Stool samples show microbial enzyme driving bowel disease

Jan. 31, 2022

Researchers at University of California San Diego School of Medicine have identified a class of microbial enzymes that drive ulcerative colitis and have demonstrated a potential route for therapeutic intervention, according to a news release from the university.

The study was published in Nature Microbiology.

Ulcerative colitis, a subtype of inflammatory bowel disease, is a chronic ailment of the colon affecting nearly one million individuals in the United States. It is thought to be linked to disruptions in the gut microbiome — the bacteria and other microbes that live inside us — but no existing treatments actually target these microorganisms.

“Studies continue to show correlations between gut health and microbial constituents, but these trends don’t exactly explain how the bacteria cause disease or what we can do about it,” said study co-senior author David J. Gonzalez, PhD, Associate Professor of Pharmacology at UC San Diego School of Medicine and Skaggs School of Pharmacy and Pharmaceutical Sciences. “This is the first study with experimental evidence that pinpoints a specific microbe driving ulcerative colitis, the protein class it expresses, and a promising solution.”

Researchers hypothesize that ulcerative colitis may be triggered by bacterial proteases that damage the colonic epithelium and allow an influx of immune cells to drive further inflammation.

Gonzalez and his collaborators are leaders in multi-omics — an approach that combines state-of-the-art genomics, proteomics, metabolomics, and peptidomics to uncover the contents of a biological sample with unprecedented detail. The process of “digitizing” a sample allows the team to examine its biology at multiple scales and develop new hypotheses of disease progression.

To study the gut microbiome, researchers said the most useful biological sample is patient stool. It is also far less invasive to collect than more traditional blood or tissue samples.

The team found that roughly 40% of ulcerative colitis patients show an overabundance of proteases — enzymes that break down other proteins — originating from the gut resident Bacteroides vulgatus. They then showed that transplanting high-protease feces from human patients into germ-free mice induced colitis in the animals. However, the colitis could be significantly reduced by treating the mice with protease inhibitors.

The team suggested that a stressor in the gut, such as nutrient deprivation, may increase protease production in an attempt to use proteins as an alternative nutrient source. However, these bacterial proteases may be damaging to the colonic epithelium or lining of the colon, allowing an influx of immune cells to then further exacerbate the disease.

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