We are only just beginning to understand how drugs affect our microbiome, and vice versa. The impact of antibiotics on the gut microbiota has been well studied but during the last decade, studies in population-based cohorts have found relationships between commonly used non-antibiotic drugs and the gut microbiota.
For instance, commonly used drugs such as proton pump inhibitors, osmotic laxatives, inflammatory bowel disease medication, female hormones, anxiolytics, antidepressants, antihistamine and opioids influence both gut microbiota composition and function.
In the context of microbiome studies looking at metabolic diseases or conditions, changes in the composition of the gut microbiota and bile acid levels have been involved not only in the hyperglycemia-lowering action of metformin, but also in its gastrointestinal side effects. However, the extent to which the metabolic benefits of other drugs including statins is mediated by the gut microbiota remains elusive.
Writing in Nature, Vieira-Silva and colleagues report a decrease in gut microbes associated with inflammation in individuals with obesity associated with the use of statin drugs.
It has been suggested that human gut microbiomes may fall into four distinct types or enterotypes depending on the abundance of particular microbial species called Bacteroides 1, Bacteroides 2, Prevotella and Ruminococcaceae. Based on this classification approach, the authors explored enterotype data for 888 individuals with different degrees of obesity who were recruited as part of the European Union-funded MetaCardis project.
The gut microbiota of individuals with obesity classified into one of four enterotypes (i.e. Bacteroides 1, Bacteroides 2, Ruminococcaceae and Prevotella). The surprising observation made by the researchers was that while the Bacteroides 2 enterotype was more frequent in people with a higher body mass index, it was lower than expected in individuals with obesity who were taking statins (comprising about 12% of those studied). This observation was also confirmed in an independent data set from the Flemish Gut Flora Project.
This enterotype was previously found to be increased in patients with primary sclerosing cholangitis and inflammatory bowel disease and, compared with individuals with other enterotypes, it has also been linked to a lower load of gut microbes and higher inflammatory markers.
These findings, however, do not capture the situation for all those with obesity, with the lower prevalence of the Bacteroides 2 enterotype only found in 5.9% of the population who were obese and taking statins, compared with their counterparts with obesity who were not taking statins (17.7% of the obese population).
Rather than being a discrete group, the authors report that the Bacteroides 2 enterotype consists of a mix of gut bacteria characterized by a low microbial load and a paucity of butyrate producers. Butyrate is involved in maintaining hypoxic conditions within the colon environment, it contributes to avoiding an altered gut microbiota composition, and has been involved in keeping at bay systemic inflammation of the body, which is a common hallmark in obesity and metabolic syndrome.
To sum up, this is the first study in a large cohort reporting statins as a relevant confounding factor in explaining an obesity-associated gut microbiota. Due to the cross-sectional design of the study, these findings cannot confirm whether the decrease in Bacteroides 2 enterotype is directly caused by statins or can be explained by another factor associated with statin use (for instance, it could be that those taking statins have a better diet and lifestyle).
At this point, gut microbes’ contribution to the known anti-inflammatory actions of statins that contribute to their clinical benefit remains to be seen in clinical trials, by exploring whether statins may lead to reduced levels of Bacteroides 2 enterotypes in individuals with obesity.
Weersma RK, Zhernakova A, Fu J. Interaction between drugs and the gut microbiome. Gut. 2020. doi: 10.1136/gutjnl-2019-320204.
Vieira-Silva S, Falony G, Belda E, et al. Statin therapy is associated with lower prevalence of gut microbiota dysbiosis. Nature. 2020. doi: 10.1038/s41586-020-2269-x.