CoChat
Sign Up
Cited by 319Parkinson's Disease Mechanisms and TreatmentsBerberine and alkaloids researchGut microbiota and health

The DOI matches its Crossref record; 81 of the 81 references it cites were found in a registry or an index.

Oral berberine improves brain dopa/dopamine levels to ameliorate Parkinson’s disease by regulating gut microbiota

Open access
Wang, Yan, Tong, Qian, Ma, Shu-Rong, Zhao, Zhen-Xiong, Pan, Li-Bin, Cong, Lin, Han, Pei, Peng, Ran, Yu, Hang, Lin, Yuan, Gao, Tian-Le, Shou, Jia-Wen, Li, Xiao-Yang, Zhang, Xian-Feng, Zhang, Zheng-Wei, Fu, Jie, Wen, Bao-Ying, Yu, Jin-Bo, Cao, Xuetao, Jiang, Jian-Dong·2021·Signal Transduction and Targeted Therapy
DOI 10.1038/s41392-020-00456-5PMC PMC7902645
Open this paper in CoChat — free accountOpen PDF

Abstract

The phenylalanine–tyrosine–dopa–dopamine pathway provides dopamine to the brain. In this process, tyrosine hydroxylase (TH) is the rate-limiting enzyme that hydroxylates tyrosine and generates levodopa ( l -dopa) with tetrahydrobiopterin (BH 4 ) as a coenzyme. Here, we show that oral berberine (BBR) might supply H • through dihydroberberine (reduced BBR produced by bacterial nitroreductase) and promote the production of BH 4 from dihydrobiopterin; the increased BH 4 enhances TH activity, which accelerates the production of l -dopa by the gut bacteria. Oral BBR acts in a way similar to vitamins. The l -dopa produced by the intestinal bacteria enters the brain through the circulation and is transformed to dopamine. To verify the gut–brain dialog activated by BBR’s effect, Enterococcus faecalis or Enterococcus faecium was transplanted into Parkinson’s disease (PD) mice. The bacteria significantly increased brain dopamine and ameliorated PD manifestation in mice; additionally, combination of BBR with bacteria showed better therapeutic effect than that with bacteria alone. Moreover, 2,4,6-trimethyl-pyranylium tetrafluoroborate (TMP-TFB)-derivatized matrix-assisted laser desorption mass spectrometry (MALDI-MS) imaging of dopamine identified elevated striatal dopamine levels in mouse brains with oral Enterococcus , and BBR strengthened the imaging intensity of brain dopamine. These results demonstrated that BBR was an agonist of TH in Enterococcus and could lead to the production of l -dopa in the gut. Furthermore, a study of 28 patients with hyperlipidemia confirmed that oral BBR increased blood/fecal l -dopa by the intestinal bacteria. Hence, BBR might improve the brain function by upregulating the biosynthesis of l -dopa in the gut microbiota through a vitamin-like effect.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1038/s41392-020-00456-5

