Population-based, lifestyle-microbiota interactions to identify mediators of the gut-liver axis

The gut-liver axis plays a central role in the effective food intake and its subsequent processing in the liver (Schneider, Albers, et al.). During human evolution, this intricate system has been optimized to extract as many nutrients as possible from the food supplied. The intestine and liver communicate by close bidirectional connections via the bile duct, portal vein and systemic circulation (Schneider, Elfers, et al.). The liver communicates with the intestine by dispersing bile acids and bioactive mediators through the bile ducts and systemic circulation. In the intestine, these mediators are metabolized as endogenous substrates with the help of the intestinal microbiota (Schneider, Candels, et al.). The intestine forms one of the largest interfaces that exposes the human organism to the environment as well as exogenous substrates (food, environmental influences). While food components are absorbed, further processed, and transported via the portal vein, bacterial components or toxins must be filtered to prevent systemic bacterial translocation (Mandato et al.). The liver receives 2/3 of its blood supply via the portal veins and is thus permanently exposed to products of microbial metabolism as well as food components. In doing so, it protects the host from bacterial translocation and systemic infections through the reticuloendothelial system. 
Therefore, it is plausible that the triangle of diet, microbiota and liver health can be modulated to prevent liver disease. Liver disease accounts for over 2 million deaths worldwide each year (Blachier et al.; Tapper and Parikh). Although liver-related morbidity and mortality represent two of the most pressing global health challenges, preventative strategies utilizing microbiota changes through nutrition are scarce. (Blachier et al.) Hence, new universally available and well-tolerated options for liver disease prevention are urgently needed. One potential avenue is exploring the use of nutrition for liver disease prevention. (Mandato et al.) Most studies focused on liver disease and nutrition concentrated on how to prevent malnutrition in patients with already existing liver disease.(“EASL Clinical Practice Guidelines on Nutrition in Chronic Liver Disease.”) Less is known about the preventative effects of nutrition on liver disease development. 
Current state of research and preliminary work
One example of how nutrition may protect from liver disease is the growing evidence that supports the potential benefits of Vitamin E on non-alcoholic fatty liver disease (NAFLD) development and NASH (non-alcoholic steatohepatitis). (Scorletti et al.). A potential mechanism by which Vitamin E protects from liver damage is that Vitamin E limits membrane injury precipitated through reactive oxygen species and is considered a promising antioxidant (Scorletti et al.). Still, there is only scarce data on how Vitamin E might affect the microbiome. The American Association for the Study of Liver Disease and the European Association for the Study of the Liver guidelines recommend Vitamin E supplementation in patients with biopsy-proven NASH without diabetes.(“EASL Clinical Practice Guidelines on Nutrition in Chronic Liver Disease.”) Recently, we could show that also nutritional Vitamin E intake is associated with reduced risk of NAFLD development in a population-based cohort (Scorletti et al.). 
This approach could also be used to look at the development of other liver diseases as well as liver-related mortality and it should not only be focused on Vitamin E, but it should also explore a wide range of nutrients that could induce positive effects on liver health.
Another example highlighting the relevance of gut microbiota in precision nutrition is the relationship between red meat consumption and the development of cardiovascular diseases. Here, increased levels of trimethylamine (TMA), produced by gut microbiota, and the proatherogenic metabolites like trimethylamine-N-oxide (TMAO) were observed in mice as well as humans, to increase the risk of cardiovascular diseases (Verhaar et al.). This is a clear example of how population-based studies can identify useful nutritional associations, that can then be characterized in mice models (Thøgersen et al.).
Similarly, it has been shown that the substitution of sugar with sweeteners led to the development of glucose intolerance in the subgroup of individuals having specific microbiota changes(Suez et al.). Therefore, gut microbiota composition is evolving as a top focus in nutritional interventions, and the impact of specific dietary factors on the diversity of the gut microbiome is of growing interest. However, the translation of the emerging evidence from mouse and cell models into clinically relevant dietary advice is one of the main challenges of clinical nutrition. Many factors need to be considered to design personalized nutritional solutions for individuals to prevent liver diseases. Moreover, some changes in diet (e.g., low fibre) are already associated with detrimental changes in the gut microbiota on the long term, but still the effects on liver disease development are unknown. (Ursell et al.; Schneider, Candels, et al.; Schneider, Elfers, et al.) One of the ultimate goals of the promising field of precision nutrition is the design of tailored nutritional recommendations to treat or prevent liver diseases. An update on the complex relationship between nutrition, microbiome, and the liver is the aim of this project.
