IntroductionInflammation contributes to the pathogenesis of numerous medical disorders that commonly affect older adults, including osteoporosis, diabetes mellitus, cardiovascular disease, and dementia (1-10); this is often referred to as inflammaging (3,11). Beyond chronological aging, the postmenopausal state may independently contribute to greater inflammation in older women. In animal models, chemical or surgical menopause leads to downregulation of epithelial junction proteins, gut barrier dysfunction, and increased gut permeability (12). This, in turn, permits the translocation of microbes from the intestinal lumen into the subepithelial space, triggering immune cells to produce proinflammatory cytokines (12). Whether an increase in gut permeability accompanies the menopause transition (MT) in humans is uncertain. If gut permeability does increase, whether it is associated with inflammation and end-organ manifestations is also unknown.The overarching goals of this pilot study were to determine if gut permeability increases during the MT and, if such an increase were confirmed, to explore whether gut permeability is associated with inflammation and bone mineral density (BMD). In this report, subsequent use of the term "gut permeability" refers to its indirect assessment using these blood markers. We used bone as a model end-organ system because increased gut permeability mediates inflammation and hypogonadal BMD loss in rodents, and probiotics that reduce gut permeability (12) or inflammation (13-15) can decrease bone resorption (12-15) and prevent bone loss (12, 15). Our primary hypothesis was that gut permeability increases from pre-to BACKGROUND. Inflammation is implicated in many aging-related disorders. In animal models, menopause leads to increased gut permeability and inflammation. Our primary objective was to determine if gut permeability increases during the menopause transition (MT) in women. Our exploratory objectives were to examine whether greater gut permeability is associated with more inflammation and lower bone mineral density (BMD).
METHODS.We included 65 women from the Study of Women's Health Across the Nation (SWAN). Key measures were markers of gut permeability (gut barrier dysfunction, fatty acid binding protein 2 [FABP2]) and immune activation secondary to gut microbial translocation (LPS binding protein [LBP], soluble CD14 [sCD14]), inflammation (high-sensitivity CRP), and lumbar spine (LS) or total hip (TH) BMD.
RESULTS.In our primary analysis, FABP2, LBP, and sCD14 increased by 22.8% (P = 0.001), 3.7% (P = 0.05), and 8.9% (P = 0.0002), respectively, from pre-to postmenopause. In exploratory, repeated measures, mixed-effects linear regression (adjusted for BMI, age at the premenopausal visit, race/ ethnicity, and study site), greater gut permeability was associated with greater inflammation, along with lower LS and TH BMD.
CONCLUSION.Gut permeability increases during the MT. Greater gut permeability is associated with more inflammation and lower BMD. Future studies should examine the...