Society: AGA

Introduction: Shifts towards high-fat, low-fiber diets, may contribute to the rising incidence of esophageal adenocarcinoma (EAC). In mice high-fat diet promotes EAC, possibly through effects on the gut microbiome and the systemic bile acid pool. Reflux bile acids are thought to promote EAC, but the role of systemic bile acids is unknown. The aim of this study was to assess associations between systemic bile acids and stages of progression in Barrett’s esophagus (BE).
Methods: Subjects with and without BE were enrolled from three sites. Targeted bile acid profiling on serum collected on the day of endoscopy was performed by LC-MS. A subset (73%) of subjects completed a 12-month food frequency questionnaire. MANOVA was performed to assess global bile acid differences across groups. Principal components analyses were performed to identify drivers of global bile acid composition. Individual bile acid comparisons across groups were performed only for Kruskal-Wallis ANOVA p<0.05. Logistic regression analyses were performed to assess associations between logarithmically-transformed bile acid levels and neoplastic stages of BE.
Results: A total of 141 subjects were enrolled with bile acids profiled (49 non-BE; 92 BE: 44 no dysplasia (ND), 9 indefinite (IND), 17 low-grade dysplasia (LGD), 16 high-grade dysplasia (HGD), 6 EAC). Lower Healthy Eating Index score (HEI), older age, and higher BMI were associated with increased levels of several individual bile acids, with an inverse association with PPI use. Global bile acid pools were distinct comparing non-BE and BE subjects (p=0.002) and between non-BE and stages of BE neoplasia (p=0.004). Principal components analyses demonstrated that associations between bile acids and HGD/EAC were driven by the unconjugated primary bile acids cholic acid (CA) and chenodeoxycholic acid (CDCA) as well as forms of ursodeoxycholic acid (UDCA). There were clear shifts in individual bile acids with progression to HGD/EAC. (Fig 1) Increasing CA was associated with HGD/EAC in univariate analyses (Fig 2) and remained significant after adjusting for established EAC risk factors (vs. non-BE; aOR 2.03, 95%CI 1.11-3.71). Similar trends were seen after adjustment for HEI, fat, and fiber intake. CA and CDCA were highly correlated; the two combined were also associated with HGD/EAC (aOR 1.81, 95%CI 1.04-3.13). There were non-significant trends towards decreased levels of unconjugated and conjugated forms of UDCA associated with HGD/EAC.
Conclusions: Alterations in serum bile acids are independently associated with advanced neoplasia in BE and may contribute to neoplastic progression. Future studies should explore associated gut microbiome changes such as bacterial deconjugation via bile salt hydrolase, pro-neoplastic effects of CA and CDCA and protective effects of UDCA, and whether these bile acids represent viable therapeutic targets.

<b>Figure 1. </b>Heatmap of relative risk ratios from polytomous logistic regressions for associations of BE stages compared to controls for serum bile acid levels.

Figure 1. Heatmap of relative risk ratios from polytomous logistic regressions for associations of BE stages compared to controls for serum bile acid levels.

<b>Figure 2.</b> Cholic acid was significantly increased across stages of progression to EAC (p for trend=0.002).

Figure 2. Cholic acid was significantly increased across stages of progression to EAC (p for trend=0.002).

Michael Quante

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