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Cited by 136Parkinson's Disease Mechanisms and TreatmentsProbiotics and Fermented FoodsGut microbiota and health

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Probiotics synergized with conventional regimen in managing Parkinson’s disease

Open access
Sun, Hairong, Zhao, Feiyan, Liu, Yuanyuan, Ma, Teng, Jin, Hao, Quan, Keyu, Leng, Bing, Zhao, Junwu, Yuan, Xiaoling, Li, Zhenguang, Li, Fang, Kwok, Lai-Yu, Zhang, Shukun, Sun, Zhihong, Zhang, Jinbiao, Zhang, Heping·2022·npj Parkinson's Disease
DOI 10.1038/s41531-022-00327-6PMC PMC9130297
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Abstract

Parkinson’s disease (PD) is mainly managed by pharmacological therapy (e.g., Benserazide and dopamine agonists). However, prolonged use of these drugs would gradually diminish their dopaminergic effect. Gut dysbiosis was observed in some patients with PD, suggesting close association between the gut microbiome and PD. Probiotics modulate the host’s gut microbiota beneficially. A 3-month randomized, double-blind, placebo-controlled clinical trial was conducted to investigate the beneficial effect of probiotic co-administration in patients with PD. Eighty-two PD patients were recruited and randomly divided into probiotic [ n = 48; Bifidobacterium animalis subsp. lactis Probio-M8 (Probio-M8), Benserazide, dopamine agonists] and placebo ( n = 34; placebo, Benserazide, dopamine agonists) groups. Finally, 45 and 29 patients from Probio-M8 and placebo groups provided complete fecal and serum samples for further omics analysis, respectively. The results showed that Probio-M8 co-administration conferred added benefits by improving sleep quality, alleviating anxiety, and gastrointestinal symptoms. Metagenomic analysis showed that, after the intervention, there were significantly more species-level genome bins (SGBs) of Bifidobacterium animalis , Ruminococcaceae , and Lachnospira , while less Lactobacillus fermentum and Klebsiella oxytoca in Probio-M8 group ( P < 0.05). Interestingly, Lactobacillus fermentum correlated positively with the scores of UPDRS-III, HAMA, HAMD-17, and negatively with MMSE. Klebsiella oxytoca correlated negatively with feces hardness. Moreover, co-administering Probio-M8 increased SGBs involved in tryptophan degradation, gamma-aminobutyric acid, short-chain fatty acids, and secondary bile acid biosynthesis, as well as serum acetic acid and dopamine levels ( P < 0.05). Taken together, Probio-M8 synergized with the conventional regimen and strengthened the clinical efficacy in managing PD, accompanied by modifications of the host’s gut microbiome, gut microbial metabolic potential, and serum metabolites.

