Over the full course of the project, we have made significant and transformative progress on all proposed scientific objectives, yielding advances that have substantially impacted both basic understanding and translational perspectives in the field of host-microbiota interactions in metabolic and inflammatory diseases.
Aim 1.
We initially established ex vivo assays to systematically evaluate the impact of dietary emulsifiers on human microbiotas, leveraging both in vitro microbiota models (MBRA) and gnotobiotic mice. Our pioneering work revealed that exposure to emulsifiers consistently alters the compositional and functional landscape of human microbiotas. Notably, we identified both susceptible and resistant microbiota phenotypes and began to elucidate the underlying molecular determinants and bacterial players underlying this differential response. Advanced techniques, including laser capture microdissection and high-resolution spatial profiling, allowed the robust identification and isolation of mucus-invading bacteria in both preclinical models and human biopsies. These efforts led to the first comprehensive catalog of mucus-infiltrating "invaders" in the context of metabolic disorders, several of which were found to possess heightened pro-inflammatory and metabolic disease-promoting capacities when transplanted into germ-free.
Aim 2.
Building on our initial discoveries, we successfully demonstrated that both Akkermansia muciniphila supplementation and immunization strategies targeting flagellin represent viable modalities to block microbiota encroachment. Our studies—culminating in multiple high-profile publications—established that A. muciniphila can prevent emulsifier-induced metabolic derangement by preserving mucosal barrier integrity and modulating local immune responses. Similarly, our translational work revealed that vaccination against flagellin not only reduced bacterial penetration into the mucus but also conferred substantial protection against both colitis and obesity in preclinical models. Mechanistic insights indicated that these interventions restructure microbiota spatial organization and function, and our findings provide a solid foundation for future microbiome-targeted therapies.
Aim 3.
We have now completed extensive recruitment, sample collection, and spatial-microbiome profiling from well-characterized human cohorts with metabolic disease, and innovative clinical trials assessing the effect of emulsifier consumption in humans (as recently published in Gastroenterology 2022). This work confirmed our initial hypotheses drawn from animal models: patients with metabolic syndrome harbor an increased burden of mucus-infiltrating bacteria. Longitudinal and interventional analyses have provided strong evidence that these "invader" taxa are associated with disease severity and can actively drive metabolic inflammation and barrier disruption. For the first time, we isolated and characterized human-derived bacteria that, when transferred to recipients, recapitulate key aspects of metabolic pathophysiology, providing a crucial proof-of-concept for causality.
Exploitation and Dissemination
The results of this project have been widely disseminated across >60 peer-reviewed publications—including in prestigious journals (see publication list attached)—as well as through invited plenary talks, major symposia, and extensive outreach activities targeting clinicians, regulatory bodies (e.g. EFSA, WHO), and the general public. Several key data sets—such as those establishing inter-individual variability in microbiota response to emulsifiers and personalization of fiber interventions—have already been taken up in translational clinical protocols and dietary guideline discussions. Intellectual property has been protected through patents.
