2-deoxy-D-glucose mitigates Citrobacter rodentium and dibenzazepine-induced gastrointestinal damage and colitis: novel implications of 2-DG polypharmacopea

Abstract

Purpose

Citrobacter rodentium (CR) infection coupled with blocking Notch/Wnt signaling via γ-secretase inhibitor dibenzazepine (DBZ) disrupts the gastro-intestinal (GI) barrier and induces colitis, akin to ionizing radiation (IR)-induced GI-injury. We investigated the effects of 2-deoxy-D-glucose (2-DG) to ameliorate the CR-DBZ-induced GI damage.

Materials and methods

NIH:Swiss outbred mice were inoculated with 10⁹CFUs of CR orally. DBZ was administered intraperitoneally (10 μM/kg b.wt; for 10 days 2 days post-CR infection). Mice were fed with 0.4% 2-DG (w/v) daily in drinking water. For microbiota depletion, antibiotics (Abx), 1 g/l metronidazole, and 0.2 g/l ciprofloxacin were administered for 10 days in drinking water. Oxidative stress, survival assay, colonic crypt hyperplasia, Notch/Wnt downstream signaling, immunomodulation, and bacterial dysbiosis were measured.

Results

We show that real-time visualization of reactive oxygen species (ROS) is similar during CR-induced colonic infection and IR-induced GI-damage. The histology revealed that dietary 2-DG mitigates CR + DBZ-induced colitis and improves survival compared with CR + DBZ alone. These changes were phenocopied in Abx-treated mice. Both 2-DG and Abx reduced dysbiosis, increased proliferation, inhibited pro-inflammatory response, and restored Hes-1 and β-catenin protein levels, in the crypts.

Conclusion

The energy disruptor 2-DG mitigates bacterial infection and its responsive hyperplasia/colitis, indicating its utility as a mitigator of infection/IR-induced GI-damage.

Keywords:

• Transmissible murine crypt hyperplasia
• dibenzazepine
• 2-deoxy-D-glucose
• Citrobacter rodentium
• inflammation
• dysbiosis

Acknowledgements

RVLP acknowledges NCI-SBIR for the support by the NIH.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

All data generated and analyzed during this study are included in this published article.

Additional information

Funding

This work was supported by the NCI-SBIR grant [NCI 75N91019C000043 and 75N91019C000016].

Notes on contributors

Ishfaq Ahmed

Dr. Ishfaq Ahmed is an Assistant Professor at Kansas City Kansas Community College and the experimental work was conducted during his stay in Dr. Umar’s lab.

Amit Verma

Dr. Amit Verma is an expert radiobiologist at PACT & Health and involved in the scientific and medical writing.

Shahid Umar

Dr. Shahid Umar is a Professor in the Department of Surgery at University of Kansas Medical Center and an expert on elucidating mechanisms of signal transduction in response to bacterial infection.

Rao V. L. Papineni

Dr. Rao V. L. Papineni is an Adjunct Faculty member of KUMC and CEO of PACT & Health. He is an expert in the fields of molecular pathophysiology and translational theranostics. Dr. Papineni is the earliest proponent of infection/Radiation-injury similarities and the use of 2-DG for the COVID-19 management.