Cites

81 of 81 references verified0 citation errors · 0 not checkable

Statistics

Figures

Fig. 1 BBR increased dopa/dopamine production in the gut microbiota in vivo. a Dopa/dopamine significantly increased in the feces of ICR mice at 0, 6, 12, and 24 h after oral administration of BBR (100 and 200 mg/kg, respectively; mean ± SD, *P < 0.05, **P < 0.01 for dopa and ***P < 0.001 for dopamine). b Dopa/dopamine showed a dose- and time-dependent increase in plasma after BBR treatment (mean ± SD, *P < 0.05 and **P < 0.01 for dopa; *P < 0.05, ***P < 0.001 for dopamine). c Dopa/dopamine showed a similar dose- and time-dependent increase in the brain after BBR treatment (mean ± SD, *P < 0.05 and **P < 0.01 for dopa; *P < 0.05, **P < 0.01, and ***P < 0.001 for dopamine). d Intraperitoneal injection (i.p.) of BBR into the ICR mice did not increase the levels of dopa/dopamine in the feces, plasma, and brain at any of the study time points, which was different from the results of BBR in oral administration (mean ± SD, NS no significance). e Mass spectra of 15N-dopamine and dopamine in mouse brains. f Intestinal 15N-Tyr was the raw material for the synthesis of 15N-dopamine in brain. Pretreating the mice with antibiotics for 3 days attenuated the effect of BBR on 15N-dopamine production (mean ± SD, **P < 0.01, ***P < 0.001), and oral administration of BBR significantly increased 15N-dopamine in the brain (*P < 0.05)
Fig. 1 BBR increased dopa/dopamine production in the gut microbiota in vivo. a Dopa/dopamine significantly increased in the feces of ICR mice at 0, 6, 12, and 24 h after oral administration of BBR (100 and 200 mg/kg, respectively; mean ± SD, *P < 0.05, **P < 0.01 for dopa and ***P < 0.001 for dopamine). b Dopa/dopamine showed a dose- and time-dependent increase in plasma after BBR treatment (mean ± SD, *P < 0.05 and **P < 0.01 for dopa; *P < 0.05, ***P < 0.001 for dopamine). c Dopa/dopamine showed a similar dose- and time-dependent increase in the brain after BBR treatment (mean ± SD, *P < 0.05 and **P < 0.01 for dopa; *P < 0.05, **P < 0.01, and ***P < 0.001 for dopamine). d Intraperitoneal injection (i.p.) of BBR into the ICR mice did not increase the levels of dopa/dopamine in the feces, plasma, and brain at any of the study time points, which was different from the results of BBR in oral administration (mean ± SD, NS no significance). e Mass spectra of 15N-dopamine and dopamine in mouse brains. f Intestinal 15N-Tyr was the raw material for the synthesis of 15N-dopamine in brain. Pretreating the mice with antibiotics for 3 days attenuated the effect of BBR on 15N-dopamine production (mean ± SD, **P < 0.01, ***P < 0.001), and oral administration of BBR significantly increased 15N-dopamine in the brain (*P < 0.05)CC BY · PubMed Central
Fig. 2 BBR stimulated intestinal bacteria to produce dopa/dopamine. a Levels of dopa/dopamine increased significantly at 0, 6, 12, and 24 h after BBR treatment (10 and 20 μg/mL, respectively) in the intestinal bacteria of SD rats in vitro (mean ± SD, *P < 0.05, **P < 0.01, and ***P < 0.001, for dopa and dopamine). b Effect of BBR (10 μg/mL) in ten intestinal bacterial strains in vitro. Out of the ten strains, four bacterial strains (E. faecalis, E. faecium, P. mirabilis, and L. acidophilus) showed a significant increase in dopa after BBR treatment (10 and 20 µg/mL for 12 h), six had almost no change in dopa production. Of note, the increase in dopa by E. faecalis and E. faecium showed a dose-dependent manner with BBR. The BBR-induced dopamine production profile in the ten strains was different from that of dopa, that is, three bacterial strains (E. faecalis, E. faecium, and S. epidermidis) showed a significant increase in dopamine after BBR treatment (10 µg/mL for 12 h), seven had almost no change on dopamine production. Of note, the increase in dopamine by E. faecalis and E. faecium showed a similar dose-dependent manner with BBR. c Changes in the intestinal bacterial composition as a result of BBR treatment. The heat map of the top 50 bacterial genera exhibited the most substantial change in abundance after exposure to BBR; the proportion of dopa/dopamine-producing bacteria increased, including Enterococcus, Escherichia–Shigella, Pseudomonas, and Lactobacillus (labeled with the red “*”)
