Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Moser, A.
Microbiota in immune-mediated diseases
Doktoratsstudium der Medizinischen Wissenschaft; Humanmedizin; [ Dissertation ] Graz Medical University; 2017. pp.
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- Autor*innen der Med Uni Graz:
- Betreuer*innen:
- Hoegenauer Christoph
- Strobl Herbert
- Altmetrics:
- Abstract:
- Background: A variety of immune-mediated diseases comprising multiple sclerosis (MS), a disabling autoimmune disease of the central nervous system and diarrhea-predominant irritable bowel syndrome (IBS-D), a functional gastrointestinal disorder, are recently intriguingly linked to structure and function of the gastrointestinal microbiota. Thereby, an altered microbial composition of the intestinal microbiota affects metabolite production, intestinal barrier and mucosal immune function but human data remain to be scarce. In IBS-D, probiotics and to a lesser extent synbiotics are an evidence-supported treatment. Mechanisms of action are not fully understood. This dissertation therefore investigates the gastrointestinal tract (mucosal immune cells, short-chain fatty acids (SCFAs) and fecal microbiota) of patients with MS compared to heathy controls. Furthermore, the investigation of the effects of a four-week oral synbiotic treatment on gastrointestinal mucosa-associated immune cells, mucosal and fecal microbiota, fecal short-chain fatty acids and fecal zonulin in ten patients with IBS-D was performed. Methods: Mucosal specimens were collected during ileocolonoscopy from fifteen untreated MS patients and ten controls for FACS analysis. Furthermore, stool samples were collected for measurement of fecal short-chain fatty acids (SCFAs) using GC-MS and for bacterial community profiling using 16S rRNA gene analysis. The gastrointestinal microenvironment in ten patients with IBS-D was compared before and after a four-week synbiotic treatment. Endoscopic evaluation of the upper and lower gastrointestinal tract to collect mucosal specimens for FACS analysis (duodenum and proximal colon) and mucosal 16S rRNA gene analysis (gastric corpus, duodenum, proximal colon) was performed. Moreover, analysis of fecal SCFAs using GC-MS, fecal zonulin using ELISA and fecal 16S rRNA gene analysis was performed. Results: The colonic microenvironment of MS patients shows differences at the levels of mucosal immune cells, bacterial metabolites and the composition of the intestinal microbiota compared to controls. FACS analysis of colonic mucosal specimens showed decreased numbers of total dendritic cells (DC), CD103+ tolerogenic DCs and CD4+CD25+127- regulatory T-cells (Tregs) in the distal but not proximal colon of MS patients. GC-MS measurement of fecal samples depicted reductions of fecal SCFAs (especially acetate and butyrate) in MS patients. Additionally, fecal 16S rRNA gene analysis revealed alterations of bacterial strains predominantly belonging to the Clostridiales order. The gastrointestinal microenvironment of ten IBS-D patients treated with open-label oral synbiotics for four weeks depicted changes in various sites and on different levels of the gastrointestinal tract after treatment. FACS analysis of mucosal immune cells showed a treatment-induced reduction of CD4+ T cells in the proximal colon. Synbiotics increased diversity in gastric and duodenal mucosal specimens and increased fecal abundance of Lactobacillaceae after treatment. Synbiotics induced fecal SCFAs (acetate and butyrate) and reduced fecal zonulin concentration accompanied by a reduction in symptom severity. Conclusion: The data of this dissertation indicate a regional regulatory deficiency of mucosal DCs and Tregs in the distal colon of MS patients being associated to a reduction of fecal SCFAs triggered by specific microbial alterations. Even though these observational data are not implying causality, the observed findings strengthen a role of intestinal immune system in MS. In IBS-D patients, oral synbiotics may influence the human gastrointestinal tract on different levels and sites. The observed effects substantially differ between regions and may influence distinct members of the gastrointestinal ecosystem driving improvement of symptoms in patients. While not implying causality, these findings warrant further investigation of synbiotic treatment in IBS-D.