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Diet, the maladaptation of intestinal stem cells and obesity, T2DM and GI cancers

It is known that a long-term diet high of sugar and fat disrupts the ability of the body to constantly renew and develop all types of intestinal cells from intestinal stem cells, crucial for the natural adaptability of the digestive system. This maladaptation can contribute to the development of obesity, type 2 diabetes and gastrointestinal cancers.

Intestinal stem cells in green, cell division in red (Credit Helmholtz Munich, Anika Böttcher)

The molecular mechanisms behind this maladaptation are part of the research field of Dr Heiko Lickert and his group at Helmholtz Munich and the Technical University of Munich. Using a mouse model, the researchers are investigating the effects of a high-sugar and high-fat diet and compared it with a control group. The current study, 'Diet-induced alteration of intestinal stem cell function underlies obesity and prediabetes in mice', was been published as a cover story in Nature Metabolism.

"The first thing we noticed was that the small intestine increases greatly in size on the high-calorie diet," explained study leader, Dr Anika Böttcher. "Together with Fabian Theis' team of computational biologists at Helmholtz Munich, we then profiled 27,000 intestinal cells from control diet and high fat/high sugar diet-fed mice. Using new machine learning techniques, we thus found that intestinal stem cells divide and differentiate significantly faster in the mice on an unhealthy diet."

The researchers hypothesise that this is due to an upregulation of the relevant signalling pathways, which is associated with an acceleration of tumour growth in many cancers.

"This could be an important link: Diet influences metabolic signalling, which leads to excessive growth of intestinal stem cells and ultimately to an increased risk of gastrointestinal cancer," added Böttcher.

With the help of this high-resolution technique, the researchers have also been able to study rare cell types in the intestine, for example, hormone-secreting cells. Among their findings, they were able to show that an unhealthy diet leads to a reduction in serotonin-producing cells in the intestine. This can result in intestinal inertia (typical of diabetes mellitus) or increased appetite. Furthermore, the study showed that the absorbing cells adapt to the high-fat diet, and their functionality increases, thus directly promoting weight gain.

These and other findings from the study lead to a new understanding of disease mechanisms associated with a high-calorie diet.

"What we have found out is of crucial importance for developing alternative non-invasive therapies," added study leader, Dr Heiko Lickert, in summarising the results.

To date, there is no pharmacological approach to prevent, stop or reverse obesity and diabetes. Only bariatric surgery causes permanent weight loss and can even lead to remission of diabetes, Lickert explained. However, these surgeries are invasive, non-reversible and costly to the healthcare system. Novel non-invasive therapies could happen, for example, at the hormonal level through targeted regulation of serotonin levels. The research group will examine this and other approaches in subsequent studies.

Further reading

To access this paper, please click here


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