Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Wurm, P.
Biogeography of the human gastro-intestinal microbiota in health and disease and its reconstitution by fecal microbiota transplantation
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Graz Medical University; 2018. pp. 145
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- Autor*innen der Med Uni Graz:
- Betreuer*innen:
- Gorkiewicz Gregor
- Hoegenauer Christoph
- Altmetrics:
- Abstract:
- Numerous studies have shown that clinical interventions in the stomach result in alterations of the fecal microbiota, which indicates an important function of the stomach in gastrointestinal (GI) homeostasis. Therefore, in this thesis we gradually characterize the human mucosal and luminal microbiota of the stomach including the adjacent mucosa from esophagus and duodenum using 16S rRNA amplicon sequencing and compare it to the stomach microbiota of mice and gerbils. We found that the luminal microbiota in humans is dominated by Firmicutes and Bacteroidetes. Nevertheless both fractions show big variations that that are not associated with any health status. The composition of the stomach microbiota depends on the influx from upstream GI locations while selectively enriching (Rothia mucilaginosa, Porphyromonas and Lachnospiraceae) and depleting (Streptococcus) specific bacterial taxa throughout the stomach mucosa. The taxonomic composition shows big differences in gerbils and mice compared to humans. While all three are dominated by the same class order (Lactobacillales), different genera are present in human (Streptoccocus) and animals (Lactobacillus). These findings are of significant interest as gerbils and mice represent important models for stomach infectious disease research, especially studies focusing on H. pylori and gastric cancer. In addition, this work shows that concomitant treatment with antibiotics and corticosteroids in critically ill patients in the sterile environment of intensive care units (ICU) can result in a severe form of apoptotic enterocolitis accompanied by a strong induction of CD8+ T-cells. The patients presented a dramatic depletion of the endogenous gastrointestinal microbiota that is characterized by a severe reduction of microbial diversity, absolute bacterial 16S rRNA genes and short chain fatty acids (SCFA). The disease could not be associated to any specific infectious agent. Instead strong fluctuations in the colonic and fecal microbiota determined by skin or oropharynx commensals are, which are usually absent in the lower gastro-intestinal tract, indicate a loss of colonization resistance in these patients. We show that a single fecal microbial transplantation (FMT) has the XII capability to change this conditions and helps patients to recover from an apoptotic antibiotic-associated enterocolitis in the ICU. This work also investigates the efficacy of repeated FMTs in patients with chronic active ulcerative colitis (UC), who already had treatment failures for at least one immunosuppressive agent and/or anti-TNF-antibody. UC is associated with dysbiosis of the gastrointestinal microbiota. In this open controlled trial 27 patients received a 10-day antibiotic treatment. While one group of the trial received repeated FMTs afterwards the other patients were not treated with FMT. The antibiotics control group had a drop-out rate of 50% and only 1/10 (10%) patient showed a clinical response, in the FMT-group on the other hand 10/17 (59%) patients showed a response and 4/17 (24%) a remission. Additionally we could identify a signature in the donor microbiota that is associated with signs of clinical remission in patients. The microbial composition from these donors significantly separates from other donor samples based on unweighted UniFrac distance. Its features are high concentrations of Akkermansia muciniphila, Ruminococcus spp. and an increased richness based on observed species. We could show that the efficacy of FMT in UC patients is influenced by the taxonomic composition of the donor microbiota and that specific donor selection or microbial preparations might lead to new treatments for UC.