CoChat
Sign Up
Cited by 383Berberine and alkaloids researchGut microbiota and healthProbiotics and Fermented Foods

The DOI matches its Crossref record; 61 of the 63 references it cites were found in a registry or an index.

Gut microbiome-related effects of berberine and probiotics on type 2 diabetes (the PREMOTE study)

Open access
Zhang, Yifei, Gu, Yanyun, Ren, Huahui, Wang, Shujie, Zhong, Huanzi, Zhao, Xinjie, Ma, Jing, Gu, Xuejiang, Xue, Yaoming, Huang, Shan, Yang, Jialin, Chen, Li, Chen, Gang, Qu, Shen, Liang, Jun, Qin, Li, Huang, Qin, Peng, Yongde, Li, Qi, Wang, Xiaolin, Kong, Ping, Hou, Guixue, Gao, Mengyu, Shi, Zhun, Li, Xuelin, Qiu, Yixuan, Zou, Yuanqiang, Yang, Huanming, Wang, Jian, Xu, Guowang, Lai, Shenghan, Li, Junhua, Ning, Guang, Wang, Weiqing·2020·Nature Communications
DOI 10.1038/s41467-020-18414-8PMC PMC7538905
Open this paper in CoChat — free accountOpen PDF

Abstract

Human gut microbiome is a promising target for managing type 2 diabetes (T2D). Measures altering gut microbiota like oral intake of probiotics or berberine (BBR), a bacteriostatic agent, merit metabolic homoeostasis. We hence conducted a randomized, double-blind, placebo-controlled trial with newly diagnosed T2D patients from 20 centres in China. Four-hundred-nine eligible participants were enroled, randomly assigned (1:1:1:1) and completed a 12-week treatment of either BBR-alone, probiotics+BBR, probiotics-alone, or placebo, after a one-week run-in of gentamycin pretreatment. The changes in glycated haemoglobin, as the primary outcome, in the probiotics+BBR (least-squares mean [95% CI], -1.04[-1.19, -0.89]%) and BBR-alone group (-0.99[-1.16, -0.83]%) were significantly greater than that in the placebo and probiotics-alone groups (-0.59[-0.75, -0.44]%, -0.53[-0.68, -0.37]%, P < 0.001). BBR treatment induced more gastrointestinal side effects. Further metagenomics and metabolomic studies found that the hypoglycaemic effect of BBR is mediated by the inhibition of DCA biotransformation by Ruminococcus bromii. Therefore, our study reports a human microbial related mechanism underlying the antidiabetic effect of BBR on T2D. (Clinicaltrial.gov Identifier: NCT02861261).

