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BACKGROUND: The role of changes in gut microflora on upper gastrointestinal (UGI) perforations is not known. We conducted a retrospective case-control study to examine the relationship between antibiotic exposure—a proxy for microbiome modulation— and UGI perforations in a national sample. METHODS: We queried a 5% random sample of Medicare (2009–2013) to identify patients ≥ 65 years old hospitalized with UGI (stomach or small intestine) perforations using International Classification of Diseases diagnosis codes. Cases with UGI perforations were matched with 4 controls, each based on age and sex. Exposure to outpatient antibiotics (0–30, 31–60, 61–90 days) prior to case patients’ index hospitalization admission data was determined with Part D claims. Univariate and multivariable regression analyses were performed to evaluate the effect of antibiotic exposure on UGI perforation. RESULTS: Overall, 504 cases and 2016 matched controls were identified. Compared to controls, more cases had antibiotic exposure 0–30 days (19% vs. 3%, p < 0.001) and 31–60 days (5% vs. 2%, p < 0.001) prior to admission. In adjusted analyses, antibiotic exposure 0–30 days prior to admission was associated with 6.8 increased odds of an UGI perforation (95% CI 4.8, 9.8); 31–60 days was associated with 1.9 increased odds (95% CI 1.1, 3.3); and 61–90 days was associated with 3.7 increased odds (95% CI 2.0, 6.9). CONCLUSIONS: Recent outpatient antibiotic use, in particular in the preceding 30 days, is associated with UGI perforation among Medicare beneficiaries. Exposure to antibiotics, one of the most modifiable determinants of the microbiome, should be minimized in the outpatient setting.

Pregnancy is a physiological state of continuous adaptation to changing maternal and fetal nutritional needs, including a reduction of maternal insulin sensitivity allowing for appropriately enhanced glucose availability to the fetus. However, excessive insulin resistance in conjunction with insufficient insulin secretion results in gestational diabetes mellitus (GDM), greatly increasing the risk for pregnancy complications and predisposing both mothers and offspring to future metabolic disease. Here, we report a signaling pathway connecting pregnancy-associated plasma protein A (PAPPA) with adipose tissue expansion in pregnancy. Adipose tissue plays a central role in the regulation of insulin sensitivity, and we show that, in both mice and humans, pregnancy caused remodeling of adipose tissue evidenced by altered adipocyte size, vascularization, and in vitro expansion capacity. PAPPA is known to be a metalloprotease secreted by human placenta that modulates insulin-like growth factor (IGF) bioavailability through prolteolysis of IGF binding proteins (IGFBPs) 2, 4, and 5. We demonstrate that recombinant PAPPA can stimulate ex vivo human adipose tissue expansion in an IGFBP-5– and IGF-1–dependent manner. Moreover, mice lacking PAPPA displayed impaired adipose tissue remodeling, pregnancy-induced insulin resistance, and hepatic steatosis, recapitulating multiple aspects of human GDM. In a cohort of 6361 pregnant women, concentrations of circulating PAPPA are inversely correlated with glycemia and odds of developing GDM. These data identify PAPPA and the IGF signaling pathway as necessary for the regulation of maternal adipose tissue physiology and systemic glucose homeostasis, with consequences for long-term metabolic risk and potential for therapeutic use.