effects were due to the probiotics or to the vitamin D. In the 3 RCTs that showed no difference between probiotic and placebo(Reference Ghalandari, Assarzadegan and Habibi72,Reference Sun, Zhao and Liu74,Reference Yang, He and Xu77) , Yang et al. (Reference Yang, He and Xu77) administered the probiotics as a drink containing only Lactobacullis paracasei Shirota. In the Sun et al. (Reference Sun, Zhao and Liu74) trial, the intervention of Probio-M8 showed significant between-group differences in UPDRS III scores after 1 month but after 3 months there was no significant difference between the groups. In this trial(Reference Sun, Zhao and Liu74), it is unclear whether blinding was undertaken for outcome assessors or trial investigators, which could have contributed to lack of difference between the two groups. Ghalandari et al. (Reference Ghalandari, Assarzadegan and Habibi72) tested probiotics over 8 weeks and similarly showed no difference in motor function between the groups (Table 4).
When GI symptoms were examined, Ghalandari et al. (Reference Ghalandari, Assarzadegan and Habibi72) showed that the frequency of bowel movements significantly increased in the probiotic group in patients who had a diagnosis of constipation. This confirmed the results of Tan et al. (Reference Tan, Lim and Chong71), who demonstrated in a similar population that GI symptoms improved after 4 weeks of probiotic capsules compared to placebo. Interestingly, in a separate trial by Yang et al. (Reference Yang, He and Xu77), the use of only Lacticaseibacillus paracasei Shirota showed significant improvements across all domains of GI function and comfort, including constipated related quality of life. Even the use of probiotic sachets by Sun et al. (Reference Sun, Zhao and Liu74) as opposed to capsules, demonstrated the same effects where after 3 months, all secondary outcomes improved except assisted defecation by hand. Two other trials corroborated the findings of the previously mentioned RCTs(Reference Zali, Hajyani and Salari70,Reference Sun, Zhao and Liu74) (Table 4). In contrast, constipation symptoms did not significantly improve relative to a standard gastrointestinal drug Trimebutine after 3 months of probiotic use; however, this was in a patient group with mild to moderate GI symptoms, and did not verify constipation using the Rome III/IV criteria similar to the other trials(Reference Georgescu, Ancusa and Georgescu76).
Synbiotics
A prebiotic is a substrate that confers a health benefit through utilisation by host microorganisms, and synbiotics are simply a combination of pre and probiotics(Reference Swanson, Gibson and Hutkins83,Reference Gibson, Hutkins and Sanders84) . While there have been no RCTs investigating the effects of prebiotics in PD patients, three trials have examined synbiotics. One trial(Reference Barichella, Pacchetti and Bolliri79) examined the impact on constipation syndrome, and two examined(Reference Ibrahim, Ali and Manaf78,Reference Magistrelli, Contaldi and Visciglia80) both constipation syndrome and motor function following synbiotic supplementation of 4, 8, and 12 weeks, respectively (Table 4). Similar to the RCTs of probiotics, there have been positive findings in constipation-related endpoints, with 2 of the 3 trials reporting improvement in bowel function(Reference Ibrahim, Ali and Manaf78,Reference Barichella, Pacchetti and Bolliri79) . However, Magistrelli et al.(Reference Magistrelli, Contaldi and Visciglia80) did not investigate between-group differences. Furthermore, this trial did not specify the mode of administration of the synbiotics (Table 4). Of note, in the Ibrahim et al. trial(Reference Ibrahim, Ali and Manaf78), there was a considerable dropout rate due to adverse effects, with 8 of 27 participants experiencing abdominal bloating, dizziness or other effects. These adverse effects were not seen in either of the two other trials and the reason for this discrepancy is unclear. Interestingly, the synbiotics that were tested in the two RCTs with positive findings were administered differently, whereby in one RCT a powder was mixed with water(Reference Ibrahim, Ali and Manaf78) and in the other, a milk formulation was used(Reference Barichella, Pacchetti and Bolliri79) (Table 4). Thus, the mode of synbiotic administration might be less important than the specific microbial strains and prebiotic fibres used. Overall, future trials should emulate probiotic RCTs and use large sample sizes for longer study periods.
