WINSTON-SALEM (NC) – Why do orally-administered drugs for diabetes work for some people but not others?According to researchers at Wake Forest School of Medicine, bacteria that make up the gut microbiome may be the culprit.
In a review of more than 100 current published studies in humans and rodents, the School of Medicine team examined how gut bacteria either enhanced or inhibited a drug’s effectiveness. The review is published in the Dec.11 edition of the journal eBiomedicine (DOI: 10.1016/j.ebiom.2018.11.046).
“For example, certain drugs work fine when given intravenously and go directly to the circulation, but when they are taken orally and pass through the gut, they don’t work,” said Hariom Yadav, Ph.D., assistant professor of molecular medicine at the School of Medicine, a part of Wake Forest Baptist Medical Center.
“Conversely, metformin, a commonly used anti-diabetes drug, works best when given orally but does not work when given through IV.”
The review examined interactions between the most commonly prescribed anti-diabetic drugs with the microbiome. Before being absorbed into the bloodstream, many orally-administered drugs are processed by intestinal microbial enzymes. As a result, the gut microbiome influences the metabolism of the drugs, thereby affecting patients’ responses, Yadav said.
Type-2 diabetes, a disease characterized by carbohydrate and fat metabolism abnormalities, has recently become a global pandemic. One main function of gut microbiota is to metabolize non-digestive carbohydrates and regulate a person’s metabolism.
“Our review showed that the metabolic capacity of a patient’s microbiome could influence the absorption and function of these drugs by making them pharmacologically active, inactive or even toxic,” he said. “We believe that differences in an individual’s microbiome help explain why drugs will show a 90 or 50 percent optimum efficacy, but never 100 percent.”
The researchers concluded that modulation of the gut microbiome by drugs can represent a target to improve, modify or reverse the effectiveness of current medications for type-2 diabetes. However, currently there aren’t ways to do that.
“This field is only a decade old, and the possibility of developing treatments derived from bacteria related to or involved in specific diseases is tantalizing,” Yadav said.
Co-authors are Andrew Whang, M.D., and Ravinder Nagpal, Ph.D., of Wake Forest School of Medicine.
Funding for the review was provided by the Center for Diabetes, Obesity and Metabolism, the Center of Cardiovascular Sciences, the Claude D. Pepper Older Americans Center and the Clinical and Translational Science Center at Wake Forest Baptist Medical Center, as well as the U.S. Department of Defense PR170446.
Xavier Gruffat, pharmacist, from Creapharma.com could interview Hariom Yadav in December 2018:
Creapharma.com – In the press release you mentioned that metformin works best when given orally but does not work when given through IV,could you explain the reasons of this interesting difference, perhaps in termof metabolism?
Harom Yadav – This is because, metformin manipulate microbiome and the bacteria that increased after metformin treatment have several beneficial effects, for example, (1) Increased Akkermansiamuciniphila is known to be anti-inflammatory (inflammation is high in obesityand diabetes that contributes to insulin resistance), and (2) metformin treatment increases beneficial metabolites like short chain fatty acids i.e.acetate, propionate and butyrate, that are known to improve diabetes and obesity.
Did you notice an anti-diabetic drug that is almost the opposite as metformin,namely works when given through IV but does not work well when givenorally?
So-far not 100% sure, there is any example. Normally, oral route is preferential route for developing any pharma drugs, however, due to limitations of the nature of drugs, other routes of administrations are adopted. For example, anti-diabetic drugs like insulin and GLP-1 agonists are given IV/IP, because they are in proteinacious in nature andmost likely will be digested if given orally. However, the response of GLP-1agonists and insulin treatments varies a lot from person-to-person, because one person might have different gut microbiome than others but on the same time eats different diets. It is complex interaction among drugs-host-microbiome-diets for regulating blood glucose and metabolism, andcan go both directions, meaning drug impacting host metabolism can impact gut microbiome, but on the same time gut microbiome changes can impact the response of drug to reduce blood glucose and other metabolic functions.
Did you notice some important differences between classes of anti-diabetic drugs like GLP-1 receptoranalogues (e. g. exenatide, liraglutide, dulaglutide, semaglutide,lixisenatide) or DPP-4 inhibitors (e.g. alogliptinum) or even insulin and the impact of the microbiome?
It’s an interesting question, so far not known, but we are investigating this in our current experiments.
Is there some tips people taking anti-diabetic drugs could follow to reduce the impact of the microbiome like taking probiotics?
Yes, there are evidences that each individual glycemic index is different for same food, because of differences in their gut microbiome. There is a new tool recently launched (called: DayTwo: https://www.daytwo.com/) that gives an idea for people how they can control better their blood glucose,while feeding right things to their gut microbiome and have drugs more effective.
December 13, 2018 (Update: May 20, 2020). By Xavier Gruffat. Source: Press relase and interview with Harom Yadav (by e-mail on December 12 and 13, 2018). Reference:
eBiomedicine (DOI: 10.1016/j.ebiom.2018.11.046). Picture: Adobe Stock.