Optimalisering: A microbial principle for modifying gut microbiota

Optimal health is important for the well-being and welfare of production animals, but is also important for product quality, and eventually the consumer. In this context the animals' gut health is particularly relevant. Modern industrial animal production often induces unwanted aberrations in the animals' gut microbiota which again may affect nutrient uptake, gut health in general, and the animals' ability to defeat infectious diseases. Also, the prevalence of non-infectious diseases is enhanced in modern animal husbandry. Accordingly, substantial amounts of research are currently invested in measures to improve gut health and welfare of production animals. Such measures include feed supplements like probiotics and prebiotics. We have recently identified a soil bacterium (McB) that exerts potent effects on microbiota composition in experimental animals. Laboratory experiments demonstrate that this soil bacterium binds specifically to an important type of immune cells, namely dendritic cells (DC) in both mice and humans. The binding between McB and DCs affects the properties of the DCs, among other things regarding their production of important signaling molecules, cytokines, that subsequently influence the differentiation and maturation of other immune cells, particularly effector T lymphocytes. In a comparative study with two established probiotic bacteria, McB induced a characteristic pattern of gene expression in human DCs compared with the two other bacteria. This gene expression pattern may explain some of the unique properties of McB, both in laboratory and animal studies. Repeated experiments in mouse models of diet-induced obesity demonstrate that inclusion of McB in the feed reproducibly increases the presence of beneficial gut bacteria while at the same time reducing the numbers of bacteria associated with an unhealthy gut flora. Experiments in RAG2(-/-) mice, i.e. mice without T and B lymphocytes, suggest that the effects on gut microbiota depend on these immune cells that represents the adaptive immune system. Important in this context may be the finding that McB in the feed strongly induces a special type of regulatory T cells, both in the small and large bowel mucosa. Whether this is a direct effect of McB interacting with immune cells or an indirect effect of changes in the gut microbiota, remains to be demonstrated. Still, an important consequence of the changes in gut microbiota is associated with an acute reduction in body fat as well as parameters linked to metabolic syndrome like improved glucose regulation and insulin sensitivity. Additionally, fat storage in the liver is profoundly reduced as well as the concomitant influx of inflammatory immune cells characteristic of obesity and non-alcoholic fatty liver disease (NAFLD). It is well established that the barrier properties of the gut mucosa are important for efficient uptake of nutrients as well as hindering the passage of unwanted compounds and microorganisms from the intestines into the body. Reduced barrier function is reported in many conditions like metabolic syndrome, cancers, coronary vascular disease, allergies and autoimmune diseases. Studies in the mouse models indicate that McB in the feed have beneficial effects on the barrier properties of the gut epithelium by enhancing the regeneration of the intestinal epithelium. Additionally, mucus production is enhanced, and the composition of mucus constituents changes in a way that is associated with good gut health. Overall, the project has demonstrated that microbial stimuli represented by a non-commensal soil bacterium may impact the many complex mechanisms regulating the immune system of the gut, the gut epithelium and the balance between the multitude of gut bacterial species. Additionally, these changes are connected to beneficial effects on metabolic processes, energy storage and inflammation which is a common trait of many non-infectious conditions in both production animals and humans. The results from this project also suggest that even environmental microorganisms are of significance for the health and well-being of mammals. Still, more studies are necessary to identify the active components behind the described effects. The project has also revealed that the protocol used to grow the bacteria has consequences for the biological activity of the preparation. Important studies have been carried out to optimize the conditions for efficient production of McB, but more work is still needed in this area.

Prosjektet dokumenterer at en miljøbakterie som ikke tilhører pattedyrs normale tarmflora, kan påvirke mekanismer for regulering av energiomsetning og -lagring, infeksjonsforsvar og inflammasjon, og ikke minst sammensetning av tarmens mikrobiota. Prosjektet har betydning for forståelsen av samspillet mellom miljøet, maten og pattedyrs helse. I prosjektet er det etablert samarbeid med anerkjente forskningsmiljøer i Norge, Danmark og i Canada. Arbeidet har omfattet spesialiteter innen medisin, cellebiologi, mikrobiologi, ernæringsbiologi og immunologi. Det er etablert ny kunnskap om betingelser og teknologiske løsninger for effektiv produksjon av miljøbakterien ved fermentering. Det har vært gjennomført møter med representanter for både farmasøytisk- og fôrindustri. Prosjektarbeidet har avdekket problemstillinger som må løses i videre arbeid. Prosjektpartnerne ønsker å skaffe finansiering til videre satsing. Potensialet vurderes som spesielt stort innen produksjons- og kjæledyrernæring.

Optimal health is of vital importance for the performance of production animals, and gut health is considered synonymous with animal health and is the new paradigm in food animal production. Gut health determines the ability of animals to withstand infections and diseases. Currently, there is a great concern about the use of growth-promoting antibiotics in livestock feed, and significant research efforts are scrutinizing pro- and prebiotics as feed supplements to improve gut health of production animals.The growing epidemic of obesity and its associated disorders like cardiovascular disease, type 2 diabetes, hyperlipidemia, non-alcoholic fatty liver disease represents a heavy burden to healthcare systems globally. According to the World Health Organization obesity has more than doubled since 1980, and currently ~390 million women and ~280 million men are considered obese. Obesity is one of the biggest drivers of chronic diseases and healthcare costs in the United States. Recent insight into the significance of our gut microbiota for human physiology provides strong evidence for intestinal microbe-host interactions being a key player in metabolic diseases.We have recently identified a bacterium with potent anti-inflammatory properties in select animal experimental models. Also, we have confirmed the anti-inflammatory properties in a mouse model of diet-induced obesity (DIO). Thus, oral administration of a pure microbial preparation has a profound impact on inflammation, conditions associated with metabolic syndrome and gut microbiota composition in mammals. The present project holds promise in two areas of great potential: 1) as feed supplement to improve livestock gut health by promoting a healthier microbiota composition, reduce inflammation and enhance mucosal immunity, and 2)in the treatment or prevention of obesity and conditions associated with metabolic syndrome and other lifestyle diseases in humans.