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/s41467-020-18414-8

Cites

61 of 61 references verified0 citation errors · 0 not checkable

Statistics

Figures

Fig. 1 Flow diagram of participant enrolment in the PREMOTE Trial.
Fig. 1 Flow diagram of participant enrolment in the PREMOTE Trial.CC BY · PubMed Central
Fig. 2 BBR significantly altered gut microbiome symbiosis after 13 weeks of treatment. a Gene count (upper panel) and Shannon index (lower panel) of genes in different arms, baseline and post treatment; Plac, Placebo, n = 96; Prob, probiotics treatment, n = 98; BBR, berberine treatment, n = 85; Prob + BBR: berberine plus probiotics treatment, n = 102; *P < 0.05, **P < 0.01, ***P < 0.001, two-sided Kruskal–Wallis test. Dark lines in the boxes indicate medians, the width of the notches is the IQR, the lowest and highest values within 1.5 times the IQR from the first and third quartiles. b Distance-based redundancy analysis (dbRDA) plot based on Bray–Curtis distances of species in post-treatment samples was performed to assess the difference between the four treatment arms (Permanova P < 0.001). Projection of species-level gut microbiome samples constrained by treatment methods. Marginal box plots show the separation of the constrained projection coordinates (boxes show medians and quartiles, error bars extend to most the extreme value within 1.5 interquartile ranges), Plac, n = 96; Prob, n = 98; BBR, n = 85; Prob + BBR, n = 102. c Venn diagram showing the overlapping of microbial species among the four treatment arms that were altered from baseline to post treatment, two-sided Wilcoxon matched-pairs signed-rank test, q < 0.05. d Heatmap of gut microbial species that showed significantly changed their relative abundances (RAs) post treatment vs. baseline. Plac, n = 96; Prob, n = 98; BBR, n = 85; Prob + BBR: n = 102. The changes in nine species in probiotics formula ingested by participants were separately shown below. *q < 0.05, two-sided Wilcoxon match-pairs signed-rank test. The colour key represents the Z score. Bifidobacterium catenulatum–Bpc, B. catenulatum–Bifidobacterium pseudocatenulatum complex. Source data and exact P-value are provided in the Source Data file.
Fig. 2 BBR significantly altered gut microbiome symbiosis after 13 weeks of treatment. a Gene count (upper panel) and Shannon index (lower panel) of genes in different arms, baseline and post treatment; Plac, Placebo, n = 96; Prob, probiotics treatment, n = 98; BBR, berberine treatment, n = 85; Prob + BBR: berberine plus probiotics treatment, n = 102; *P < 0.05, **P < 0.01, ***P < 0.001, two-sided Kruskal–Wallis test. Dark lines in the boxes indicate medians, the width of the notches is the IQR, the lowest and highest values within 1.5 times the IQR from the first and third quartiles. b Distance-based redundancy analysis (dbRDA) plot based on Bray–Curtis distances of species in post-treatment samples was performed to assess the difference between the four treatment arms (Permanova P < 0.001). Projection of species-level gut microbiome samples constrained by treatment methods. Marginal box plots show the separation of the constrained projection coordinates (boxes show medians and quartiles, error bars extend to most the extreme value within 1.5 interquartile ranges), Plac, n = 96; Prob, n = 98; BBR, n = 85; Prob + BBR, n = 102. c Venn diagram showing the overlapping of microbial species among the four treatment arms that were altered from baseline to post treatment, two-sided Wilcoxon matched-pairs signed-rank test, q < 0.05. d Heatmap of gut microbial species that showed significantly changed their relative abundances (RAs) post treatment vs. baseline. Plac, n = 96; Prob, n = 98; BBR, n = 85; Prob + BBR: n = 102. The changes in nine species in probiotics formula ingested by participants were separately shown below. *q < 0.05, two-sided Wilcoxon match-pairs signed-rank test. The colour key represents the Z score. Bifidobacterium catenulatum–Bpc, B. catenulatum–Bifidobacterium pseudocatenulatum complex. Source data and exact P-value are provided in the Source Data file.CC BY · PubMed Central
Fig. 3 BBR altered microbial BA metabolism and correlated with blood BAs and clinical outcomes. a Changes in RAs of bile acid-inducible (Bai) genes induced by the treatments of four arms. hsdh, hydroxysteroid dehydrogenase; Bsh, gene encoding bile salt hydrolase. The Z-score was calculated with the two-sided Wilcoxon matched-pairs signed-rank test. A Z-score > 0 indicated an increase after treatment, while a z-score < 0 indicated a decrease after treatment. *P < 0.01, **P < 0.001, ***P < 0.0001; Plac, Placebo, n = 96; Prob, probiotics treatment, n = 98; BBR, berberine treatment, n = 85; Prob + BBR, berberine plus probiotics treatment, n = 102. b Comparisons of bile acid (BA) composition between baseline and post treatment in the four arms. CA, cholic acid; CDCA, chenodeoxycholic acid; DCA, deoxycholic acid; GCA, glycocholic acid; GCDCA, glycochenodeoxycholic acid; GDCA, glycodeoxycholic acid; GLCA, glycolithocholic acid; GUDCA, glycoursodeoxycholic acid; LCA, lithocholic acid; TCA, taurocholic acid; TCDCA, taurocholic chenodeoxycholic acid; TDCA, taurodeoxycholic acid; TLCA, taurolithocholic acid; TUDCA, tauroursodeoxycholic acid; UDCA, ursodeoxycholic acid. *q < 0.01, **q < 0.001, ***q < 0.0001, two-sided Wilcoxon match-pairs signed-rank test. c Correlations between microbial BA genes and blood BA compositions at the baseline (upper panel) vs. post treatment (lower panel) for all participants, Spearman correlation, colour key represented rho value, *q < 0.01. d Heatmap of correlations between the blood BAs and clinical outcomes. Multivariate GEE controlling for age, sex and BMI. The colour key represents the β-value, *q < 0.01. e Plasma FGF19 levels pre and post treatment, *P < 0.05, **P < 0.01, ***P < 0.001, two-sided Wilcoxon matched-pairs signed-rank test, dark lines in the boxes indicate medians, the width of the notches is the IQR, the lowest and highest values within 1.5 times the IQR from the first and third quartiles, Plac, n = 96; Prob, n = 98; BBR, n = 85; Prob + BBR: n = 102. 12a/nonBA, 12a-hydroxylated/non–12a-hydroxylated bile acids; 2hPPG, post-load plasma glucose; cp120, post-load serum C peptide; FPG, fasting plasma glucose; HbA1c, glycated haemoglobin; HOMA-IR, homoeostasis model assessment index for assessing insulin resistance; HOMA-β, homoeostasis model assessment index for assessing β-cell function; ins120, post-load serum insulin; TC, total cholesterol; Uncon/Con BA, unconjugated/conjugated bile acids. Baseline, baseline levels; post, post-treatment levels. Source data and exact P-value are provided in the Source Data file.
