Diabetes Drug Helps Patients by Modifying the Microbiome
Tuesday, December 11, 2018
IRP investigators and their collaborators have discovered that the widely used diabetes drug metformin works by altering the gut microbiome.
The more scientists have learned about the community of benign bacteria inside our bodies, known as the microbiome, the more effort they have put into recruiting it in the fight against disease. What’s more, scientists occasionally discover that treatments long thought to work completely independently of our native microbes also relieve symptoms by interacting with them. New IRP research into the most commonly used medication for type 2 diabetes has led to just such a revelation by demonstrating that its benefits stem in part from its ability to kill off a particular species of bacteria in the human digestive tract.1
Patients with type 2 diabetes cannot adequately control the amount of sugar, or glucose, in their blood. The resulting chronically high blood sugar can eventually cause numerous problems, including cardiovascular disease and nerve damage. A drug called metformin is typically the first prescribed to lower blood sugar in these patients. Most studies of metformin suggest that it works by altering the way the liver produces glucose, but the question is far from settled.
“Most of those studies are done in cell culture, not in animals or humans, so there’s been a huge controversy surrounding the mechanism by which metformin works,” says IRP senior investigator Frank J. Gonzalez, Ph.D., the senior IRP author on the study.
In fact, evidence has recently emerged that metformin can alter the gut microbiome and that this change likely contributes to the drug’s effects on blood sugar.2 However, the causal link between an altered microbiome and lower blood sugar remained a mystery.
To solve this riddle, Dr. Gonzalez’s collaborator, Dr. Changtao Jiang of Peking University in Beijing, China, organized a clinical study to administer metformin to patients recently diagnosed with type 2 diabetes who had never taken the medication before. The researchers then analyzed pre- and post-treatment stool samples from the patients to identify the types and amounts of bacteria living in their digestive tracts. Just three days of metformin treatment dramatically lowered the number of bacteria in the gut from a group called Bacteroides, particularly a species called Bacteroides fragilis, or B. fragilis for short.
In addition, after metformin treatment, the patients’ blood and stool contained more of a chemical called glycoursodeoxycholic acid (GUDCA), which belongs to a class of molecules called bile acids that play important roles in digestion and other metabolic processes. The higher GUDCA levels, Dr. Gonzalez’s and Dr. Jiang’s groups discovered, were directly related to the decrease in B. fragilis because those bacteria convert GUDCA into a different molecule. The researchers also revealed that GUDCA inhibits a protein called the farnesoid X receptor (FXR) found in the digestive system and liver and known to be involved in multiple metabolic diseases like type 2 diabetes and non-alcoholic fatty liver disease3,4. Prior studies had shown that intestinal FXR activation increases the body’s production of fatty acid molecules called ceramides that contribute to metabolic disease when present at high levels4,5. All together, these results suggest that metformin alleviates diabetes symptoms by killing off B. fragilis, which decreases FXR activation and the resulting production of ceramides by boosting levels of FXR-inhibiting GUDCA.
“There’s a huge field that examines the effects of gut microbiota, but it’s largely descriptive — there’s no mechanism,” Dr. Gonzalez says. “This is one of the first studies to show, using a drug that’s been used in humans for 50 years, that gut bacteria can be changed by a drug other than an antibiotic, and that this causes a favorable metabolic effect.”
In additional experiments, after clearing mice’s intestines of bacteria using antibiotics, the researchers implanted them with stool samples taken from some of the patients either before or after the patients were given metformin, a process known as a fecal transplant. Mice given post-metformin fecal transplants had much lower levels of B. fragilis in their guts than mice given pre-metformin transplants, and they also had lower levels of intestinal FXR activation, confirming that metformin’s effects on the gut microbiome quiet intestinal FXR. Giving GUDCA to obese mice also reduced FXR activation in the gut and improved their metabolic problems.
Dr. Gonzalez’s lab is now working to identify other compounds that block FXR in the gut. Some of the intestinal FXR inhibitors his team has developed are being tested by a biotech company as potential therapies for metabolic disorders.
“I think there’s great translational potential for this work,” Dr. Gonzalez says, “It has important implications for developing new drugs and the potential for modifying the gut bacteria and its derived metabolites as a mechanism for treating metabolic diseases.”
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 Gut microbiota and intestinal FXR mediate the clinical benefits of metformin. Sun L, Xie C, Wang G, Wu Y, Wu Q, Wang X, Liu J, Deng Y, Xia J, Chen B, Zhang S, Yun C, Lian G, Zhang X, Zhang H, Bisson WH, Shi J, Gao X, Ge P, Liu C, Krausz KW, Nichols RG, Cai J, Rimal B, Patterson AD, Wang X, Gonzalez FJ, Jiang C. Nat Med. 2018 Nov 5. doi: 10.1038/s41591-018-0222-4.
 Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug. Wu H, Esteve E, Tremaroli V, Khan MT, Caesar R, Mannerås-Holm L, Ståhlman M, Olsson LM, Serino M, Planas-Fèlix M, Xifra G, Mercader JM, Torrents D, Burcelin R, Ricart W, Perkins R, Fernàndez-Real JM, Bäckhed F. Nat Med. 2017 Jul;23(7):850-858. doi: 10.1038/nm.4345.
 FXR signaling in the enterohepatic system. Matsubara T, Li F, Gonzalez FJ. Mol Cell Endocrinol. 2013 Apr 10;368(1-2):17-29. doi: 10.1016/j.mce.2012.05.004.
 An Intestinal Microbiota–Farnesoid X Receptor Axis Modulates Metabolic Disease. Gonzalez FJ, Jiang C, Patterson AD. Gastroenterology. 2016 Nov;151(5):845-859. doi: 10.1053/j.gastro.2016.08.057.
 An Intestinal Farnesoid X Receptor-Ceramide Signaling Axis Modulates Hepatic Gluconeogenesis in Mice. Xie C, Jiang C, Shi J, Gao X, Sun D, Sun L, Wang T, Takahashi S, Anitha M, Krausz KW, Patterson AD, Gonzalez FJ. Diabetes. 2017 Mar;66(3):613-626. doi: 10.2337/db16-0663.