The gut microbiota is key to regulating host metabolism. Changes to the intestinal microbiota, and intestinal ecology at large, casually contribute to metabolic disorders, including type 2 diabetes mellitus (T2DM).¹ Thus, treatments that influence the microbiome may improve glucose homeostasis, insulin sensitivity and inflammation. Berberine and probiotics are two such treatments.

A recent umbrella meta-analysis of 11 randomised, controlled trials found that berberine supplementation effectively improved fasting blood glucose, glycated haemoglobin (HbA1c), homoeostasis model assessment for insulin resistance (HOMA-IR), insulin, interleukin (IL)-6, tumour necrosis factor-alpha (TNF-α), and C-reactive protein (CRP) levels in patients with T2DM and polycystic ovary syndrome (PCOS).² Favourable changes to glycaemic control, insulin sensitivity and inflammation are speculated to be partially due to microbiome-related changes.³

Another meta-analyse of 46 randomised, controlled trials showed that probiotics and synbiotics can improve the glycaemic profile of patients with prediabetes and T2DM. Significant reductions in fasting plasma glucose, insulin, HbA1c, and HOMA-IR; and a significant increase in the quantitative insulin-sensitivity check index (QUICKI) were reported.⁴

The PREMOTE study and other clinical trials have investigated whether the combination of berberine and probiotics have greater effects on the improvement of metabolic homeostasis than either treatment alone. The PREMOTE study was a double-blind, randomised, placebo-controlled trial in 409 newly diagnosed, drug-naïve T2DM patients in China. It investigated the effects of oral berberine (1200 mg/day) and probiotics in glycaemic control, mediated by the gut microbiome. The 12-week treatment of either berberine alone, probiotics alone, berberine and probiotics, or placebo took place after a one-week run-in of gentamycin, a broad-spectrum antibiotic.

The changes in glycated haemoglobin (HbA1c), as the primary outcome, were significantly different between the four groups (p<0.001). The mean changes in HbA1c in the berberine and probiotics group (-1.04) and berberine only group (-0.99) were greater than that of the probiotics only group (-0.53) and placebo group (-0.59).

Berberine-containing treatments brought about similar improvements in the other metabolic parameters (i.e. secondary outcomes), such as fasting plasma glucose, blood triglycerides, total cholesterol, and low-density lipoprotein (LDL) cholesterol levels, except for HOMA-IR, which was significantly lowered by berberine and probiotics but not by berberine alone.

Berberine was able to induce global alterations in gut microbiome composition. Further metagenomic and metabolomic studies found that the hypoglycaemic effect of berberine was mediated by inhibition of the biotransformation of deoxycholic acid (DCA), a secondary bile acid, by Ruminococcus bromii.⁵ Briefly, DCA negatively impacts glycaemic control by altering insulin signalling.^6,7 It is also worth noting that the antidiabetic drug, metformin, works via a similar mechanism to improve glucose tolerance. Metformin modulates Bacteroides fragilis levels, resulting in a change of bile acid composition and bile acid signalling in the gut.⁸

Subgroup analysis in the PREMOTE study revealed that probiotics species, except for B. longum, exhibited a dose-response relationship with improvement in HbA1c levels in the participants aged 50 years and older in the berberine and probiotics study arm.

Overall, the trial demonstrated that a microbial-related mechanism potentially underlies the antidiabetic effect of berberine. Results suggested that improvements in metabolic health are expected with probiotic co-supplementation among older diabetic patients.⁵

Indeed, research outside of the PREMOTE study supports the co-prescription of Bifidobacterium-containing probiotics and berberine as a viable and safe treatment option for addressing hyperglycaemia in an older study population (mean age >50 years). The combination has been shown to significantly reduce HbA1c, compared to placebo. The same magnitude of effect was not seen with either berberine (1000 mg/day) or Bifidobacterium supplementation alone. Significant favourable effects on fasting plasma glucose occurred with berberine and probiotic co-supplement and berberine-only treatment.⁹

Other evidence showed that berberine (1200 mg/day) and multi-strain probiotics outperformed placebo or probiotic-only treatment in T2DM patients aged 50 years and older, based on changes in HbA1c. However, the difference between co-supplementation and berberine-only treatment did not reach statistically significance in this randomised, controlled trial.¹⁰

Further study on the PREMOTE cohort showed that combined berberine and probiotic supplementation can significantly lower postprandial lipidaemia, a contributor to cardiovascular disease (CVD) risk in diabetes. This effect was linked to the changes in faecal Bifidobacterium breve levels and expressions of genes in B. breve that regulate fatty acid metabolism, responding to berberine-only treatment and combined treatment with probiotics. Overall, authors confirmed that berberine and probiotics exerted synergistic antidiabetic and hypolipidaemic effects via the gut microbiome.¹¹

Taken together, this evidence appears to encourage the co-administration of berberine and Bifidobacterium-containing probiotics for improving metabolic homeostasis in older diabetic patients. As part and parcel of this discussion, practitioners are called to acknowledge that prescriptions must be personalised. In this instance, T2DM patients aged 50 years and older would appear to benefit the most.