Fig. 3 BBR altered microbial BA metabolism and correlated with blood BAs and clinical outcomes. a Changes in RAs of bile acid-inducible (Bai) genes induced by the treatments of four arms. hsdh, hydroxysteroid dehydrogenase; Bsh, gene encoding bile salt hydrolase. The Z-score was calculated with the two-sided Wilcoxon matched-pairs signed-rank test. A Z-score > 0 indicated an increase after treatment, while a z-score < 0 indicated a decrease after treatment. *P < 0.01, **P < 0.001, ***P < 0.0001; Plac, Placebo, n = 96; Prob, probiotics treatment, n = 98; BBR, berberine treatment, n = 85; Prob + BBR, berberine plus probiotics treatment, n = 102. b Comparisons of bile acid (BA) composition between baseline and post treatment in the four arms. CA, cholic acid; CDCA, chenodeoxycholic acid; DCA, deoxycholic acid; GCA, glycocholic acid; GCDCA, glycochenodeoxycholic acid; GDCA, glycodeoxycholic acid; GLCA, glycolithocholic acid; GUDCA, glycoursodeoxycholic acid; LCA, lithocholic acid; TCA, taurocholic acid; TCDCA, taurocholic chenodeoxycholic acid; TDCA, taurodeoxycholic acid; TLCA, taurolithocholic acid; TUDCA, tauroursodeoxycholic acid; UDCA, ursodeoxycholic acid. *q < 0.01, **q < 0.001, ***q < 0.0001, two-sided Wilcoxon match-pairs signed-rank test. c Correlations between microbial BA genes and blood BA compositions at the baseline (upper panel) vs. post treatment (lower panel) for all participants, Spearman correlation, colour key represented rho value, *q < 0.01. d Heatmap of correlations between the blood BAs and clinical outcomes. Multivariate GEE controlling for age, sex and BMI. The colour key represents the β-value, *q < 0.01. e Plasma FGF19 levels pre and post treatment, *P < 0.05, **P < 0.01, ***P < 0.001, two-sided Wilcoxon matched-pairs signed-rank test, dark lines in the boxes indicate medians, the width of the notches is the IQR, the lowest and highest values within 1.5 times the IQR from the first and third quartiles, Plac, n = 96; Prob, n = 98; BBR, n = 85; Prob + BBR: n = 102. 12a/nonBA, 12a-hydroxylated/non–12a-hydroxylated bile acids; 2hPPG, post-load plasma glucose; cp120, post-load serum C peptide; FPG, fasting plasma glucose; HbA1c, glycated haemoglobin; HOMA-IR, homoeostasis model assessment index for assessing insulin resistance; HOMA-β, homoeostasis model assessment index for assessing β-cell function; ins120, post-load serum insulin; TC, total cholesterol; Uncon/Con BA, unconjugated/conjugated bile acids. Baseline, baseline levels; post, post-treatment levels. Source data and exact P-value are provided in the Source Data file.CC BY · PubMed Central
Fig. 4 R. bromii was inhibited by BBR to attenuate DCA transformation. a The two-panel heatmap on the left shows the correlations between the key BBR responsive species and with major clinical outcomes and plasma levels of bile acid. The colour key shows Rho calculated by partial Spearman’s correlation with adjustment for age, sex and BMI. Δ of clinical parameters or BAs = 100% × (baseline value − post treatment value)/baseline value. Species in blue represent depleted species and species in orange represent enriched species after BBR treatments. *P < 0.05. b Bile acid transformation assay for R. bromii. The percentage composition of deoxycholic acid (DCA) and lithocholic acid (LCA) in the culture media with which R.bromii had grown for 24 h with primary bile acid (CA and CDCA) treatment were measured by LC/MS. n = 3, data are shown as the mean ± SD. c The growth curve of R. bromii with different concentrations of BBR in the in vitro culture experiment, demonstrated a significant inhibitory effect of BBR on R. bromii starting at a concentration of 25 μg ml−1, n = 3, P < 0.001, determined by two-way repeated-measures ANOVA, data are shown as the mean ± SD. Bifidobacterium catenulatum − Bpc, B. catenulatum–Bifidobacterium pseudocatenulatum complex. Source data and exact P-value are provided in the Source Data file.
Fig. 4 R. bromii was inhibited by BBR to attenuate DCA transformation. a The two-panel heatmap on the left shows the correlations between the key BBR responsive species and with major clinical outcomes and plasma levels of bile acid. The colour key shows Rho calculated by partial Spearman’s correlation with adjustment for age, sex and BMI. Δ of clinical parameters or BAs = 100% × (baseline value − post treatment value)/baseline value. Species in blue represent depleted species and species in orange represent enriched species after BBR treatments. *P < 0.05. b Bile acid transformation assay for R. bromii. The percentage composition of deoxycholic acid (DCA) and lithocholic acid (LCA) in the culture media with which R.bromii had grown for 24 h with primary bile acid (CA and CDCA) treatment were measured by LC/MS. n = 3, data are shown as the mean ± SD. c The growth curve of R. bromii with different concentrations of BBR in the in vitro culture experiment, demonstrated a significant inhibitory effect of BBR on R. bromii starting at a concentration of 25 μg ml−1, n = 3, P < 0.001, determined by two-way repeated-measures ANOVA, data are shown as the mean ± SD. Bifidobacterium catenulatum − Bpc, B. catenulatum–Bifidobacterium pseudocatenulatum complex. Source data and exact P-value are provided in the Source Data file.CC 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 63 references

