NORGUT: EXPLORING THE METABOLIC SIGNATURES OF DISEASE AND DRUG ASSOCIATED GENOMIC FEATURES OF THE GUT MICROBIOTA IN NORWAY

The gut microbiota could be considered a separate organ system, which influences our health by modulating the immune system, digestion and other process. In the NORGUT project, we investigated the gut microbiota of diseases with manifestations in and symptoms from the gastrointestinal tract. These include inflammatory bowel disease, biliary disease, immunodeficiencies and heritable diarrheal conditions, and we have also taken an interest in heart failure, which is also associated with intestinal affection. Besides characerization of the gut microbiota in these condition, we have in parallel studied what we assume are biochemical "footprints" in the blood of gut bacterial activity. We also investigated how the gut microbiota and its footprints are affected by common drugs or probiotics. In the project, we have in the group established and improved a complete analytical pipeline of the gut microbiota using modern genetics methods (sequencing technology). We have applied these methods in the disease conditions listed above. We have have identified extensive microbial alterations, often characterized by reduced diversity. One important observation is that some studies show associations between the microbial profile and footprints in the blood, like markers of gut leakage and systemic immune activation, as well as byproducts of microbial metabolism. These findings strengthen the rationale for microbiota targeted treatment trials that have been completed in e.g. immunodeficiencies and heart failure. In the late phase of the project we worked to establish even more advanced methodology to study all bacterial genes and bacterial functions, which we believe are important for disease development. NORGUT also contributed to the www.microbiota.no website and the national microbiota conference which took place for the sixth time in 2019, and represented an important basis for a regional research network in clinical microbiota science.

Prosjektet NORGUT har funnet at flere betennelsesdrevne sykdommer er assosiert med endret tarmflora og at tarmflorarettet terapi kan ha betydning. Hovedeffekten av prosjektet er derfor: 1) Helt ny kunnskap om de undersøkte sykdommene utgjør grunnlaget for en rekke nye studier som vi tror vil svare på om tarmfloraen har betydning for hvordan vi behandler sykdommene. 2) NORGUT-prosjektet har bidratt til at vi har fått et sterkt miljø for klinisk tarmfloraforskning både i omfang og metodologisk. Dette er viktig for å utbre kunnskap om dette. NORGUT har også hatt stor betydning for å kunne bli tildelt internasjonale midler, blant annet fra det europeiske forskningsrådet ERC. 3) Den tarmflorarettede forskningen i NORGUT har vært med å øke interessen slik at det nå er flere titalls forskningsgrupper som undersøker tarmfloraen innenfor mange andre sykdomstilstander. Dette er viktig for å identifisere områder hvor tarmfloraterapi kan være med å bedre helsetilbudet.

Alterations in the bacterial flora of the gut (the gut microbiota) contribute to human diseases, ranging from metabolic and cardiovascular diseases to cancer and autoimmunity. In the aftermath of recent landmark papers establishing such associations, there is a need to explore the underlying mechanisms of the gut microbial influence on human physiology. Since the impact of geography on the gut microbiota is profound, national (Norwegian) initiatives are warranted. Studies utilizing genomic technology in assessing shifts in the gut microbiota are still developing and challenges range broadly, from poor understanding of technical limitations to a general lack of consensus for relevant study designs. In the present project proposal, I ambitiously aim to utilize my broad background from the application of high-throughput technologies in human genetics to establish a Norwegian pipeline for standardized assessments of the genomics of the gut microbiota. I will then use the established tools for assessments of features of the gut microbiota in the context of two principle human study designs: case-control cross-sectional (four inflammatory diseases with variable degrees and types of bowel manifestations, WP1) and interventional (rifaximin and rosuvastatin, WP2). The project aims to explore the specific impact of the changes to the gut microbiota that are observed in these studies on bile acid and lipid profiles. The proposed studies are innovative, yet based on pilot experiments that along with contributions from several leading international experts in the field will ensure feasibility of the proposed work packages. I aim to use the context of the proposed project to position myself as an independent researcher actively contributing to the development of an immature field of research, at the same time enhancing the quality of research on the gut microbiota in Norway by national online dissemination of established standards and sharing of technical resources (WP3).