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Prolong antibiotics; Gulf War Illness; TGF-β; miR-21; PTEN; Lachnospiraceae spp.; renal fibrosis








Gulf War (GW) veterans show gastrointestinal disturbances and gut dysbiosis. Prolonged antibiotic treatments commonly employed in veterans, especially the use of fluoroquinolones and aminoglycosides, have also been associated with dysbiosis. This study investigates the effect of prolonged antibiotic exposure on risks of adverse renal pathology and its association with gut bacterial species abundance in underlying GWI and aims to uncover the molecular mechanisms leading to possible renal dysfunction with aging. Using a GWI mouse model, administration of a prolonged antibiotic regimen involving neomycin and enrofloxacin treatment for 5 months showed an exacerbated renal inflammation with increased NF-κB activation and pro-inflammatory cytokines levels. Involvement of the high mobility group 1 (HMGB1)-mediated receptor for advanced glycation end products (RAGE) activation triggered an inflammatory phenotype and increased transforming growth factor-β (TGF-β) production. Mechanistically, TGF-β- induced microRNA21 upregulation in the renal tissue leads to decreased phosphatase and tensin homolog (PTEN) expression. The above event led to the activation of protein kinase-B (AKT) signaling, resulting in increased fibronectin production and fibrosis-like pathology. Importantly, the increased miR-21 was associated with low levels of Lachnospiraceae in the host gut which is also a key to heightened HMGB1-mediated inflammation. Overall, though correlative, the study highlights the complex interplay between GWI, host gut dysbiosis, prolonged antibiotics usage, and renal pathology via miR-21/PTEN/AKT signaling.


Funding: This study was supported by VA Merit Award I01CX001923-01 awarded to Saurabh Chatterjee.

Institutional Review Board Statement: The Institutional Review Board at the University of South Carolina granted approval for the study protocol (Animal Protocol Number: 2419-101345-072318; approval date: 23 July 2020). All procedures involving animals adhered to the local standards set by the Institutional Animal Care and Use Committee (IACUC).

Acknowledgments: We would like to thank COSMOSID (Microbial Genomic Platform, Germantown, MD, USA) for their assistance in microbiome analysis. We would also like to thank the Experimental Tissue Resource (ETR) ILAB facility located at UC Irvine Medical Centre, Orange, California for technical support.

Creative Commons License

Creative Commons Attribution 4.0 International License
This work is licensed under a Creative Commons Attribution 4.0 International License.



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