Shifting the Gut Microbiome in People with Type 2 Diabetes

Could metformin and Scutellaria baicalensis be an example of a positive drug/herb interaction?

By Bert Mathieson, ND, RD, LD, CDE

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Reference

Shin NR, Gu N, Choi HS, Kim H. Combined effects of Scutellaria baicalensis with metformin on glucose tolerance of patients with type 2 diabetes via gut microbiota modulation. Am J Physiol Endocrinol Metab. 2020;318(1):E52-E61.

Study Objective

The objective of this study was to determine if a combination treatment with Scutellaria baicalensis (SB) and metformin could positively affect type 2 diabetes–related parameters via modulation of gut microbiota.

Design

This was a 20-week, double-blind, randomized, crossover trial. Subjects were randomly assigned to 1 of the following 2 sequence groups: 1) SB + metformin in period 1, to placebo + metformin in period 2; or 2) placebo + metformin in period 1, to SB + metformin in period 2. There was a “washout period” of 4 weeks before the participants “crossed over” to their next assigned sequence.

In the SB + metformin treatment period, the subjects received 4 capsules of SB (3.52 grams of freeze-dried hot-water extract SB per 12 capsules) along with their normal prescribed dose of metformin (at least 500 mg) 3 times per day 30 minutes after meals for 8 weeks.

Participants

Twelve subjects completed this study and were included in the analysis. The participants were men and woman between the ages of 20 to 75 who had been diagnosed with type 2 diabetes at least 3 months prior to the initiation of the study. They were all taking at least 500 mg of metformin daily and had fasting blood sugars between 110 to 180 mg/dL or a glycated hemoglobin between 8.0 to 9.0.

Study Parameters Assessed

This study sought to assess changes in urine and serum biochemistry, oral glucose tolerance, and stool microbiota in treatment and placebo groups.

Primary Outcome Measures

The researchers assessed the following primary outcome measures: glucose tolerance, liver enzymes, gene expression of interleukin-2 (IL-2) and tumor necrosis factor alpha (TNFα) as markers of inflammation, gene expression of AMPK , GLUT4, and PI3K as markers of glucose metabolism, and blood lipids.

Key Findings

There was a statistically significant improvement in oral glucose tolerance noted in the combined SB/metformin group vs. the placebo group.

The gene expression of TNFα (measured as mRNA by real-time polymerase chain reaction [PCR] in blood) showed a statistically significant decrease in the SB/metformin group. There was also a decreased gene expression of IL-6 in the SB/metformin group, but the decrease was not statistically significant.

The stool samples from the SB/metformin group showed significantly less Bifidobacterium and significantly more Lactobacillus and Akkermansia than the stool samples from the placebo group.

Practice Implications

It is fascinating how much the concept of the human gut as an “ecosystem” has come into vogue with the investigation of the gut microbiota’s effects on just about everything in recent years. It is rather satisfying to see this trend since “treat the gut” has been a common refrain in naturopathic medicine for decades.

Perhaps we can now effectively harness the power of the gut microbiome to improve outcomes in our patients with type 2 diabetes. Or perhaps we have been doing that for years without knowing? Like a kid in the back of a car, I find myself asking, “Are we there yet?” Can we give a patient with type 2 diabetes a probiotic supplement or an herb to shift their gut microbiota to exert a positive effect on glycemic control?

Two earlier reviews that addressed this topic essentially concluded that we were not there yet.1,2 Animal studies appeared promising, but human data were lacking, and the studies were conflicting. However, the current human study does support the idea that shifting the human gut microbiota is a viable way to improve glycemic control.

Perhaps we can now effectively harness the power of the gut microbiome to improve outcomes in our patients with type 2 diabetes.

The common tools diabetics have to work with consist of diet, exercise, medication, supplements, stress control, etc. Perhaps we are now in the era when we are realizing that we had another valuable tool all along: the manipulation of the gut microbiota through botanical medicine.

Bodogai et al performed an interesting animal study on “healthy aged” mice and macaques.3 Their data showed that insulin resistance was provoked by the accumulation of 4BL cells in the gut. The 4BL cells were found to be related to changes in gut commensal bacteria and decreases in the bacterial metabolite known as butyrate. Butyrate is a familiar substance in naturopathic medicine and is sometimes utilized in “gut healing” plans for our patients.

The proliferation of 4BL cells was caused by interaction with C-C chemokine receptor 2 (CCR2)+ monocytes triggered by gut hyper-permeability and the resulting infiltration of endotoxins into the bloodstream. The gut hyper-permeability was triggered by the depletion of Akkermansia muciniphila and reduced butyrate concentration in the gut.

The interesting thing about the Bodogai et al study was that the resulting insulin resistance was reversible by supplementing the animals with Akkermansia muciniphila or using the antibiotic enrofloxacin (which increased the Akkermansia). Treatment with butyrate or antibodies to CCR2+ monocytes and 4BL cells also had the same effect.

In contrast to the Bodogai et al study, the current study under review found that, rather than directly giving a probiotic, you can use Scutellaria baicalensis in conjunction with metformin to shift the gut microbiota (specifically Lactobacillus and Akkermansia) in a direction that positively affects glycemic control and markers of inflammation. I would call this a “positive” medication/herb interaction. The fact that this medication/herbal combination also lowered gene expression of TNFα is another bonus given the inflammatory nature of diabetes.

About the Author

Bert Mathieson, ND, MA, RD, LD, CDE, is a naturopathic doctor, registered dietitian, and certified diabetes educator. He is the medical director at New Hampshire Natural Health Clinic in Bedford, New Hampshire. Mathieson is a general family practitioner and has special interests in diabetes, Lyme disease, and cancer. He is a member of the Oncology Association of Naturopathic Physicians (OncANP) and the International Lyme and Associated Diseases Society (ILADS). In his spare time he enjoys competing internationally in freestyle skateboarding and kayaking with his wife, Kitty.

References

  1. ­­Bordalo Tonucci L, Dos Santos KM, De Luces Fortes Ferreira CL, Ribeiro SM, De Oliveira LL, Martino HS. Gut microbiota and probiotics: focus on diabetes mellitus. Crit Rev Food Sci Nutr. 2017;57(11):2297-2309.
  2. Brunkwall L, Orho-Melander M. The gut microbiome as a target for prevention and treatment of hyper glycaemia in type 2 diabetes: from current human evidence to future possibilities. Diabetologia. 2017;60(6): 943-951.
  3. Bodogai M, O’Connell J, Kim K, et al. Commensal bacteria contribute to insulin resistance in aging by activating innate B1a cells. Sci Transl Med. 2018;10(467):eaat4271.