With respect to motor function, Magistrelli et al. (Reference Magistrelli, Contaldi and Visciglia80) reported within-group improvements in UPDRS-III scores after treatment with synbiotics, however between-group results were not reported. Additionally, more than 75 % of participants were male and it is unclear if assessors were blinded to the allocated treatment(Reference Magistrelli, Contaldi and Visciglia80). In the other trial by Ibrahim et al. (Reference Ibrahim, Ali and Manaf78) the trial may not have been adequately powered to detect any change, as UPDRS part III score was a secondary outcome (Table 4).
Overall, across all RCTs of probiotics and synbiotics in PD, there is considerable heterogeneity between trials in choice of intervention itself and the relevant comparator (Table 4). One of these differences is the bacterial species that were used as probiotics, with none of the studies having used the same combination of bacteria. Furthermore, the dose of bacteria used varied across trials with little justification for this difference. Additionally, the route of administration varied between capsules and powders, which could result in altered microbial bioavailability(Reference Baral, Bajracharya and Lee85). The comparators used in the RCTs were also different across trials, ranging from fibres that may have had a prebiotic effect such as maltodextrin to different types of milk. Despite these differences, the use of biotics is showing promise as a treatment for constipation syndrome. However, further research is needed where standardised methods of administration, dosage and composition of biotics are used, allowing better comparison between the RCTs. There is little available trial data on biotics and motor function and disease progression, making it difficult to draw conclusions.
Conclusion
Dietary approaches, focusing on improving dietary patterns, increasing the intake of individual foods and beverages, and supplementing nutrients, bioactive compounds, and biotics, have started to gain traction in recent decades due to their hypothesised disease-modifying and symptomatic-relief properties. However, as demonstrated in the present review, the evidence from robust RCTs on diet-related approaches and their role in ameliorating PD progression, severity, and motor and GI-related symptoms is currently lacking.
For dietary patterns, protein redistribution diets have shown promise, compared to standard diets, in improving motor scores; however, caution is warranted to ensure adequate protein intake. In contrast, evidence for the MedDiet and KD efficacy is mixed and in need of further investigation. In terms of individual food and beverages, MP is an encouraging natural alternative to pharmaceutical levodopa preparations and in particular could be used in low-income settings due to its low cost and availability. However, dosing is more difficult to standardise, and the lack of carbidopa or benserazide co-supplementation results in more adverse effects than pharmaceutical alternatives. The efficacy of the remaining food and beverages explored in the included RCTs requires further corroboration through additional clinical trials. Nutrients and bioactive compounds, in turn, have produced conflicting findings, limiting the generalisability of reported results. Due to these inconsistencies, future trials must be undertaken combining different nutrients and doses across diverse PD subpopulations. Finally, supplementation of pro- and synbiotics have consistently demonstrated efficacy in improving constipation symptoms. Mixed results were observed however for motor improvement. Further investigation is required into optimising the bacterial strains that are used, the appropriate dosing regimens, and best route of administration.
Crucially, many trials that aimed to assess changes in PD progression did not have a sufficiently long study duration to do so. Since the average progression in UPDRS-III is ∼2–3 points per year, a few weeks or even months of intervention is unlikely to demonstrate disease-modifying effects, which may be substantial over a prolonged period(Reference Holden, Finseth and Sillau86). This is a major practical limitation of the majority of current dietary intervention trials. Another significant caveat of dietary interventions is their reliance on self-administered questionnaires for dietary assessment, which are often flawed and may lead to random and systematic measurement errors(Reference Bailey87). Finally, the current review solely examined the impact of diet on PD progression and severity, motor symptoms, and non-motor symptoms related to the GI tract. PD is a heterogenous disorder with wide-ranging clinical phenotypes; thus, robust RCTs are required to examine the impact of various dietary approaches on the broad assortment of symptoms of PD, in order to provide the necessary evidence that will underpin dietary guidelines for this population.
To conclude, further RCTs are needed to inform dietary guidelines aimed at mitigating disease progression, severity and both motor and non-motor symptoms in PD.
Acknowledgements
Not applicable
Authorship contributions
F.E.L., A.P. and M.S.S. conceptualised the article. A.P. and M.S.S. wrote the first draft with input from F.E.L., C.G. and V.D. who also provided critical revision. All authors reviewed the final draft for submission.
Financial support
F.E.L. is funded by the High Value Nutrition National Science Challenge and by the University of Auckland, New Zealand. A.P. is funded by the Aotearoa Foundation, New Zealand. M.S.S. is a recipient of the University of Auckland Doctoral Scholarship.
Competing interests
F.E.L. has received a speaker honorarium from Abbvie. No other authors declare any competing interests.
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