Browsing by Subject "Dysbiosis"

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Contamination-controlled upper gastrointestinal microbiota profiling reveals salivary-duodenal community types linked to opportunistic pathogen carriage and inflammation
(2025) Schmidt, Nina S.; Dörner, Elisabeth; Podlesny, Daniel; Bohlhammer, Elisabeth; Bubeck, Alena M.; Ruple, Hannah K.; Tetzlaff-Lelleck, Vivian; Sina, Christian; Schmidt, Herbert; Fricke, Florian W.
The upper gastrointestinal (uGI) microbiota has been implicated in infectious, metabolic, and immunological conditions, yet remains poorly characterized due to invasive sampling and low microbial biomass. We developed and validated a contamination-controlled 16S rRNA gene and transcript-based protocol to profile the murine and human uGI microbiota from low-biomass samples. We applied this protocol to murine esophageal, gastric, and duodenal tissues, and to human saliva, gastric, and duodenal aspirates from patients undergoing endoscopy for suspected food-related, mild GI symptoms. Our objective was to identify conserved compositional and structural uGI microbiota patterns and assess their clinical relevance in relation to pathogen burden and inflammation. In mice, we found evidence for transcriptionally inactive and active intestinal taxa along the uGI tract, supporting horizontal microbiota transfer. In humans, we identified two distinct, inversely correlated salivary microbiota types – one dominated by the Prevotella 7 genus – which were conserved in the duodenum. The Prevotella 7-dominated uGI microbiota type was associated with lower relative abundances of gastrointestinal and extraintestinal opportunistic pathogens. These patterns were reproducible in an independent cohort and associated with lower systemic TNF-α levels. Our findings suggest that noninvasive salivary microbiota profiling can stratify individuals based on uGI microbiota composition and inflammation-associated risk traits, offering new opportunities for clinical applications and translational studie
Strain-resolved analysis of the human intestinal microbiota
(2022) Podlesny, Daniel; Fricke, Florian W.
The gut microbiota is ascribed a crucial role in human health, particularly in regulating immune and inflammatory responses, which is why it is being associated with a wide range of diseases, including obesity, diabetes, and cancer. Nonetheless, fundamental ecological questions of microbiome establishment, stability and resilience, as well as its transmission across hosts and generations remain incompletely understood, partly due to the lack of methods for high-resolution microbiome profiling. New insights in this field can therefore directly contribute to the development of bacterial and microbiota-based therapies. This work introduces SameStr, a novel bioinformatic program for strain-resolved metagenomics that allows for the specific tracking of microbes across samples, enabling the detection and quantification of microbial transmission and persistence, as well as the observation of direct strain competition. Deployed across cohorts to process over 4200 metagenomes, SameStr enabled analysis of the microbiome with unprecedented phylogenetic resolution. The data included both publicly available metagenomes and sequence data generated in collaboration with our research partners, and was examined using multivariate statistics and machine learning frameworks. First, the establishment and development of the neonatal microbiota was studied, revealing a birth mode-dependent vertical transmission of the maternal microbiota. The microbiota of neonates born by cesarean section was characterized by increased relative abundance of oxygen-tolerant and atypical organisms and showed signs of a delayed establishment of a strictly anaerobic gut environment in these children. Such birth mode-dependent differences diminished over time, yet were measurable within the first two years of life. Furthermore, strain analysis verified the transmission and colonization of parental microbes, which indicated a possible lifelong colonization by microbes from selected species. The temporal persistence of microbes was also characterized in healthy adults, revealing similar taxonomy-dependent patterns of stability. For some species, persistence has been demonstrated both in children and in adults over a period of at least two years. These species are known for their capability to metabolize host-derived glycans found both in breastmilk and intestinal mucus, pointing to a potential strategy for effective cross-generational microbiota transmission, and warranting additional research to assess the implications of their disturbed transfer for long-term health. Since their specificity allows assignment to individual hosts, fingerprints of individual microbial strains offer the potential to be used in forensics and data quality control applications. Finally, to gain new insights into the microbiota dynamics during Fecal Microbiota Transplantation (FMT), microbial strain transmission was analyzed in the context of a diverse set of patient, microbiome, and clinical conditions. In the analyzed studies, FMT was used for the experimental treatment of a variety of diseases, including colonization with drug-resistant and pathogenic microbes, metabolic and inflammatory bowel diseases, and as an adjunct to the immunotherapeutic treatment of cancer. Analyses uncovered what appear to be the universal drivers of post-FMT microbiota assembly, including clinical and ecological factors that are important for successful transplantation of donor strains. In particular, the relevance of the microbiota dysbiosis of the recipient was emphasized, which was inducible by pre-treating the patient with antibiotics or laxatives. Presumably, this can open up ecological niches in the patients intestines, which favors colonization with donor strains. Colonization rates did not play a role for the treatment success of recurrent C. difficile infections and inflammatory bowel disease, but indicated a trend associated with an improved immune response in cancer patients. Concerningly, the transfer of an atypical and potentially pro-inflammatory microbial community from one donor was also observed, calling for further investigations into the immediate and long-term clinical consequences of FMT. These analyses demonstrate the advantages of a strain-based microbiome analysis. Due to the achieved methodological accuracy, strain-resolved microbial dynamics could be precisely disentangled when comparing longitudinal samples from healthy adults as well as parent-child and patient-donor pairs. This revealed taxonomic, clinical, and ecological factors that are critical to microbiome assembly, including microbial transmission, persistence, and competition. Together, these findings lay the groundwork for future developments of precision personalized microbiota modulation therapies.