October 13, 2022 | A team of Swedish researchers from Uppsala and Lund Universities performed the world’s most extensive and detailed association study between the gut microbiome and their production of plasma metabolites. They compiled their findings into a public and interactive atlas, helping scientists perform future studies concerning the microbiome and its impact on human health.
The gut microbiome—a collection of microorganisms in the gastrointestinal tract—has consistently garnered a great deal of attention due to its production of metabolites. Metabolites are relatively small molecules formed when microbes break down food or other substances in the intestines. Many metabolites are released into the bloodstream, making their way to other organs, and eliciting a cascade of downstream reactions.
It is well known that metabolites play a significant role in human health and wellness, but scientists have struggled to pinpoint the specific microbes that produce certain metabolites and why.
Determined to create a strong link between the two concentrations, the Swedish team used 8,583 fecal and blood samples to characterize the interactions between the gut microbiome and plasma metabolome: a host’s complete collection of metabolites in the blood.
The team retrieved fecal and blood samples from participants enrolled in the Swedish CArdioPulmonary bioImage Study (SCAPIS). SCAPIS is a population study funded by the Swedish Heart-Lung Foundation to initially procure measurements, calculate risk, and develop preventative measures for cardiopulmonary disease. With the help of SCAPIS, the Uppsala and Lund teams had data from over 30,000 participants at their disposal.
Published in Nature Communications (DOI: 10.1038/s41467-022-33050-0), the team used deep metagenomic sequencing to characterize the microbial communities taxonomically and functionally. Then, they compared their findings to the DNA sequences of known microbes.
Using a combination of ultra-high-performance liquid chromatography and mass spectrometry, the team identified 1,528 species of bacteria, archaea, and eukaryotes, with each sample containing an average of 325 species and 1,153 metabolites.
After mapping individual microbial genes, the team linked 1,295 plasma metabolites to 90 unique microbial functions. Generally, gut microbes are responsible for breaking down macromolecules, like amino acids (protein) and carbohydrates (sugar), to assist with human digestion and metabolism. Metabolites are often the byproducts of these reactions, holding the potential to promote wellness or disease, depending on the host’s internal milieu.
For example, the team observed a significant association between the bacteria in the Eubacteriales order and the metabolite p-cresol, a uremic toxin. These bacteria produce p-cresol after breaking down the amino acid tyrosine. P-cresol is also found in high concentrations among patients diagnosed with renal disease. Furthermore, healthy mice inoculated with the microbial content of the renal patients also demonstrated high p-cresol levels.
Conversely, several strains of Faecalibacterium prausnitzii were associated with low levels of p-cresol, and patients suffering from renal diseases often contain low concentrations of this species. The team postulates that increased F. prausnitzii concentrations in the gut could reduce uremic toxins and delay kidney disease progression.
Exogenous Influences on the Gut Microbiota
When the microbiome becomes unbalanced—where pathogenic microbes outnumber their symbiotic counterparts in a condition called dysbiosis—it creates an internal environment ripe for disease (Nature Reviews Microbiology, DOI: 10.1038/s41579-020-0433-9).
A portion of the team’s study included testing various exogenous substances, such as medication and food, to determine how those elements affect individual species in the gut.
“Earlier studies have shown that the large bacterial community in our digestive system produce a variety of molecules, with the potential to enter the bloodstream and to impact our health,” said Tove Fall, Science for Life Laboratory and Uppsala University Department of Medical Sciences molecular epidemiology professor, in a press release. “Conversely, medication or dietary components may affect the microbiota composition before entering the circulation. Characterization of these interactions is an important step towards understanding the effects of the gut microbiota on health.”
Omeprazole is a common drug and protein pump inhibitor (PPI) designed to decrease stomach acid production to mitigate symptoms of acid reflux and other reflux diseases. The team discovered that patients with omeprazole in their system demonstrated high concentrations of Veillonella and Streptococcus genera—traditionally a component of the oral flora—as a part of their gut microbiota.
The researchers also measured patients with significant concentrations of metformin—an anti-diabetic drug—and found that increased metformin levels were associated with high Escherichia marmotae and E. coli levels as well as low Romboutsia timonensis, Intestinibacter sp., and Intestinibacter bartlettii levels.
Additionally, increased coffee intake was associated with high concentrations of S. salivariusa and bacteria from the Eubacteriales order, known competitors of the pathogenic strains of the genus Streptococcus. While the team acknowledges that more studies are needed in this area, their findings suggest that coffee—one of the most consumed beverages worldwide—can alter gut microbiota composition and indirectly ward off pathogenic bacteria.
To share their work, the team created a public, interactive, and searchable online atlas—the GUTSY Atlas—to help researchers pinpoint plasma metabolite biomarkers for microbial species, especially in patients who experience adverse health effects due to acute dysbiosis. The atlas is hosted on a public website by SciLife Data Centre, an institution focusing on the Swedish advancement of biomolecular sciences.
“The large number of samples containing high-quality data allowed us to identify many novel associations. We have therefore chosen to publish all of our findings in an online open resource for the research community to use for their varying needs,” said Koen Dekkers, Uppsala University lead author.
As the team compiles more information, they hope the atlas will be used in future studies, helping scientists to understand the microbiota's influence on specific aspects of human health. Even now, it can be used as a diagnostic and therapeutic tool for patients with renal disease, guiding clinicians to treat certain conditions with designer microbial strains.