Altered Duodenal Mucosa-Associated Microbiota and Immune Profiles in Functional Dyspepsia: A Study of Host-Microbiome Homeostasis

Abstract

Recent work suggests an altered duodenal mucosa-associated microbiota (MAM) in patients with functional dyspepsia (FD) when compared to outpatient controls, these differences may reflect alterations in host-microbiome homeostasis. Given that specific mucosal immune signatures have been identified in FD, we hypothesised that these changes would be associated with specific microbial changes. We aimed to profile the duodenal MAM to identify microbes associated with known changes in FD mucosal and peripheral immune homeostasis. Duodenal biopsies were collected from 11 asymptomatic outpatient controls and 17 FD patients. Separate biopsies were collected for MAM 16S rRNA amplicon sequencing, histological evaluation, and mucosal lamina propria mononuclear cell (LPMC) isolation. Where available peripheral blood mononuclear cells (PBMC) were isolated from whole blood. PBMC and LPMC populations were analysed for CD4 and CD8 T cell populations by flow cytometry. Initial comparisons of histological and immune measures revealed significant differences between FD and outpatient controls, with decreased villi goblet cells and increased LPMC CD4 Central Memory, LPMC CD8, and PBMC CD4+ Central Memory Th17 in FD compared to controls. While microbiome profiles varied between groups, specific associations with the histological and immunological scoring found that in controls, villi goblet cells correlated positively with Massilia and negatively with Exiguobacterium, while FD patients showed no significant correlations. Additionally, controls exhibited a negative correlation between LPMC CD4 Central Memory and Veillonella, with FD patients showing no significant correlation. Notably, FD patients demonstrated a significant negative correlation between LPMC CD8 and Sulfophobococcus, and a positive correlation between PBMC CD4+ Central Memory Th17 and both Gemella and Fusobacterium. ImportanceWhile several papers have reported the alteration in FD duodenal MAM, study numbers are low and consensus on specific biomarker signatures within the microbiome have not been reached. Our findings contribute to this growing body of evidence, indicating that patients with FD exhibit distinct alterations in duodenal MAM and immune profiles compared to outpatient controls. Furthermore, the immune-microbiome associations present in control populations were absent in FD patients suggesting a loss of host-microbiome homeostasis that may contribute to FD pathophysiology. Our work highlights potential microbial biomarkers which may be a consequence or driver of the mucosal micro-inflammation state which is a characteristic of FD. Future work is required to validate whether these specific microbes are responsible for driving inappropriate host immune responses to inform treatment strategies and assist with disorder diagnosis.