This study is being conducted to determine if vitamin D supplementation increases the level of a protein that may be involved in decreasing the risk of esophageal cancer in patients with Barrett's esophagus. Subjects with Barrett's esophagus will take vitamin D supplementation for 2-12 weeks depending on the severity of their condition, and receive an upper endoscopy procedure before and after vitamin D supplementation trial.

28-day run-in phase during which subjects are treated with a proton pump inhibitor (omeprazole 20 mg po q day or an equivalent dose of another proton pump inhibitor). The purpose of the run-in phase is to minimize esophagitis, which can cause histologic changes that can be confused with dysplasia. After the run-in phase, subjects will undergo an upper endoscopy for Barrett's surveillance or Barrett's mapping as part of routine clinical care. At the time of endoscopy, research biopsies will be obtained for the study. Subjects eligible and continuing in the study will take vitamin D3 (Cholecalciferol) 50,000 IU capsules once weekly with or without daily metformin for a total of two or twelve weeks depending on the severity of Barrett's esophagus. After completion of vitamin D3 subjects will return for an EGD (endoscopy) and biopsies for the research study.

Inclusion Criteria:

• Known diagnosis of short-segment or long-segment Barrett's esophagus as previously made by upper endoscopy showing salmon-colored distal esophageal mucosa and biopsies revealing intestinal metaplasia with goblet cells. Potential study subjects may be contacted by mailings or phone calls or may be approached in clinic. Additionally, potential study subjects may be approached using a web-based recruitment tool. Informed consent will be obtained by a research coordinator or study investigator.
• Subjects may be taking calcium supplements or have previous history of hypercalcemia
• Subjects may have diabetes mellitus
• Subjects may have a history of prior malignancy except for esophageal adenocarcinoma
• Willing to donate 90 mL of blood and endoscopic mucosal biopsies for research

The following additional inclusion criteria apply for patients in the Vitamin D/metformin sub-arm of the low grade dysplasia/no dysplasia arm:

• At least 2 cm circumferential Barrett's esophagus segment length (C2M2 by Prague C & M criteria)
• Normal renal function (defined as creatinine within normal institutional limits)

Exclusion Criteria:

• Pregnancy
• Known chronic liver disease (Child's B cirrhosis)
• Known chronic kidney disease (creatinine ≥ 3.0)
• Esophageal adenocarcinoma
• Allergic reaction to omeprazole
• Allergic reaction to vitamin D
• Unable or unwilling to provide informed consent
• Known hypercalcemia
• Previous ablative therapy for Barrett's esophagus
• Patients on a stable (>/=4 week duration) dose of >2000 IU/day (or equivalent) of vitamin D supplementation

The following additional exclusion criteria apply for patients in the Vitamin D/metformin sub-arm of the no dysplasia/low grade dysplasia arm:

• Allergic reaction to metformin
• History of diabetes mellitus
• History of lactic acidosis
• History of B12 deficiency
• Participants may not be using metformin, cimetidine (Tagamet) furosemide (Lasix), nifedipine (Cardizem), or any other drug contraindicated for use with metformin.
• Treatment with other oral hypoglycemic agents
• Participants planning to undergo elective radiologic studies involving intravascular administration of iodinated contrast materials.
• Known chronic kidney disease with creatinine greater than normal institutional limits