The human microbiome is a fascinating thing, teeming with all sorts of microorganismal flora and fauna. Scientists often rely on stool samples to study the microbiome since those are readily available and easy to collect. However, stool may not provide the most reliable snapshots of the human microbiome (1). 

In research recently published in Nature, scientists at Stanford University, Envivo Bio, and the University of California, Davis developed a series of pills that take microbiome samples at various points as they travel through the gastrointestinal (GI) tract (2). When they sequenced the samples using multiple multiomic techniques, they discovered that the microbiome is vastly diverse even within one human being, and that even small changes in diet or antibiotic use can change the microbiome. The scientists hope that these findings will help determine how the human microbiome changes during health and disease. 

According to Dari Shalon, the chief executive officer of Envivo Bio, the different parts of the GI tract are “very different ecosystems, much like a desert to a rainforest.” To explore these various locales, “there really does need to be a device like the Magic School Bus that you swallow and goes through to collect [samples],” he added. 

Shalon and the team at Envivo Bio developed their own Magic School Bus: a pill-shaped capsule with a pH-sensitive outer layer that dissolves at a specific point in the GI tract. When the outer layer dissolves, a one-way valve pulls fluid into a small inflatable bladder that seals shut once it’s full. Because different points in the GI tract such as the small intestine and the stomach have different pHs, generating a variety of pills responsive to different pHs allowed the scientists to pull microbiome samples from specific points in the GI tract.  

To test the pills, the team recruited 15 healthy study participants to swallow four pills each (with each pill responding to a different pH) either twice daily or on two consecutive days. When they sequenced the RNA from these samples, they discovered that the microbiome varied considerably at different points in the GI tract and that stool sampling did not capture that variability. 

“There’s enormous potential as you think about how the environment is changing as you go down the intestinal tract,” said Kerwyn Casey Huang, a microbiologist at Stanford University and coauthor of the study. Identifying how something like diet or disease affects the variation in the individual microbiome “may even provide the potential to start discovering these important health associations,” he added. 

The scientists also detected which participants had previously taken antibiotics (approximately 1 and 5 months before the study, respectively), purely from the sequencing results. “We only found out that they were taking antibiotics because their data was so incongruous with everyone else,” said Jessica Grembi, a clinical microbiologist at Stanford University and study coauthor. Beyond seeing clear differences in the microbiome, they also found differences in bile acid composition, which is critical for digestion and absorption. These results, Grembi added, point to how the microbiome is critical for many processes including bile acid production, and that antibiotic use can potentially affect these processes even months down the line. 

“[This pill] is a unique technology that gets us information that we’ve long wanted,” said Cynthia Sears, a microbiologist at Johns Hopkins University who was unaffiliated with the study. She is interested in seeing how the pill can capture microbiome differences during a gastrointestinal disease like colon cancer. It’s an interest shared by Grembi, who hopes to use the pill to study malnutrition. Because the bacteria captured in the pill remain alive through the sampling process, the scientists want to see how these microorganisms work when cultured outside the body. 

While much more human testing is needed, the team is excited that swallowing a little pill can provide an in-depth look at the human gut. This technology “makes it natural to think about sampling from many places and many times from one person, and it makes that straightforward and inexpensive,” Huang said. 

References

1. Tang, Q. et al. Current Sampling Methods for Gut Microbiota: A Call for More Precise Devices. Frontiers in Cellular and Infection Microbiology  10, (2020).
2. Shalon, D. et al. Profiling the human intestinal environment under physiological conditions. Nature  617, 581–591 (2023).