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Fig. 1 Experimental design, data analysis, and clinical indexes of Parkinson’s disease. a The workflow of sampling, sequencing and metagenome-assembled genomes (MAGs) binning of gut microbiota and serum neurotransmitters, all elements in this image were the graph of results of this article or created by in iPad. b Statistical differences in the clinical parameters within and between groups were evaluated with paired t-tests and t-tests, respectively. Significant p values between sample pairs are shown. Boxplot elements: center line, median; box limits, upper and lower quartiles; whiskers, 1.5x interquartile range; points, outliers. Each dot represents a data point of a participant, and data of the same participant at different time points are connected by straight lines. “Pro” and “Pla” represent the Probio-M8 group and Placebo group, respectively. “0d”, “1 M”, and “3 M” represent the baseline before the intervention, 1 and 3 months after intervention, respectively. UPDRS-III, MMSE, PDSS, HAMA, HAMD-17, PAC-QOL represent Unified PD Rating Scale-III, Mini-mental State Examination, Parkinson’s Disease Sleep Scale, Hamilton Anxiety Scale, Hamilton Depression Scale-17, Patient-Assessment of Constipation Quality of Life, respectively.
Fig. 1 Experimental design, data analysis, and clinical indexes of Parkinson’s disease. a The workflow of sampling, sequencing and metagenome-assembled genomes (MAGs) binning of gut microbiota and serum neurotransmitters, all elements in this image were the graph of results of this article or created by in iPad. b Statistical differences in the clinical parameters within and between groups were evaluated with paired t-tests and t-tests, respectively. Significant p values between sample pairs are shown. Boxplot elements: center line, median; box limits, upper and lower quartiles; whiskers, 1.5x interquartile range; points, outliers. Each dot represents a data point of a participant, and data of the same participant at different time points are connected by straight lines. “Pro” and “Pla” represent the Probio-M8 group and Placebo group, respectively. “0d”, “1 M”, and “3 M” represent the baseline before the intervention, 1 and 3 months after intervention, respectively. UPDRS-III, MMSE, PDSS, HAMA, HAMD-17, PAC-QOL represent Unified PD Rating Scale-III, Mini-mental State Examination, Parkinson’s Disease Sleep Scale, Hamilton Anxiety Scale, Hamilton Depression Scale-17, Patient-Assessment of Constipation Quality of Life, respectively.CC BY · PubMed Central
Fig. 2 Microbial diversity and differentially abundant species-level genome bins (SGBs) between groups. a Shannon diversity index of the fecal microbiome at 0d, 1 M, and 3 M in placebo and Probio-M8 groups, respectively. Statistical differences in the Shannon diversity index within groups were evaluated with paired t-tests. Each dot represents a data point of a participant, and data of the same participant at different time points are connected by straight lines. Boxplot elements: center line, median; box limits, upper and lower quartiles; whiskers, 1.5x interquartile range; points, outliers. b Left panel, principal coordinates analysis (PCoA) score plots of two groups at different time points. Samples of each subgroup are represented by a different color. Right panel, P value and R value of analysis of similarities (ANOSIM, 999 permutations). c Longitudinal comparisons of an abundance of SGBs of the same group between different time points. All the shown SGBs were not significantly different between groups at baseline but only increased/decreased significantly during the trial. Significant differences in specific SGBs between 0d and other time points are represented by *P < 0.05 and **P < 0.01; between 1 M and 3 M are represented by #P < 0.05. d Horizontal comparisons between an abundance of SGBs of Probio-M8 and placebo groups at the same time point. All the shown SGBs were not significantly different between groups at baseline but became significantly differential abundant during/after the intervention. Significant differences: *P < 0.05, **P < 0.01, and ***P < 0.001. The red corner rectangles in (c) and (d) represents an abundance of SGBs on an arbitrary scale. “Pro” and “Pla” represent the Probio-M8 group and Placebo group, respectively. “0d”, “1 M”, and “3 M” represent the baseline before intervention, 1 and 3 months after intervention, respectively.
Fig. 2 Microbial diversity and differentially abundant species-level genome bins (SGBs) between groups. a Shannon diversity index of the fecal microbiome at 0d, 1 M, and 3 M in placebo and Probio-M8 groups, respectively. Statistical differences in the Shannon diversity index within groups were evaluated with paired t-tests. Each dot represents a data point of a participant, and data of the same participant at different time points are connected by straight lines. Boxplot elements: center line, median; box limits, upper and lower quartiles; whiskers, 1.5x interquartile range; points, outliers. b Left panel, principal coordinates analysis (PCoA) score plots of two groups at different time points. Samples of each subgroup are represented by a different color. Right panel, P value and R value of analysis of similarities (ANOSIM, 999 permutations). c Longitudinal comparisons of an abundance of SGBs of the same group between different time points. All the shown SGBs were not significantly different between groups at baseline but only increased/decreased significantly during the trial. Significant differences in specific SGBs between 0d and other time points are represented by *P < 0.05 and **P < 0.01; between 1 M and 3 M are represented by #P < 0.05. d Horizontal comparisons between an abundance of SGBs of Probio-M8 and placebo groups at the same time point. All the shown SGBs were not significantly different between groups at baseline but became significantly differential abundant during/after the intervention. Significant differences: *P < 0.05, **P < 0.01, and ***P < 0.001. The red corner rectangles in (c) and (d) represents an abundance of SGBs on an arbitrary scale. “Pro” and “Pla” represent the Probio-M8 group and Placebo group, respectively. “0d”, “1 M”, and “3 M” represent the baseline before intervention, 1 and 3 months after intervention, respectively.CC BY · PubMed Central
