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Gut Microbiome Makeup Influenced by Medication Use, Other Factors

NEW YORK (GenomeWeb) – Medications and other factors influence the makeup of people's gut microbiomes, according to pair of studies appearing in Science today.

In two separate studies, a Dutch-led team and a Belgian-led team of researchers examined physiological, biomedical, and environmental factors that affect the composition of the gut microbiomes of thousands of people. Both groups found that a number of factors such as age, gender, and diet can affect the gut microbiome composition to varying degrees, but that medications — especially antibiotics — had the greatest influence on the bacteria present.

"Our research has given us a tremendous amount of new insight into the microbiota composition of normal people like you and me," Jeroen Raes, KU Leuven researcher and the senior author of the Belgian study, said in a statement. "You need to understand what's normal before you can understand and treat disease."

In the first study, a University of Groningen-led team performed deep sequencing on stool samples collected from 1,135 Dutch individuals taking part in the LifeLines program. At the same time, the researchers amassed data from these individuals on some 207 factors from milk consumption to medication use to levels of neuroendocrine system activation marker chromogranin A, to correlate with the sequencing results.

The most dominant bacteria phyla the researchers uncovered in their cohort were Firmicutes and Bacteroidetes, but they noted high inter-individual variation. Some three dozen of the factors the researchers examined were associated with microbial diversity, 31 with richness, and 34 with functional richness.

Age and gender, the Groningen-led team noted, were linked with microbial composition distance and diversity, and with functional richness — women had higher richness, and such richness increased with age.

Diet also influenced microbial diversity in the gut. The researchers reported that people who ate more yogurt or drank buttermilk had greater gut bacterial diversity, while drinking whole milk or a high-calorie diet decreased diversity.

"In total, we found 60 dietary factors that influence the diversity [of the gut microbiome]. What these mean exactly is still hard to say," first author and Groningen researcher Alexandra Zhernakova said in a statement. "But there is a good correlation between diversity and health: greater diversity is better."

As expected, antibiotic use also affected the makeup of the microbiome, the researchers reported, noting significant decreases in two species belonging to the Bifidobacterium genus. Less expected, they also found that other medications such as proton-pump inhibitors, metformin, and statins affected its composition as well. For instance, PPI users exhibited changes to 33 bacterial pathways, including 2,3-butanediol biosynthesis, while those taking metformin had an increased abundance of Escherichia coli and correlated with the D-glucarate and D-galactarate and pyruvate fermentation pathways.

Low levels of CgA, that marker of neuroendocrine system activation, were linked with higher diversity, higher functional richness, and increased consumption of fruits and vegetables, the researchers found. Elevated CgA levels, meanwhile, were linked with high fecal levels of calprotectin, high blood triglyceride levels, and self-reported irritable bowel syndrome. They also noted a negative association between CgA abundance and the levels of a number of Bacteroidetes species.

This, Zhernakova and her colleagues said, suggests that fecal CgA levels could be used as a marker of gut health.

The Belgian team, meanwhile, collected 1,106 stool samples from the Belgian Flemish Gut Flora Project and analyzed them using 16S ribosomal RNA gene amplicon sequencing. They validated their results using the Dutch gut microbiome cohort. The Belgian team also gathered data on participants' health and lifestyle.

They noted that the Belgian and Dutch cohorts together encompass a total richness of 664 genera, 17 of which appear to represent a core microbiome. By folding in additional data on 308 samples collected from Papua New Guinea, Peru, and Tanzania, they whittled that core microbiome down to 14 genera. Inter-individual variation in gut microbiome composition, they reported, is mostly due to fluctuations in the relative abundance of these core microbes.

They also tested the effect of 503 variables on microbiome makeup, finding that 69 of these correlated with overall community variation. Of the 26 of these variables that had analogs in the Dutch study, 24 could be validated.

"Such replication adds a tremendous amount of robustness to the results," senior author Raes said.

He and his colleagues found, for instance, that stool consistency and transit time as well as age and gender influence gut microbiome composition. Diet also influenced what microbes were present — they noted an association between beer and chocolate consumption and gut flora.

But medication, they found, had the largest explanatory power on gut microbiome composition, reflecting what the Dutch study also reported.  

Antibiotic use, particularly of β-lactams, affected what was present in the gut microbiome, but so did benzodiazepines, antidepressants, and antihistamines, the researchers found. Some 63 percent of the covariate interactions they detected were driven by medication, suggesting that medication use should be taken into account in clinical studies.