Pharmacological hypothesis: A recombinant probiotic for taming bacterial β‐glucuronidase in drug‐induced enteropathy

Abstract

Advances in pharmacomicrobiomics have shed light on the pathophysiology of drug‐induced enteropathy associated with the therapeutic use of certain non‐steroidal anti‐inflammatory drugs, anticancer chemotherapies and immunosuppressants. The toxicity pathway results from the post‐glucuronidation release and digestive accumulation of an aglycone generated in the context of intestinal dysbiosis characterized by the expansion of β‐glucuronidase‐expressing bacteria. The active aglycone could trigger direct or indirect inflammatory signaling on the gut epithelium. Therefore, taming bacterial β‐glucuronidase (GUS) activity is a druggable target for preventing drug‐induced enteropathy. In face of the limitations of antibiotic strategies that can worsen intestinal dysbiosis and impair immune functions, we hereby propose the use of a recombinant probiotic capable of mimicking repressive conditions of GUS through an inducible plasmid vector.

Estrobolome and Hepatocellular Adenomas—Connecting the Dots of the Gut Microbial β-Glucuronidase Pathway as a Metabolic Link

“…This is the most frequently observed mechanism leading to the gastrointestinal side effects caused by certain non-steroidal anti-inflammatory drugs (like diclofenac or indomethacin) or chemotherapy drugs (such as regorafenib or irinotecan). It involves enterohepatic recirculation and the enzymatic activity of gut microbiome β-glucuronidase overgrowth [55]. In another recent study by Bhatt et al, it was demonstrated that pharmacological intervention on the bacterial β-glucuronidase species proved to be helpful for irinotecan tolerance by reducing the gastrointestinal toxic side effects.…”

“…The GUS may represent a modifiable factor. Additionally, the inhibition of the enzymatic activity of such species could contribute to better chemotherapy outcomes with fewer adverse effects, thereby affecting the efficacy and adherence to such treatment in pancreatic or colorectal cancer patients [55,56].…”

“…In terms of novel and future approaches and manipulation of microbiota, the concept of pharmaco-microbiomics is evolving; it comprises the complex study of microbiome interactions with the bioavailability, toxic adverse effects, and bioactivity of various drugs. The perspective of pharmacomicrobiomics addresses genomics, pharmacologic, and microbiologic aspects of this special relationship between medication and gut microbiota [55].…”

Limosilactobacillus reuteri in immunomodulation: molecular mechanisms and potential applications

“…Probiotics colonize and regulate the unbalanced microflora of the host, directly acting on host epithelial and immune cells and regulating the epithelial or immune cells of specific tissues of the host through their metabolites in situ or by entering the circulation and remodeling the microenvironment of the lesion site ( 2 ). Unlike drugs, probiotics are associated with less side-effects, such as intestinal ecological disorder and immune dysfunction ( 3 ). Various forms of probiotic preparations are available.…”