Translated from the German language original
So, if we were mice, we would have the ability to cure just about anything? No, not quite. In fact, the question should rather be asked the other way round: If humans were like mice, would we then be free of all therapeutic necessities? Probably not, is what the experienced reader of medical journals interjects. What has not already been praised, extolled and marketed as the future of all therapies for humans? Only to be discarded in the big box of futile healing efforts after failed attempts to transfer the results from the "furry" to the "naked mouse", the "two-legged rat" that is the human being. After all, people aren't rodents and so caution is called for when it comes to transferring results between the two species.
Yet, what if the prestigious "Gastroenterology" journal were to write in its current issue of a closed chain of evidence established by a study in mice? What if the steps leading from a high-fat diet to an increased likelihood of developing colorectal cancer were essentially proven in mice? If so, it would definitely be worth the read, even with the utmost caution about the relevance of medical studies on rodents for humans.1
Chinese researchers led by Jia Yang studied the effects of a high-fat diet (HFD) in two strains of mice. The strains represented either sporadic cases of colorectal carcinoma (CRC) after treatment with the CRC-inducing agent azoxymethane (AOM) or, in a different, genetically predisposed strain, genetically determined CRC. In addition, the researchers had a control group and a group of germ-free mice that were used to study the effects of transferring feces from the first two mouse strains.
These are the results obtained by the scientists:
The body weight of the HFD groups was significantly higher than that of the animals in the control group (CG) at the end of the 22-week study period. At the same time, CRC was more prevalent among the HFD animals, and the tumors had more mass on average than those in the CG. Adenocarcinoma occurred predominantly. Among the genetically modified mice on HFD, administering antibiotics depleted the intestinal flora and, simultaneously, significantly decreased both the number and size of tumors. Thus, although HFD was associated with CRC, the state of the intestinal flora affected the prevalence and size of tumors.
HFD mice showed a marked depletion of their microbiome. Pathological bacteria increased in these mice, and the Alistipes species were particularly conspicuous. The pathological cell growth of species that tend to inhibit, such as Parabacteroides, declined at the same time, resulting in an overall gut flora under HFD that promoted the uncontrolled growth of CRC.
The quality of the barrier function of the epithelium was evaluated by measuring lipopolysaccharides in the serum, which a functioning epithelial barrier retains to a large extent. Overall, the HFD was found to significantly inhibit the barrier function of the intestinal epithelium.
The transfer of stool from the test groups to previously germ-free mice showed that the HFD altered the spectrum of germs traceable in the microbiome. Tumorigenic variants increased in number while anti-carcinogenic species diminished.
The study further showed that the HFD resulted in a significantly altered spectrum of intestinal metabolites. In particular, lysophosphatidylcholine (LPC) and its metabolite LPA appeared in increased amounts. Further analysis conducted during the study linked both to the development of CRC and to the weakening of the intestinal epithelium's barrier function.
As a consequence of high fat nutrition, numerous oncogenes were found to be upregulated and many tumor suppressor genes were simultaneously downregulated in the mice.
The study showed that fecal transplantation to germ-free mice resulted in pathological changes in cell junctions and increased cell proliferation.
In summary, this means that high amounts of fats in the diet alter the microbiome in a way that encourages tumors. The altered microbiome leads to a different spectrum of detectable metabolites, which additionally promotes cell proliferation of colon cells and at the same time weakens the barrier function of the colon epithelium.
According to recent studies, between 30% and 70% of the CRC risk is attributed to obesity, as is prevalent especially in western countries as a consequence of high-fat diets. For the first time, this current study was able to demonstrate step by step how a HFD alters the microbiome in the intestine of mice and additionally promotes tumorigenesis due to a modified spectrum of metabolites. In addition, the protective barrier function of the intestinal epithelium is reduced.
According to both the editors of the journal and the scientists directly involved in the study, many of the results are easily applicable to humans or have already been observed in humans. Conclusions can therefore be drawn from the mouse study to the development of tumors in people.
Therapeutic influence on the microbiome and the metabolites present in the intestine could therefore represent a promising approach for the prevention of CRC resulting from high-fat diets, the authors of the study conclude. It should therefore definitely be pursued as a means of CRC prevention in humans.
References:
1. Yang J, et al. High-Fat Diet Promotes Colorectal Tumorigenesis Through Modulating Gut Microbiota and Metabolites. Gastroenterology 2021; 162: 135-149. https://www.gastrojournal.org/action/showPdf?pii=S0016-5085%2821%2903439-9