Fig. 3 Association between fecal species-level genome bins (SGBs) of patients with Parkinson’s disease (PD) and clinical indicators of Parksoion-associated symptoms. Association between gut microbiota and a mental state (represented by Hamilton Anxiety Scale, Hamilton Depression Scale-17, and Mini-mental State Examination) and sleep quality (represented by PDSS) of patients, b patient’s disease progression (Unified Parkinson Disease Rating Scale-III), and c constipation-related symptoms (feces hardness and numbers of spontaneous defecation). Marker SGBs for PD were marked by a green star. “+” and “−” represent a positive and negative association, respectively.
Fig. 3 Association between fecal species-level genome bins (SGBs) of patients with Parkinson’s disease (PD) and clinical indicators of Parksoion-associated symptoms. Association between gut microbiota and a mental state (represented by Hamilton Anxiety Scale, Hamilton Depression Scale-17, and Mini-mental State Examination) and sleep quality (represented by PDSS) of patients, b patient’s disease progression (Unified Parkinson Disease Rating Scale-III), and c constipation-related symptoms (feces hardness and numbers of spontaneous defecation). Marker SGBs for PD were marked by a green star. “+” and “−” represent a positive and negative association, respectively.CC BY · PubMed Central
Fig. 4 Profiles of gut metabolic modules (GMMs) and predicted metabolites after 1- and 3-month intervention. a Distribution of selected GMMs (relating to the development, pathophysiology, and immunity related to Parkinson’s disease) across significant differential species-level genome bins (SGBs) between probio-M8 (Pro) and placebo (Pla) groups. b Procrustes analyses performed on the predicted microbiomes and metabolomes of the probio-M8 (Pro) and placebo (Pla) groups at day 0 (0d), 1 month (1 M), and 3 months (3 M), showing positive cooperativity between the microbiome and metabolome profiles (correlation = 0.329; P = 0.001). c, d Principal coordinates analysis (PCoA) score plots and Adonis test of the Probio-M8 (Pro) and placebo (Pla) groups at days 0 (0d), 1 month (1 M), and 3 months (3 M) showing changes in predicted bioactive metabolites. Symbols representing samples of individuals at different time points are shown in different colors. Significant differences between groups were evaluated by the adonis test. e Boxplots showing the contents of predicted differential bioactive metabolites that were responsive to Probio-M8 adjuvant treatment, P < 0.05 was considered statistically significant. Boxplot elements: center line, median; box limits, upper and lower quartiles; whiskers, 1.5x interquartile range; points, outliers.
Fig. 4 Profiles of gut metabolic modules (GMMs) and predicted metabolites after 1- and 3-month intervention. a Distribution of selected GMMs (relating to the development, pathophysiology, and immunity related to Parkinson’s disease) across significant differential species-level genome bins (SGBs) between probio-M8 (Pro) and placebo (Pla) groups. b Procrustes analyses performed on the predicted microbiomes and metabolomes of the probio-M8 (Pro) and placebo (Pla) groups at day 0 (0d), 1 month (1 M), and 3 months (3 M), showing positive cooperativity between the microbiome and metabolome profiles (correlation = 0.329; P = 0.001). c, d Principal coordinates analysis (PCoA) score plots and Adonis test of the Probio-M8 (Pro) and placebo (Pla) groups at days 0 (0d), 1 month (1 M), and 3 months (3 M) showing changes in predicted bioactive metabolites. Symbols representing samples of individuals at different time points are shown in different colors. Significant differences between groups were evaluated by the adonis test. e Boxplots showing the contents of predicted differential bioactive metabolites that were responsive to Probio-M8 adjuvant treatment, P < 0.05 was considered statistically significant. Boxplot elements: center line, median; box limits, upper and lower quartiles; whiskers, 1.5x interquartile range; points, outliers.CC BY · PubMed Central
Fig. 5 Differences in serum short-chain fatty acids (SCFAs) and neuroactive compounds between Probio-M8 (Pro) and placebo (pla) groups and proposed model of probiotic-driven pathways modulating the gut-brain-axis in patients with Parkinson’s disease. a–e Significant differences in serum SCFAs and neuroactive compounds between the probiotic and placebo groups at 1 month (1 M) and 3 months (3 M), error bars represented SD; P < 0.05 was considered statistically significant. f Schematic diagram illustrating key probiotic-driven pathways that modulated the gut-brain-axis and host response. UPDRS-III, MMSE, HAMA, HAMD-17, PDSS, and PAC-QOL represent Unified PD Rating Scale-III, Mini-mental State Examination, Hamilton Anxiety Scale, Hamilton Depression Scale-17, Parkinson’s Disease Sleep Scale, Patient-Assessment of Constipation Quality of Life, respectively. GABA and SCFAs represent gamma-aminobutyric acid and short-chain fatty acids.
Fig. 5 Differences in serum short-chain fatty acids (SCFAs) and neuroactive compounds between Probio-M8 (Pro) and placebo (pla) groups and proposed model of probiotic-driven pathways modulating the gut-brain-axis in patients with Parkinson’s disease. a–e Significant differences in serum SCFAs and neuroactive compounds between the probiotic and placebo groups at 1 month (1 M) and 3 months (3 M), error bars represented SD; P < 0.05 was considered statistically significant. f Schematic diagram illustrating key probiotic-driven pathways that modulated the gut-brain-axis and host response. UPDRS-III, MMSE, HAMA, HAMD-17, PDSS, and PAC-QOL represent Unified PD Rating Scale-III, Mini-mental State Examination, Hamilton Anxiety Scale, Hamilton Depression Scale-17, Parkinson’s Disease Sleep Scale, Patient-Assessment of Constipation Quality of Life, respectively. GABA and SCFAs represent gamma-aminobutyric acid and short-chain fatty acids.CC BY · PubMed Central

