Exploring gut microbiota modulating strategies: from experimental insights to translational applications

From training our immune systems and protecting us from pathogens to harvesting energy from our diet and even influencing our behavior, the microbes in our gut have been indispensable to our evolution, physiology and health. Gut microbiota (GM) composition and function are continuously shaped by host genetics, age, diet, lifestyle and medications. Disruptions in the GM structure and activity are increasingly linked to the risk and severity of numerous diseases, including cancer, metabolic disorders, autoimmune and neurological diseases, as well as responses to therapies. Consequently, strategies to modulate the GM, ranging from dietary interventions, prebiotics, probiotics, synbiotics and postbiotics to fecal microbiota transplantation (FMT), are being actively explored for preventive and therapeutic purposes. This thesis comprises five studies investigating GM-modulating interventions across experimental, preclinical and translational settings. First, a miniaturized ex vivo batch fermentation model of a minimal GM was developed to screen plant-derived nutraceuticals for prebiotic activity, enabling assessment of diet-derived compounds with potential metabolic and gastrointestinal benefits. Second, a novel species, Faecalibacterium khanii, was characterized as a candidate next-generation probiotic, revealing distinct dietary substrate utilization patterns, including pectin. In paediatric hematopoietic stem cell transplantation, where GM disruption is common and clinically consequential, two studies evaluated GM-targeted approaches. A multicenter cohort study compared enteral and parenteral nutrition, demonstrating GM-related mechanisms supporting broader adoption of enteral feeding. Complementarily, a case study of FMT in steroid-refractory graft-versus-host disease illustrated how comprehensive microbial restoration can improve clinical outcomes. Finally, multi-omics analysis in a hepatocellular carcinoma (HCC) rat model identified GM signatures associated with lenvatinib response, including enrichment of Akkermansia. Postbiotic preparations from Akkermansia muciniphila were tested for cytotoxic and pro-oxidative effects on HCC cell lines, showing an additive effect with lenvatinib treatment. Collectively, these findings highlight the therapeutic potential of GM modulation while underscoring the need for context-specific, mechanism-driven and precision-based strategies.