Fig. 2 BBR stimulated intestinal bacteria to produce dopa/dopamine. a Levels of dopa/dopamine increased significantly at 0, 6, 12, and 24 h after BBR treatment (10 and 20 μg/mL, respectively) in the intestinal bacteria of SD rats in vitro (mean ± SD, *P < 0.05, **P < 0.01, and ***P < 0.001, for dopa and dopamine). b Effect of BBR (10 μg/mL) in ten intestinal bacterial strains in vitro. Out of the ten strains, four bacterial strains (E. faecalis, E. faecium, P. mirabilis, and L. acidophilus) showed a significant increase in dopa after BBR treatment (10 and 20 µg/mL for 12 h), six had almost no change in dopa production. Of note, the increase in dopa by E. faecalis and E. faecium showed a dose-dependent manner with BBR. The BBR-induced dopamine production profile in the ten strains was different from that of dopa, that is, three bacterial strains (E. faecalis, E. faecium, and S. epidermidis) showed a significant increase in dopamine after BBR treatment (10 µg/mL for 12 h), seven had almost no change on dopamine production. Of note, the increase in dopamine by E. faecalis and E. faecium showed a similar dose-dependent manner with BBR. c Changes in the intestinal bacterial composition as a result of BBR treatment. The heat map of the top 50 bacterial genera exhibited the most substantial change in abundance after exposure to BBR; the proportion of dopa/dopamine-producing bacteria increased, including Enterococcus, Escherichia–Shigella, Pseudomonas, and Lactobacillus (labeled with the red “*”)CC BY · PubMed Central
Fig. 3 BBR activated the pathway for dopa/dopamine synthesis in the gut microbiota. a The activity of TH and DDC increased after treating the gut bacteria of SD rats with BBR at 12 h (10 μg/mL, *P < 0.05, **P < 0.01), but weakened when TH inhibitor (BLMA5, 100 μM) or the DDC inhibitor (benserazide, 100 μM) was incubated with BBR as a whole (mean ± SD, *P < 0.05, **P < 0.01). The TH inhibitor BLMA or DDC inhibitor benserazide did not change the abundance of the intestinal bacteria at 50 or 100 μM. The activity of TH and DDC increased after treating the gut bacteria of SD rats with BBR at 12 h (10 μg/mL, *P < 0.05, **P < 0.01), but weakened when the TH inhibitor (BLMA5, 100 μM) or DDC inhibitor (benserazide, 100 μM) was incubated with BBR as a whole (mean ± SD, *P < 0.05, **P < 0.01). b Levels of BH4 (the coenzyme of TH) increased significantly at 6 and 12 h after BBR or dhBBR treatment (10 and 20 μg/mL, respectively) in SD gut bacteria in vitro (mean ± SD, +23%↑, +31%↑ for BBR at 20 μg/mL at 6 and 12 h, **P < 0.01, ***P < 0.001; +26%↑, +34%↑ for dhBBR at 20 μg/mL at 6 and 12 h, **P < 0.01). In addition, the level of DDC coenzyme VB6 was enhanced in the intestinal bacteria at 12 h (mean ± SD, +16%↑ for BBR at 20 μg/mL, ***P < 0.001; +19%↑ for dhBBR at 20 μg/mL, **P < 0.01). c The TH inhibitor (BLMA5, 100 μM) decreased the production of dopa in SD rat gut bacteria when treated with BBR for 6 and 12 h (*P < 0.05, **P < 0.01); DDC inhibitor (benserazide, 100 μM) also lowered the dopamine generation significantly when incubated with BBR (mean ± SD, **P < 0.01, ***P < 0.001). d The DDC inhibitor (benserazide, 100 μM) increased the generation of dopa in SD rat gut bacteria when treated with BBR (mean ± SD, *P < 0.05). e Levels of dopa/dopamine increased significantly at 6 hr after dhBBR treatment in the brain homogenate of mice in vitro (mean ± SD, **P < 0.01, ***P < 0.001). f Coincubation of mouse dopaminergic primary cells with BBR or dhBBR (10 μg/mL), significantly increased dopamine levels in the dopaminergic primary cells incubated with dhBBR (*P < 0.05). g Levels of TH/DDC increased significantly at 6 h after dhBBR treatment in the brain homogenate of mice in vitro (mean ± SD, **P < 0.01, ***P < 0.001). h Levels of BH4/VB6 increased significantly at 6 h after dhBBR treatment in the brain homogenate of mice in vitro (mean ± SD, **P < 0.01, ***P < 0.001). i BH2 decreased significantly (*P < 0.05) with increasing BH4 (*P < 0.05), when dhBBR was added to the mixture of BH2 (as substrate) and dihydrobiopterin reductase at 37 °C for 2 h. j Levels of dopa/dopamine decreased significantly at 12 h after the treatment with DHFR inhibitor (methotrexate 100 μM) in the intestinal bacteria (mean ± SD, *P < 0.05)
Fig. 3 BBR activated the pathway for dopa/dopamine synthesis in the gut microbiota. a The activity of TH and DDC increased after treating the gut bacteria of SD rats with BBR at 12 h (10 μg/mL, *P < 0.05, **P < 0.01), but weakened when TH inhibitor (BLMA5, 100 μM) or the DDC inhibitor (benserazide, 100 μM) was incubated with BBR as a whole (mean ± SD, *P < 0.05, **P < 0.01). The TH inhibitor BLMA or DDC inhibitor benserazide did not change the abundance of the intestinal bacteria at 50 or 100 μM. The activity of TH and DDC increased after treating the gut bacteria of SD rats with BBR at 12 h (10 μg/mL, *P < 0.05, **P < 0.01), but weakened when the TH inhibitor (BLMA5, 100 μM) or DDC