Prolonged Antibiotic Use in a Preclinical Model of Gulf War Chronic Multisymptom-Illness Causes Renal Fibrosis-like Pathology via Increased micro-RNA 21-Induced PTEN Inhibition That Is Correlated with Low Host Lachnospiraceae Abundance

• Published in: Cells (Basel, Switzerland) Vol. 13; no. 1; p. 56
• Main Authors: Trivedi, Ayushi, Bose, Dipro, Saha, Punnag, Roy, Subhajit, More, Madhura, Skupsky, Jonathan, Klimas, Nancy G, Chatterjee, Saurabh
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 27.12.2023; MDPI
• Subjects: Advanced glycosylation end products; AKT protein; Animals; Anti-Bacterial Agents - adverse effects; Antibiotics; Antibodies; Chemicals; Chronic Disease; Clostridiales; Cytokines; Digestive system; Dysbacteriosis; Dysbiosis; Enrofloxacin; Fibronectin; Fibrosis; Fluoroquinolones; Gastrointestinal tract; Gulf War; Gulf War Illness; HMGB1 Protein; Illnesses; Inflammation; Kidney Diseases; Laboratory animals; Lachnospiraceae; Lachnospiraceae spp; Mice; MicroRNAs; Military personnel; miR-21; miRNA; Molecular modelling; Neomycin; NF-κB protein; Pathology; Persian Gulf War; Phenotypes; Prolong antibiotics; Proto-Oncogene Proteins c-akt; PTEN; PTEN protein; Renal function; TGF-β; Transforming Growth Factor beta; Transforming growth factor-b; Tumor necrosis factor-TNF; War; St Louis Missouri; United States > US; PTEN; Gulf War Illness; TGF-β; miR-21; Prolong antibiotics; renal fibrosis; Lachnospiraceae spp
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells13010056

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 microRNA-21 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 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.