Gastroesophageal reflux disease (GERD), reflux esophagitis (RE), and peptic ulcer disease (PUD) are commonly encountered in clinical practice. More than simple anatomic abnormalities, these conditions are tethered to a variety of external influences as well as those related to genomics, transcriptomics, and metabolomics. Furthermore, each of these conditions is clearly related to abnormalities of the microbiota of the oropharynx, esophagus, and gastrointestinal tract. Certain therapeutics used to address these conditions such as antibiotic agents and proton pump inhibitors worsen microbiome dysbiosis while pursuing clinical benefit. Therapeutics that protect, shape adaptively, or restore microbiota balance are key aspects of current and future therapy to pursue. How the microbiota is involved in clinical condition genesis and progression, as well as how therapeutic support or derange the microbiota are herein explored.