Since hepatic lipid metabolism and plasma lipoprotein metabolism are so tightly interconnected, treatment of steatosis may have an impact on plasma lipids, and vice versa (Katsiki et al.). Conversely, approved drugs that lower low-density lipoprotein (LDL) cholesterol by reducing hepatic VLDL secretion often exacerbate hepatic steatosis. This necessitates the development of novel system-level approaches to uncover new therapeutic targets for hepatic steatosis without increasing plasma lipids and thus chronic vascular diseases (CVD) risk. Therefore, we will analyse the effect of nutritional patterns on steatosis and lipidomic markers, to find protective nutritional patterns. 
To do so, we will utilize the large population-based dataset of the the Lifelines Biobank cohort. We would like to explore the effects of lifestyle, nutrition as well as nutritional supplements on liver disease development which, we hypothesize, might be driven by dysbiosis.

References 
Blachier, Martin, et al. “The Burden of Liver Disease in Europe: A Review of Available Epidemiological Data.” Journal of Hepatology, vol. 58, no. 3, Mar. 2013, pp. 593–608, doi:10.1016/j.jhep.2012.12.005.
“EASL Clinical Practice Guidelines on Nutrition in Chronic Liver Disease.” Journal of Hepatology, vol. 70, no. 1, Jan. 2019, pp. 172–93, doi:10.1016/j.jhep.2018.06.024.
Katsiki, Niki, et al. “Non-Alcoholic Fatty Liver Disease and Dyslipidemia: An Update.” Metabolism: Clinical and Experimental, vol. 65, no. 8, Aug. 2016, pp. 1109–23, doi:10.1016/j.metabol.2016.05.003.
Mandato, Claudia, et al. “Nutrition and Liver Disease.” Nutrients, vol. 10, no. 1, Dec. 2017, doi:10.3390/nu10010009.
Schneider, Kai Markus, Lena Susanna Candels, et al. “Gut Microbiota Depletion Exacerbates Cholestatic Liver Injury via Loss of FXR  Signalling.” Nature Metabolism, vol. 3, no. 9, Sept. 2021, pp. 1228–41, doi:10.1038/s42255-021-00452-1.
Schneider, Kai Markus, Carsten Elfers, et al. “Intestinal Dysbiosis Amplifies Acetaminophen-Induced Acute Liver Injury.” Cellular and Molecular Gastroenterology and Hepatology, vol. 11, no. 4, 2021, pp. 909–33, doi:10.1016/j.jcmgh.2020.11.002.
Schneider, Kai Markus, Stefanie Albers, et al. “Role of Bile Acids in the Gut-Liver Axis.” Journal of Hepatology, vol. 68, no. 5, May 2018, pp. 1083–85, doi:10.1016/j.jhep.2017.11.025.
Scorletti, Eleonora, et al. “Dietary Vitamin E Intake Is Associated with a Reduced Risk of Developing Digestive  Diseases and NAFLD.” The American Journal of Gastroenterology, Mar. 2022, doi:10.14309/ajg.0000000000001726.
Suez, Jotham, et al. “Artificial Sweeteners Induce Glucose Intolerance by Altering the Gut Microbiota.” Nature, vol. 514, no. 7521, Oct. 2014, pp. 181–86, doi:10.1038/nature13793.
Tapper, Elliot B., and Neehar D. Parikh. “Mortality Due to Cirrhosis and Liver Cancer in the United States, 1999-2016:  Observational Study.” BMJ (Clinical Research Ed.), vol. 362, July 2018, p. k2817, doi:10.1136/bmj.k2817.
Thøgersen, Rebekka, et al. “Background Diet Influences TMAO Concentrations Associated with Red Meat Intake  without Influencing Apparent Hepatic TMAO-Related Activity in a Porcine Model.” Metabolites, vol. 10, no. 2, Feb. 2020, doi:10.3390/metabo10020057.
Ursell, Luke K., et al. “Defining the Human Microbiome.” Nutrition Reviews, vol. 70 Suppl 1, no. Suppl 1, Aug. 2012, pp. S38-44, doi:10.1111/j.1753-4887.2012.00493.x.
Verhaar, Barbara J. H., et al. “Gut Microbiota in Hypertension and Atherosclerosis: A Review.” Nutrients, vol. 12, no. 10, Sept. 2020, doi:10.3390/nu12102982.