
January 16, 2025 I By Dave DeFusco
The human gut is a bustling ecosystem, home to trillions of microorganisms that play essential roles in maintaining health. These microbes influence everything from digestion to immunity and even drug metabolism. Among the myriad microbial enzymes at work in our gut, β-glucuronidases (GUS) have emerged as pivotal players in both the progression of cancer and the efficacy of its treatment.
A new review, “The Role of Gut Microbial β-glucuronidases in Carcinogenesis and Cancer Treatment: A Scoping Review,” published in the Journal of Cancer Research and Clinical Oncology and co-authored by Dr. Matthew Redinbo, professor of chemistry at UNC-Chapel Hill, takes a deep dive into the dual-edged role of GUS enzymes in carcinogenesis and chemotherapy, offering insights that could reshape oncology.
The gut microbiota, a complex community of bacteria, viruses, fungi and other microorganisms, is vital to human health. It metabolizes nutrients, detoxifies harmful substances and interacts with drugs; however, the gut microbiota’s role in cancer development and treatment is a double-edged sword. While it supports overall health, its enzymes—particularly GUS—can inadvertently activate carcinogens or significantly disrupt the effectiveness of chemotherapy drugs.
GUS enzymes, produced by various gut bacteria, remove glucuronic acid from compounds, a process known as deglucuronidation. This action can reactivate toxins and drugs, leading to unintended consequences. For instance, in cancer patients undergoing chemotherapy, GUS enzymes can exacerbate side effects by reactivating detoxified chemotherapeutic agents in the gut.
Dr. Redinbo and colleagues conducted a scoping review to explore the role of GUS in cancer and chemotherapy. Their analysis synthesized findings from more than a dozen studies, focusing on colorectal cancer (CRC) and the chemotherapy drug Irinotecan. The review highlighted three key areas:
- GUS and Carcinogenesis
Elevated GUS activity has been linked to colorectal cancer. CRC patients exhibit increased fecal GUS activity and distinct gut microbial compositions compared to healthy individuals. This suggests that GUS enzymes may facilitate the reactivation of carcinogens, contributing to cancer development. - GUS and Chemotherapy Toxicity
Irinotecan, a widely used chemotherapy drug, is metabolized in the liver and excreted as an inactive compound. In the gut, GUS enzymes can reactivate this compound, causing severe gastrointestinal side effects, including diarrhea and mucosal damage. These side effects limit the drug’s dosage and efficacy. - The Promise of GUS Inhibitors (GUSi)
The review underscores the potential of GUS inhibitors (GUSi) to mitigate Irinotecan’s side effects. By blocking GUS activity, these inhibitors protect the intestinal barrier, reduce toxicity and improve the tolerability of chemotherapy. In animal models, GUSi not only reduced side effects but also remarkably enhanced the anti-tumor efficacy of Irinotecan.
“This review’s findings are a call to action for the scientific and medical communities,” said Dr. Redinbo. “By targeting GUS enzymes, researchers have the potential to develop therapies that reduce the side effects of chemotherapy, improve patient outcomes and potentially prevent certain cancers.”
However, the review also highlights significant gaps in current knowledge:
- Scarcity of Human Studies
Most of the existing research is preclinical, with limited studies involving human participants. Cross-sectional studies investigating GUS activity in cancer patients are urgently needed. - Understanding GUS Diversity
GUS enzymes are not a monolithic group. They vary in structure and function, with some acting on complex carbohydrates and others on small molecules like drugs. Understanding this diversity is crucial for designing effective GUS inhibitors. - Expanding Beyond Colorectal Cancer
While the review focuses on CRC, the implications of GUS activity extend to other cancers, such as breast and ovarian cancers. High levels of estrogen, reactivated by GUS enzymes, are linked to estrogen receptor-positive cancers, suggesting a broader role for GUS in oncology.
Dr. Redinbo’s review is a pivotal step toward integrating microbiota research into oncology. It advocates for the development of targeted GUS inhibitors which could become a standard adjuvant therapy in chemotherapy, reducing toxicity and enhancing efficacy; clinical trials on humans to validate the safety and effectiveness of GUS inhibitors in cancer treatment; and holistic approaches to cancer therapy to understand the gut microbiota’s role in drug metabolism that could lead to personalized treatment strategies, optimizing drug efficacy while minimizing side effects.
“The gut microbiota is a powerful ally in health, but its enzymatic activity can also pose challenges in cancer treatment,” said Dr. Redinbo. “Our review sheds light on the intricate interplay between gut microbial GUS enzymes and chemotherapy, offering a roadmap for future research and clinical innovation. By harnessing the potential of GUS inhibitors, the medical community can take a significant step toward more effective and patient-friendly cancer therapies.”