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Nachrichten, Termine, Experten
Nachrichten, Termine, Experten
For the first time, a team of experts from the Technical University of Munich (TUM), RWTH Aachen University, and the German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE) has demonstrated the causal role of microbially produced secondary bile acids in the development of colorectal cancer in functional studies. The findings, published in the journal Gut, are associated with a high-fat Western diet and represent a crucial step towards microbiome- and nutrition-based prevention and therapeutic approaches.
Colorectal cancer (CRC) is among the most prevalent and fatal cancers worldwide. The causes are partially genetic, but mainly due to environmental and lifestyle factors. For example, the so-called Western diet, which is high in fat and meat and low in fiber, is associated with the development of CRC. This diet also influences the gut microbiome. In particular, dietary fats stimulate the production of secondary bile acids by intestinal bacteria with 7-alpha-dehydroxylation activity (7αDH-positive bacteria). The resulting deoxycholic acid (DCA) is the most common secondary bile acid, and it has long been known that elevated concentrations are associated with a risk of CRC. However, a causal role and possible underlying mechanisms are unknown and little investigated due to a lack of in vivo models.
Specialized Expert Team
To prove a causal role of 7αDH-positive bacteria in CRC, DIfE researchers, in collaboration with the Collaborative Lab ‘Westernization of Diet and the Gut’ (WESTGUT), ZIEL - Institute for Food & Health at the Technical University of Munich, and the Functional Microbiome Research Group, Institute of Medical Microbiology of the RWTH University Hospital in Aachen, designed studies that mimicked the physiological conditions of humans as closely as possible and ensured that DCA production was not due to feed additives, but exclusively by 7αDH-positive intestinal bacteria.
Use of Multidimensional Models
The research team tested its hypotheses in both animal models and human CRC cohorts. They were able to show in a genetically modified pig model (APC1311/+) - which develops polyps in the colon - that a Western diet exacerbated experimentally induced intestinal tumorigenesis.
Dr. Sören Ocvirk, Head of Gnotobiology at DIfE, adds: ‘We also observed that increased proliferation of intestinal epithelial cells was associated with elevated levels of fecal secondary bile acids, particularly DCA. We were able to reverse this association in pigs by administering cholestyramine, thus demonstrating that binding and excreting bile acids can reduce tumor growth.’
The targeted colonization of germ-free mouse strains with specific 7αDH-positive bacteria induced DCA production. This also stimulated the rapid growth of epithelial cells in the colon measured by the proliferation marker Ki67, and altered the expression of genes involved in epithelial cell differentiation.
‘In several gnotobiotic CRC models, we were able to show that 7αDH-positive bacteria increased tumor numbers in the colon of mice, while this effect was absent when 7αDH-positive intestinal bacteria could not produce DCA through a genetic modification. This proves a causal role of bacterial bile acids in the pathogenesis of CRC in an animal model,’ explains Annika Osswald from DIfE, summarizing the results of the different mouse experiments.
Confirmation of Experimental Results Based on Different Cohorts
In stool samples from participants in existing CRC cohorts, the researchers were finally able to show that patients with CRC had more 7αDH-positive intestinal bacteria, such as Clostridium scindens, compared to healthy controls. The scientists conclude that the specific detection of these bacterial species in human stool may help identify individuals at increased CRC risk due to an unhealthy diet and lifestyle early on. The introduction of personalized nutritional interventions for this group of people could, in turn, help reduce the production of secondary bile acids.
Ocvirk summarizes the study results as follows: ‘Our results show how much a Western high-fat diet and the associated changes in the gut microbiome can affect human gut health in the long term.’ Further research is needed to elucidate the underlying mechanisms and identify novel prevention and therapy strategies. To that end, additional 7αDH-positive bacterial isolates from diverse populations with different dietary habits should be identified, isolated, and characterized to better understand the influence of diet on the gut microbiome.
Background information
Bile acids are hydroxysteroids that occur as taurine or glycine conjugates as digestive components in the bile of vertebrates. Conjugated bile acids act as fat emulsifiers and contribute to the digestion of fats by activating lipases. Bile acids occurring in human bile are, for example, cholic acid, chenodeoxycholic acid, deoxycholic acid and lithocholic acid. Primary bile acids cholic acid and chenodeoxycholic acid are formed in the liver from the steroid cholesterol and subsequently secreted via bile into the small intestine. Only there and especially in the following colon they are converted by specific intestinal bacteria into secondary bile acids such as deoxycholic acid and lithocholic acid. The majority of bile acids secreted daily are reabsorbed in the lower small intestine (ileum), fed back to the liver via the portal vein, and re-excreted in the bile (enterohepatic circulation). A small portion of bile acids bypasses the enterohepatic circulation and enters the colon directly. The formation of bile acids from cholesterol is of great importance for the regulation of cholesterol and overall steroid metabolism in humans. The process represents the body's only way to excrete excess cholesterol. A pharmacological approach to hypercholesterolemia therefore consists in binding bile acids with drugs such as cholestyramine, withdrawing them from the enterohepatic circulation and thus excreting them.
Dr. Sören Ocvirk
Head of Gnotobiology at DIfE and of the Collaborative Lab ‘Westernization of Diet and the Gut’ at ZIEL - Institute for Food & Health at the TU Munich
phone: +49 33 200 88 - 2464
e-mail: soeren.ocvirk@dife.de
Osswald, A., Wortmann, E., Wylensek, D., Kuhls, S., Coleman, O. I., Peuker, K., Strigli, A., Ducarmon, Q. R., Larralde, M, Liang, W., Treichel, N. S., Schumacher, F., Volet, C., Matysik, S., Kleigrewe, K., Gigl, M., Rohn, S., Guo, C.-J., Kleuser, B., Liebisch, G., Schnieke, A., Ridlon, J. M., Bernier-Latmani, R., Zeller, G., Zeissig, S., Haller, D., Flisikowski, K., Clavel, T., Ocvirk, S.: Secondary bile acid production by gut bacteria promotes Western diet-associated colorectal cancer. Gut in press (e-pub ahead of print) (2025).[Open Access] [https://doi.org/10.1136/gutjnl-2024-332243]
https://www.dife.de/en/news/press-releases/details-press-releases/microbially-pr...
Immunofluorescence imaging of the proliferation marker Ki67 in the colon of gnotobiotic wild-type mi ...
Source: Annika Oßwald
Copyright: DIfE
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Immunofluorescence imaging of the proliferation marker Ki67 in the colon of gnotobiotic wild-type mi ...
Source: Annika Oßwald
Copyright: DIfE
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