New method discovers biomarker for inflammatory bowel disease

In recent years, microbiome research has begun to shift from the microbes themselves to the molecules they produce. After all, it is these molecules that directly interact with human cells to influence a person’s health. However, trying to identify which molecules are made by a person’s microbiome is a real challenge. A typical metabolomics study can only characterize approximately 10% of the molecular data in a human microbiome sample.

In a new study published in Nature, microbiome experts at the University of California, San Diego, are pioneering a new approach they call “reverse metabolomics.” The technique combines organic synthesis, data science and mass spectrometry to better understand which molecules are secreted by the microbiome and how they affect human health.

In their first application of inverse metabolomics, scientists discovered hundreds of molecules that had never before been observed in the human body. Using these new data, they were able to identify a new metabolomic signature for inflammatory bowel disease (IBD). The authors say these molecules could one day serve as a biomarker to diagnose IBD or as a potential therapeutic target to help treat the disease.

“We know that the microbiome is important, but we don’t know what types of molecules microbes produce or what influence they have on the human body,” said lead author Pieter C. Dorrestein, Ph.D., professor at the Skaggs School of Pharmacy and Pharmaceutical Sciences at UC San Diego. “Reverse metabolomics helps us assess whether specific molecules can be found in samples, predict which microbes produce them, and link these metabolomic signatures to health and disease.”

In a typical metabolomics study, researchers will use a tool called mass spectrometry to look for different molecules in a sample. In this technique, each molecule has its own “barcode” by which it can be identified. However, scientists need to know what these barcodes represent to describe the contents of a sample, which remains a challenge.

In the new study, Dorrestein Lab researchers took a retrospective approach. First author Emily C. Gentry, Ph.D., now an assistant professor at Virginia Tech, used organic synthesis to first produce thousands of different synthetic molecules from four classes of interest, then defined each of their barcodes.

The researchers then used publicly available metabolomics data, including those previously collected by the Crohn’s & Colitis Foundation, and searched for the new barcodes in this data. The results revealed that 145 of the synthesized bile acids were present in biological samples from public data, of which 139 had never been described before.

“If you read a biology textbook, none of these molecules will be there,” Dorrestein said. “Not only are they new to our understanding of human physiology, but they are also entirely new to science, which is quite astonishing.”

Gentry and colleagues then compared the metabolomic signatures of samples from different patient populations and discovered a strong association between a synthesized class of microbial molecules – bile amidates – and IBD. This association was then validated in several cohorts, supporting the idea that these molecules are probably involved in the pathology of IBD.

Upon closer inspection, scientists noticed that certain bile amidates were elevated in Crohn’s disease patients, particularly when they had active symptoms, but this was not the case for patients with ulcerative colitis. Models like these could one day be used to help differentiate and diagnose specific types of IBD.

Researchers then began to explore how these molecules might influence gut health. Additional experiments showed that several bile amidate compounds can promote intestinal inflammation by dysregulating T cell function. For example, one microbial compound produced a six-fold increase in a key cytokine known to be involved in pathogenesis. of Crohn’s disease.

“We use organic synthesis and data science to better understand how our bodies work at the molecular level,” Gentry said. “We are also one of the first studies to discover new human molecules using publicly available metabolomics data. As more metabolomics data becomes publicly available, reverse metabolomics will become even more informative.”

The authors say the molecules they described could one day inspire new therapies for treating IBD. For example, patients may be treated with pills containing live microbes that secrete specific molecules or drugs that inhibit the enzymes with which these disease-associated molecules interact.

“This is a remarkable achievement from our precision nutrition initiative, in which Dr. Dorrestein previously demonstrated that reverse metabolomics could identify dietary metabolites associated with disease severity in patients with IBD.” , said Andrés Hurtado-Lorenzo, Ph.D., president and vice president of Translational Research & IBD Ventures at the Crohn’s & Colitis Foundation. “Now, this groundbreaking work has progressed toward the discovery of new metabolites that show potential for diagnostic and therapeutic applications in IBD. »