inhibitor (benserazide, 100 μM) was incubated with BBR as a whole (mean ± SD, *P < 0.05, **P < 0.01). b Levels of BH4 (the coenzyme of TH) increased significantly at 6 and 12 h after BBR or dhBBR treatment (10 and 20 μg/mL, respectively) in SD gut bacteria in vitro (mean ± SD, +23%↑, +31%↑ for BBR at 20 μg/mL at 6 and 12 h, **P < 0.01, ***P < 0.001; +26%↑, +34%↑ for dhBBR at 20 μg/mL at 6 and 12 h, **P < 0.01). In addition, the level of DDC coenzyme VB6 was enhanced in the intestinal bacteria at 12 h (mean ± SD, +16%↑ for BBR at 20 μg/mL, ***P < 0.001; +19%↑ for dhBBR at 20 μg/mL, **P < 0.01). c The TH inhibitor (BLMA5, 100 μM) decreased the production of dopa in SD rat gut bacteria when treated with BBR for 6 and 12 h (*P < 0.05, **P < 0.01); DDC inhibitor (benserazide, 100 μM) also lowered the dopamine generation significantly when incubated with BBR (mean ± SD, **P < 0.01, ***P < 0.001). d The DDC inhibitor (benserazide, 100 μM) increased the generation of dopa in SD rat gut bacteria when treated with BBR (mean ± SD, *P < 0.05). e Levels of dopa/dopamine increased significantly at 6 hr after dhBBR treatment in the brain homogenate of mice in vitro (mean ± SD, **P < 0.01, ***P < 0.001). f Coincubation of mouse dopaminergic primary cells with BBR or dhBBR (10 μg/mL), significantly increased dopamine levels in the dopaminergic primary cells incubated with dhBBR (*P < 0.05). g Levels of TH/DDC increased significantly at 6 h after dhBBR treatment in the brain homogenate of mice in vitro (mean ± SD, **P < 0.01, ***P < 0.001). h Levels of BH4/VB6 increased significantly at 6 h after dhBBR treatment in the brain homogenate of mice in vitro (mean ± SD, **P < 0.01, ***P < 0.001). i BH2 decreased significantly (*P < 0.05) with increasing BH4 (*P < 0.05), when dhBBR was added to the mixture of BH2 (as substrate) and dihydrobiopterin reductase at 37 °C for 2 h. j Levels of dopa/dopamine decreased significantly at 12 h after the treatment with DHFR inhibitor (methotrexate 100 μM) in the intestinal bacteria (mean ± SD, *P < 0.05)CC BY · PubMed Central
Fig. 4 The dhBBR-mediated chemical reaction for the conversion from tyrosine to dopa. BH2 obtained H• from the dhBBR–BBR system, and its reduction was activated, in which H• from dhBBR (N7–C8) moved to the N3=C4 bond in BH2, and N3=C4 was then transformed into N3–C4 (BH2 was converted into BH4). In the meanwhile, dhBBR lost H•, and was oxidized into BBR. The increased BH4 in intestinal bacteria accelerates the transformation from tyrosine to l-dopa, in the presence of ROS (H2O2, etc.) as well as Fe2+. Accordingly, BH4 is converted into tetrahydrobiopterin–4α-carbinolamine
Fig. 4 The dhBBR-mediated chemical reaction for the conversion from tyrosine to dopa. BH2 obtained H• from the dhBBR–BBR system, and its reduction was activated, in which H• from dhBBR (N7–C8) moved to the N3=C4 bond in BH2, and N3=C4 was then transformed into N3–C4 (BH2 was converted into BH4). In the meanwhile, dhBBR lost H•, and was oxidized into BBR. The increased BH4 in intestinal bacteria accelerates the transformation from tyrosine to l-dopa, in the presence of ROS (H2O2, etc.) as well as Fe2+. Accordingly, BH4 is converted into tetrahydrobiopterin–4α-carbinolamineCC BY · PubMed Central
Fig. 5 E. faecalis and E. faecium regulated dopa/dopamine and improved brain function in PD animals in the presence of BBR. a Treating mice with both MPTP (20 mg/kg/d, s.c.) and P (200 mg/kg/d, i.p.) for 7 days successfully generated the damage to brain function (LD, ***P < 0.001; LFR, ***P < 0.001) in the model mice. Carbidopa (1 mg/kg, s.c.) in combination with l-dopa (10 mg/kg/d, s.c.) for 6 days (from days 2 to 7) decreased the LD, cylinder test value (***P < 0.001, **P < 0.01), and increased the LFR (***P < 0.001); BBR (200 mg/kg/d, orally, days 2 to 7) significantly reduced the LD, cylinder test value (***P < 0.001, *P < 0.05), and elevated the LFR (*P < 0.05). Intravenous injection of BBR (10 mg/kg, for 6 days) did not cause a significant change in the LD, LFR, or cylinder test. b Levels of dopa/dopamine in the brain on day 7 of the experiment (mean ± SD, *P < 0.05 for dopa; **P < 0.01, ***P < 0.001 for dopamine). c Number of colonies from the mice treated with the antibiotics was significantly lower than that from the normal mice (mean ± SD, ***P < 0.001). d–f Translation of E. faecalis and E. faecium into the mice treated with antibiotics significantly increased dopa (L)/dopamine (R) levels in ICR mouse brains (d, *P < 0.05, **P < 0.01, NS no significance), blood (e, *P < 0.05, **P < 0.01), and feces (f, (L), (R), *P < 0.05, **P < 0.01, ***P < 0.001). g The relative abundance of Enterococcaeae in the fecal samples of clinical subjects increased after the two-month BBR treatment. Data are represented as the mean ± SD
