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Shin NR, Gu N, Choi HS, Kim H. Combined effects ofScutellaria baicalensiswith metformin on glucose tolerance of patients with type 2 diabetes by modulating the gut microbiota.Am J Physiol Endocrinol Metab. 2020;318(1):E52-E61.
Study objective
The aim of this study was to determine whether combination treatment withScutellaria baicalensis(SB) and metformin could positively influence type 2 diabetes-related parameters by modulating gut microbiota.
Draft
This was a 20-week, double-blind, randomized, crossover study. Subjects were randomly assigned to 1 of the following 2 sequence groups: 1) SB + metformin in period 1, 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 participants “crossed over” to their next assigned sequence.
In the SB + metformin treatment period, 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) three times daily 30 minutes after meals for 8 weeks.
Participant
Twelve subjects completed this study and were included in the analysis. Participants were men and women between the ages of 20 and 75 who had been diagnosed with type 2 diabetes at least 3 months before the start of the study. They all took at least 500 mg of metformin daily and had a fasting blood glucose between 110 and 180 mg/dl or a glycated hemoglobin between 8.0 and 9.0.
Study parameters assessed
This study sought to evaluate changes in urine and serum biochemistry, oral glucose tolerance, and stool microbiota in treatment and placebo groups.
Primary outcome measures
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 insights
A statistically significant improvement in oral glucose tolerance was found in the combined SB/metformin group compared to the placebo group.
TNFα gene expression (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 reduced gene expression of IL-6 in the SB/metformin group, but the reduction was not statistically significant.
The stool samples from the SB/metformin group showed significantly lessBifidobacteriumand significantly moreLactobacilliandAkkermansiathan the stool samples from the placebo group.
Practice implications
It's fascinating how much the concept of the human gut as an "ecosystem" has become fashionable in recent years with the study of the effects of the gut microbiota on just about everything. It's very encouraging to see this trend, as "treating the gut" has been a common refrain in naturopathy 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 maybe we have been doing this for years without knowing it? Like a child in the backseat of a car, I ask myself, “Are we there yet?” Can we give a patient with type 2 diabetes a probiotic supplement or herb to alter their gut microbiota and have a positive effect on glycemic control?
Two previous reviews that addressed this topic essentially concluded that we weren't there yet.1.2Animal studies seemed promising, but human data were lacking and studies were conflicting. However, the current human study supports 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 usual tools that diabetics have to work with consist of diet, exercise, medications, supplements, stress control, etc. Perhaps we are now in the time where we realize that we have had another valuable tool all along: manipulating the gut microbiota through botanical medicine.
Bodogai et al. conducted an interesting animal study on “healthily aged” mice and macaques.3Their data showed that insulin resistance was caused by the accumulation of 4BL cells in the intestine. The 4BL cells were found to be linked to changes in commensal gut bacteria and a decrease in the bacterial metabolite known as butyrate. Butyrate is a well-known substance in naturopathy and is sometimes used in “gut healing” plans for our patients.
The proliferation of 4BL cells was caused by the interaction with CC chemokine receptor 2 (CCR2)+ monocytes, which was triggered by the hyperpermeability of the intestine and the resulting infiltration of endotoxins into the bloodstream. Intestinal hyperpermeability was triggered by the depletion ofAkkermansia muciniphilaand reduced butyrate concentration in the intestine.
The interesting thing about the study by Bodogai et al. was that the resulting insulin resistance was reversible by supplementing the animals withAkkermansia muciniphilaor with the antibiotic enrofloxacin (which theAkkermansia). Treatment with butyrate or antibodies against CCR2+ monocytes and 4BL cells also had the same effect.
In contrast to the study by Bodogai et al. The current study found that you can use a probiotic instead of giving it directlyScutellaria baicalensisin conjunction with metformin to shift the intestinal microbiota (in particularLactobacilliandAkkermansia) in a direction that has a positive effect on glycemic control and inflammatory markers. I would describe this as a “positive” drug-herb interaction. The fact that this drug/herb combination also decreased TNFα gene expression is an added bonus given the inflammatory nature of diabetes.