Knockout of TLR4 mitigates gut-immune interactions to improve reproductive and metabolic health in a PCOS mouse model 4648

Abstract Description Polycystic Ovary Syndrome (PCOS) affects millions of women globally, presenting complex reproductive and metabolic challenges linked with chronic inflammation. Research indicates that gut health, marked by elevated lipopolysaccharide (LPS) serum levels, plays a crucial role in driving this inflammation. We hypothesize that Toll-like receptor 4 (TLR4) orchestrates these disturbances in PCOS by affecting gut barrier permeability. To test this, we administered Letrozole (LET), an aromatase inhibitor, or placebo to C57BL6J (wild type) and TLR4 knockout (TLR4-/-) female mice starting at four weeks of age. After four weeks of treatment, LET-treated wild type mice experienced prolonged diestrus, while LET-treated TLR4-/- mice maintained normal estrous cycles and reduced luteinizing hormone (LH) levels. Notably, 3/5 LET-treated TLR4-/- mice produced offspring, unlike their non-reproductive wild type counterparts. Additionally, TLR4 deletion decreased body weight, improved glucose regulation, and lower serum insulin levels, even with LET treatment. LET-treated wild type disturbances coincided with increased gut permeability, a dominant Th17 cytokine signature, and elevated IgA production, absent in LET-treated TLR4-/- mice. These findings highlight TLR4’s crucial role in linking gut health to PCOS dysfunctions, suggesting new research avenues and potential treatments to improve the quality of life for millions of affected women worldwide. Funding Sources R00 HD098330-04S1 Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)