Fig. 5 E. faecalis and E. faecium regulated dopa/dopamine and improved brain function in PD animals in the presence of BBR. a Treating mice with both MPTP (20 mg/kg/d, s.c.) and P (200 mg/kg/d, i.p.) for 7 days successfully generated the damage to brain function (LD, ***P < 0.001; LFR, ***P < 0.001) in the model mice. Carbidopa (1 mg/kg, s.c.) in combination with l-dopa (10 mg/kg/d, s.c.) for 6 days (from days 2 to 7) decreased the LD, cylinder test value (***P < 0.001, **P < 0.01), and increased the LFR (***P < 0.001); BBR (200 mg/kg/d, orally, days 2 to 7) significantly reduced the LD, cylinder test value (***P < 0.001, *P < 0.05), and elevated the LFR (*P < 0.05). Intravenous injection of BBR (10 mg/kg, for 6 days) did not cause a significant change in the LD, LFR, or cylinder test. b Levels of dopa/dopamine in the brain on day 7 of the experiment (mean ± SD, *P < 0.05 for dopa; **P < 0.01, ***P < 0.001 for dopamine). c Number of colonies from the mice treated with the antibiotics was significantly lower than that from the normal mice (mean ± SD, ***P < 0.001). d–f Translation of E. faecalis and E. faecium into the mice treated with antibiotics significantly increased dopa (L)/dopamine (R) levels in ICR mouse brains (d, *P < 0.05, **P < 0.01, NS no significance), blood (e, *P < 0.05, **P < 0.01), and feces (f, (L), (R), *P < 0.05, **P < 0.01, ***P < 0.001). g The relative abundance of Enterococcaeae in the fecal samples of clinical subjects increased after the two-month BBR treatment. Data are represented as the mean ± SDCC BY · PubMed Central
Fig. 6 BBR stimulated the production of dopamine in striatum in mice transplanted with E. faecalis or E. faecium: TMP-TFB-derivatized MALDI-MS images. a The relative abundance and distributions of dopamine with a spatial resolution of 200 µm. b Rescaled image from a with baseline subtraction and total ion count normalization. c The relative abundance and distributions of dopamine with a spatial resolution of 100 µm. d The relative abundance and distributions of dopamine in half brains from the same mice in c with a spatial resolution of 200 µm. All of them showed elevated levels of dopamine after BBR addition. (group 1: normal group; group 2: antibiotic treated only; group 3: antibiotics and E. faecalis; group 4: antibiotics, E. faecalis, and BBR (200 mg/kg); group 5: antibiotics, E. faecium; and group 6: antibiotics, E. faecium, and BBR (200 mg/kg)). Blue represents the decreased level and red represents the increased level. The striatal dopamine level in the mice receiving both E. faecalis and BBR was higher than that treated with E. faecalis only (group 3 vs. group 4). The striatal dopamine in the mice receiving both E. faecium and BBR was higher than that treated with E. faecium only (group 5 vs. group 6)
Fig. 6 BBR stimulated the production of dopamine in striatum in mice transplanted with E. faecalis or E. faecium: TMP-TFB-derivatized MALDI-MS images. a The relative abundance and distributions of dopamine with a spatial resolution of 200 µm. b Rescaled image from a with baseline subtraction and total ion count normalization. c The relative abundance and distributions of dopamine with a spatial resolution of 100 µm. d The relative abundance and distributions of dopamine in half brains from the same mice in c with a spatial resolution of 200 µm. All of them showed elevated levels of dopamine after BBR addition. (group 1: normal group; group 2: antibiotic treated only; group 3: antibiotics and E. faecalis; group 4: antibiotics, E. faecalis, and BBR (200 mg/kg); group 5: antibiotics, E. faecium; and group 6: antibiotics, E. faecium, and BBR (200 mg/kg)). Blue represents the decreased level and red represents the increased level. The striatal dopamine level in the mice receiving both E. faecalis and BBR was higher than that treated with E. faecalis only (group 3 vs. group 4). The striatal dopamine in the mice receiving both E. faecium and BBR was higher than that treated with E. faecium only (group 5 vs. group 6)CC BY · PubMed Central
Fig. 7 Dopa/dopamine might be the chemical link for the crosstalk between gut and brain. The regulation of Phe–Tyr–dopa–dopamine biosynthesis in the gut microbiota by BBR could improve brain function
Fig. 7 Dopa/dopamine might be the chemical link for the crosstalk between gut and brain. The regulation of Phe–Tyr–dopa–dopamine biosynthesis in the gut microbiota by BBR could improve brain functionCC BY · PubMed Central