Other unique host and microbiome features also deserve due consideration. Besides age, diet, antibiotic usage, food supplements, underlying medical conditions, and patterns of circadian activity are factors that contribute to variability in probiotic effects.¹²

In addition, personalising the use of berberine can serve to reduce the occurrence of side effects.¹³ While oral berberine is generally well tolerated, gastrointestinal side effects have been recorded.¹⁴ Their incidence does not appear to influence the efficacy or safety of treatment.⁵

Rather than prescribing berberine as an isolated constituent, naturopaths and herbalists typically prescribe berberine-containing herbs such as Phellodendron, which has a long history of safe traditional use.¹⁵ Equally, scientific evidence shows that several flavonoids and alkaloids in Hydrastis canadensis (Golden Seal) exert additive or synergistic antimicrobial effects with berberine.¹⁶ It remains to be seen whether such synergy also applies to the antidiabetic of berberine-containing herbs, though many naturopaths would agree that there is value in prescribing the whole herb, as opposed to an isolated active constituent.

To learn more about the evidence-based applications of berberine, refer to The Benefits and Controversies of Berberine. Find this video resource in the Integria Practitioner Education Centre.

References

1. Fan Y, Pedersen O. Gut microbiota in human metabolic health and disease. Nat Rev Microbiol. 2021 Jan;19(1):55-71. DOI: 10.1038/s41579-020-0433-9

2. Nazari A, Ghotbabadi ZR, Kazemi KS, Metghalchi Y, Tavakoli R, Rahimabadi RZ, et al. The effect of berberine supplementation on glycemic control and inflammatory biomarkers in metabolic disorders: an umbrella meta-analysis of randomized controlled trials. Clin Ther. 2023 Nov;S0149-2918(23)00429-0. DOI: 10.1016/j.clinthera.2023.10.019

3. Wang H, Zhang H, Gao Z, Zhang Q, Gu C. The mechanism of berberine alleviating metabolic disorder based on gut microbiome. Front Cell Infect Microbiol. 2022;12:854885. DOI: 10.3389/fcimb.2022.854885

4. Naseri K, Saadati S, Ashtary-Larky D, Asbaghi O, Ghaemi F, Pashayee-Khamene F, et al. Probiotics and synbiotics supplementation improve glycemic control parameters in subjects with prediabetes and type 2 diabetes mellitus: a GRADE-assessed systematic review, meta-analysis, and meta-regression of randomized clinical trials. Pharmacol Res. 2022 Oct;184:106399. DOI: 10.1016/j.phrs.2022.106399

5. Zhang Y, Gu Y, Ren H, Wang S, Zhong H, Zhao X, et al. Gut microbiome-related effects of berberine and probiotics on type 2 diabetes (the PREMOTE study). Nat Commun. 2020 Oct;11(1):5015. DOI: 10.1038/s41467-020-18414-8

6. Zaborska KE, Lee SA, Garribay D, Cha E, Cummings BP. Deoxycholic acid supplementation impairs glucose homeostasis in mice. PLoS One. 2018;13(7):e0200908. DOI: 10.1371/journal.pone.0200908

7. Kuipers F, Bloks VW, Groen AK. Beyond intestinal soap--bile acids in metabolic control. Nat Rev Endocrinol. 2014 Aug;10(8):488-498. DOI: 10.1038/nrendo.2014.60

8. Sun L, Xie C, Wang G, Wu Y, Wu Q, Wang X, et al. Gut microbiota and intestinal FXR mediate the clinical benefits of metformin. Nat Med. 2018 Dec;24(12):1919-1929. DOI: 10.1038/s41591-018-0222-4

9. Ming J, Yu X, Xu X, Wang L, Ding C, Wang Z, et al. Effectiveness and safety of Bifidobacterium and berberine in human hyperglycemia and their regulatory effect on the gut microbiota: a multi-center, double-blind, randomized, parallel-controlled study. Genome Med. 2021 Aug;13(1):125. DOI: 10.1186/s13073-021-00942-7

10. Zhang Y, Yanyun G, Wang S, Ma J, Gu X, Xue Y, et al. Probiotics plus berberine as an anti-diabetic regimen in patients with type 2 diabetes, particularly in the elderly: a multicentre randomised controlled trial. SSRN. 2018. DOI: 10.2139/ssrn.3204706

11. Wang S, Ren H, Zhong H, Zhao X, Li C, Ma J, et al. Combined berberine and probiotic treatment as an effective regimen for improving postprandial hyperlipidemia in type 2 diabetes patients: a double blinded placebo controlled randomized study. Gut Microbes. 2022;14(1):2003176. DOI: 10.1080/19490976.2021.2003176

12. Zmora N, Zilberman-Schapira G, Suez J, Mor U, Dori-Bachash M, Bashiardes S, et al. Personalized gut mucosal colonization resistance to empiric probiotics is associated with unique host and microbiome features. Cell. 2018 Sep;174(6):1388-1405.e21. DOI: 10.1016/j.cell.2018.08.041

13. Cheng H, Liu J, Tan Y, Feng W, Peng C. Interactions between gut microbiota and berberine, a necessary procedure to understand the mechanisms of berberine. J Pharm Anal. 2022 Aug;12(4):541-555. DOI: 10.1016/j.jpha.2021.10.003

14. Natural Medicines Database [Internet]. Denver (CO): TRC Healthcare; 2023. Berberine; 2023 Sep [cited 2023 Nov 29]. Available from: https://naturalmedicines.therapeuticresearch.com/databases/food,-herbs-supplements/professional.aspx?productid=1126

15. Sun Y, Lenon GB, Yang AWH. Phellodendri cortex: a phytochemical, pharmacological, and pharmacokinetic review. Evid. Based Complementary Altern. Med. 2019 Apr;2019. DOI: 10.1155/2019/7621929

16. Caesar LK, Cech NB. Synergy and antagonism in natural product extracts: when 1 + 1 does not equal 2. Nat Prod Rep. 2019 Jun;36(6):869-888. DOI: 10.1039/c9np00011a