Knowledge of the histology, intestinal morphometry, and lymphocyte subpopulations in the upper oesophagogastrointestinal (UEGI) tract of healthy individuals remains limited. This gap presents a challenge for studies investigating UEGI inflammation, which often lack appropriate healthy control groups. Objective: To characterize the histology of the UEGI tract and duodenal lymphocyte subpopulations in healthy volunteers and to examine whether patients with gastroesophageal reflux disease (GERD) could serve as surrogate controls. Individuals were excluded if they had gastrointestinal symptoms, comorbidities, pregnancy, exposure to toxins, medication use, or abnormal blood test results. Subjects from both groups were further excluded if duodenal intraepithelial lymphocyte (IEL) counts were abnormal. Out of 280 screened participants, 37 met inclusion criteria (23 healthy, 14 GERD). The GERD group exhibited higher IEL counts (median [IQR]: 19.5 [17–22]) compared with healthy subjects (15 [12–18], p = 0.004), while eosinophil and mast cell numbers and intestinal morphometry were similar across groups. In the lamina propria, CD4+ T cells were reduced (p = 0.008) and CD8+ T cells were elevated (p = 0.014) in GERD. Total innate lymphoid cells (ILC) and CD3− populations were lower in GERD (p = 0.007), while intraepithelial NKT cells increased (p = 0.036) and ILC3 decreased (p = 0.049). This study provides a comprehensive reference of histology, morphometry, and duodenal lymphocyte subpopulations in healthy individuals, establishing a “gold standard” for normality. The observed differences suggest that including true healthy controls is preferable in research, though a well-defined GERD cohort may serve as an alternative when healthy subjects are unavailable.