Cited by

Sorted by citations

Related

See all

Metadata

Authors
Zhang, Y., Gu, Y., Ren, H., Wang, S., Zhong, H., Zhao, X., Ma, J., Gu, X., Xue, Y., Huang, S., Yang, J., Chen, L., Chen, G., Qu, S., Liang, J., Qin, L., Huang, Q., Peng, Y., Li, Q., Wang, X., Kong, P., Hou, G., Gao, M., Shi, Z., Li, X., Qiu, Y., Zou, Y., Yang, H., Wang, J., Xu, G., Lai, S., Li, J., Ning, G., & Wang, W.
Affiliations
  • Shanghai Jiao Tong University (CN)
  • BGI Group (China) (CN)
  • Dalian Institute of Chemical Physics (CN)
  • First Affiliated Hospital of Wenzhou Medical University (CN)
  • Nanfang Hospital (CN)
  • Minhang District Central Hospital (CN)
  • Qilu Hospital of Shandong University (CN)
  • Fujian Provincial Hospital (CN)
  • Tongji University (CN)
  • Xuzhou Central Hospital (CN)
  • Second Military Medical University (CN)
  • Johns Hopkins University (US)
Corresponding author
  • Li, Junhua
  • Wang, Weiqing
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2020-10-06
Volume
11
Issue
1
Pages
5015-5015
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-020-18414-8
PMC
PMC7538905
OpenAlex
W3092484485
Cited by
380
References
63
Citations by year
2026: 44 · 2025: 68 · 2024: 63 · 2023: 84 · 2022: 72 · 2021: 48 · 2020: 1
FWCI
31.32
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Natural Science Foundation of China (81,870,555, 91857205, 2016YFC0901200, 2018YFC1313804, 81930021)
  • Sun Yat-sen University
  • Government of Jiangsu Province
  • Huazhong University of Science and Technology
  • Science and Technology Commission of Shanghai Municipality
  • Government of Jiangxi Province
  • Tongji University
  • Zhejiang University
  • Shanghai Jiao Tong University
  • Second Military Medical University
  • Peking University
  • Nanjing University
  • Southern Medical University
  • Nanfang Hospital
  • Shanghai General Hospital
  • Fujian Provincial Hospital
  • Ruijin Hospital
  • Wuhan Union Hospital
  • School of Medicine, Shanghai Jiao Tong University
  • Tongji Medical College, Huazhong University of Science and Technology
Topics
  • Health Sciences › Medicine › Pharmacology (medical) › Berberine and alkaloids research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
  • Life Sciences › Agricultural and Biological Sciences › Food Science › Probiotics and Fermented Foods
Keywords
berberine, probiotics, type 2 diabetes, gut microbiota, HbA1c, Ruminococcus bromii, metagenomics, metabolomics, antidiabetic mechanism, newly diagnosed diabetes, gastrointestinal adverse effects
MeSH terms
Gastrointestinal Microbiome, Berberine, Diabetes Mellitus, Type 2, Female, Glycated Hemoglobin, Humans, Hypoglycemic Agents, Male, Middle Aged, Placebos, Treatment Outcome, Probiotics, Metagenome

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