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

Show all 81 references

Research works printed but not linked: 2

  1. Hu, X. C., Wan, J. W. & Hu, R. J. Analysis of clinical distribution characteristics and drug tolerance of Enterococci in Wuxi between 2008-2009. Journal of Modern. Lab. Med. 6, 125–127 (2010).
  2. Tian, H. & Cronstein, B. N. Understanding the mechanisms of action of methotrexate. Bull. NYU Hosp. Jt Dis. 65, 168–173 (2007).

Cited by

Sorted by citations

Related

See all

Metadata

Authors
Wang, Y., Tong, Q., Ma, S.-R., Zhao, Z.-X., Pan, L.-B., Cong, L., Han, P., Peng, R., Yu, H., Lin, Y., Gao, T.-L., Shou, J.-W., Li, X.-Y., Zhang, X.-F., Zhang, Z.-W., Fu, J., Wen, B.-Y., Yu, J.-B., Cao, X., & Jiang, J.-D.
Affiliations
  • Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
  • First Hospital of Jilin University (CN)
Corresponding author
  • Wang, Yan
  • Cao, Xuetao
  • Jiang, Jian-Dong
ORCID
Venue
Signal Transduction and Targeted Therapy
Publisher
Springer Science and Business Media LLC
Published
2021-02-24
Volume
6
Issue
1
Pages
77-77
ISSN
2059-3635 (ISSN-L)
DOI
10.1038/s41392-020-00456-5
PMC
PMC7902645
OpenAlex
W3132116259
Cited by
319
References
81
Citations by year
2026: 31 · 2025: 98 · 2024: 61 · 2023: 64 · 2022: 48 · 2021: 17
FWCI
22.73
Type
journal article
Language
en
Open access
Licence
Locations
  • Signal Transduction and Targeted Therapy (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 (81973290, 81573493, Z141102004414062)
Topics
  • Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
  • Health Sciences › Medicine › Pharmacology (medical) › Berberine and alkaloids research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
Keywords
berberine, Parkinson's disease, gut microbiota, dopamine, tyrosine hydroxylase, tetrahydrobiopterin, levodopa, dihydroberberine, Enterococcus faecalis, Enterococcus faecium, gut-brain axis, hyperlipidemia
MeSH terms
Gastrointestinal Microbiome, Animals, Berberine, Corpus Striatum, Dihydroxyphenylalanine, Dopamine, Humans, Levodopa, Parkinson Disease, Enterococcus faecalis, Tyrosine 3-Monooxygenase, Enterococcus faecium, Mice

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review