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  1. Hsieh, T. H. et al. Probiotics alleviate the progressive deterioration of motor functions in a mouse model of Parkinson’s disease. Brain Sci. 10, 13 (2020). · DOI · Paper page

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Metadata

Authors
Sun, H., Zhao, F., Liu, Y., Ma, T., Jin, H., Quan, K., Leng, B., Zhao, J., Yuan, X., Li, Z., Li, F., Kwok, L.-Y., Zhang, S., Sun, Z., Zhang, J., & Zhang, H.
Affiliations
  • Inner Mongolia Agricultural University (CN)
  • Shandong University (CN)
  • Taishan Medical University (CN)
  • Jinzhou Medical University (CN)
Corresponding author
  • Zhang, Jinbiao
  • Zhang, Heping
ORCID
Venue
npj Parkinson's Disease
Publisher
Springer Science and Business Media LLC
Published
2022-05-24
Volume
8
Issue
1
Pages
62-62
ISSN
2373-8057 (ISSN-L)
DOI
10.1038/s41531-022-00327-6
PMC
PMC9130297
OpenAlex
W4281396245
Cited by
136
References
90
Citations by year
2026: 20 · 2025: 39 · 2024: 46 · 2023: 20 · 2022: 11
FWCI
15.27
Type
journal article
Language
en
Open access
Licence
Locations
  • npj Parkinson s Disease (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Natural Science Foundation of China (31720103911)
  • Inner Mongolia Science & Technology Major Projects
Topics
  • Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
  • Life Sciences › Agricultural and Biological Sciences › Food Science › Probiotics and Fermented Foods
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
Keywords
Parkinson's disease, probiotics, Bifidobacterium animalis subsp. lactis, gut microbiota, benserazide, dopamine agonists, sleep quality, anxiety, gastrointestinal symptoms, Lactobacillus fermentum, Klebsiella oxytoca, tryptophan degradation, short-chain fatty acids, bile acid synthesis, dopamine levels, serum metabolites

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