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Review
. 2023 Nov 1;39(6):472-478.
doi: 10.1097/MOG.0000000000000972. Epub 2023 Aug 29.

Intestinal proteases

Sameer Rao  1   2 , Madhusudan Grover  1
Affiliations
Review

Intestinal proteases

Sameer Rao et al. Curr Opin Gastroenterol. .

Abstract

Purpose of review: Proteases constitute a group of enzymes that hydrolyze peptide bonds. Intestinal proteases are an integral part of gut homeostasis and digestion. This review discusses the broader classification of proteases, regulation of proteolytic activity (PA) in the intestinal tract, and how dysregulation of intestinal proteases contributes to the pathophysiology of conditions such as irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), and celiac disease. We also discuss recent advancements in therapeutic modulation that directly or indirectly target intestinal proteases and can be utilized to treat these illnesses.

Recent findings: Host and microbiota derived proteases have been associated with symptoms in subsets of patients with IBS, IBD and celiac disease. Elevated PA mediates barrier dysfunction, visceral hypersensitivity as well as immune activation and inflammation. Recent mechanistic studies have revealed the nature of disease-associated proteases and mechanisms regulating their activity, particularly those driven by the microbiota. Advancements in activity-based probes have allowed novel ways of in vivo imaging of PA. Newer strategies targeting proteases include monoclonal antibodies, engineered microbiota as well as specific protease inhibitors.

Summary: Significant progresses made in the detection as well as regulation of PA is likely to provide therapeutic advancements for gastrointestinal diseases.

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Conflict of interest statement

Dr. Grover has received research grants from Takeda, Donga, Alexza and Alfasigma pharmaceuticals and advisory fee from Evoke pharmaceuticals. None to report for Dr. Rao.

Figures

Figure 1:
Figure 1:. Source of proteases in the gastrointestinal tract.
Both luminal and mucosal sources contribute to the proteases which can have variable effects on gastrointestinal function (secretory, sensory and barrier properties).
Figure 2:
Figure 2:. Regulation of proteolytic activity and resulting effects on intestinal function.
Intestinal microbiota interfaces with the proteases with key commensal microbes playing a role in suppression of the PA through their β-glucuronidases. In contrast, members of a dysbiotic microbial community can produce deleterious proteases. An elevated luminal or mucosal PA can have varying effects on barrier, sensory-motor and immune functions in the intestinal tract.
See this image and copyright information in PMC

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    2. * Our work demonstrating commensal microbiota-based regulation of PA. Unconjugated bilirubin produced via microbial β-glucuronidase activity inhibits serine proteases.

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