Preclinical Pig Studies May Result in Lower Drug Failure Rates

Higher drug failure rates may be due to differences in bacterial and immune system profiles between mice and humans.

Findings from a new study suggest that the failure rate for drugs that treat conditions associated with high-calorie diets may be linked to the type of preclinical model that is used. The authors suggest that colon cancer and type 2 diabetes drug failure rates may be lessened through the use of pig models, according to the study published by the Cancer Prevention Research Journal.

Additionally, pig models may also be used to determine food-based approaches to preventing chronic diseases.

In the study, the authors discovered that pigs have gut bacterial profiles and immune systems similar to humans. Pigs also have 2 colonic stem cell populations, ASCL-2 and BMI-1.

Mice models lack colonic BMI-1 stem cells, which can influence how colon cancer forms, as well as gut permeability, according to the authors.

"Seven out of 10 deaths in the United States are due to chronic conditions," said researcher Jairam KP Vanamala, PhD. "And, yet, we have a high failure rate for drugs and treatments in studies looking to alleviate those conditions. Treatments that work in mice, do not always work well in humans. We show that a pig model may be an alternative that can help lead to better treatments and food-based prevention and therapeutic strategies."

The authors used immunofluorescence to identify stem cells in the colon of pigs fed a high-calorie diet or a standard diet. They found that the ASCL-2 and BMI-1 positive stem cells, which were similar to ones found in humans, according to the study.

"Mice models will continue to be important to study under certain conditions," Dr Vanamala said. "But, what we found is that the pig model has both a microbiome that is closer to the human microbiome and the intestinal physiology is, also, similar to humans."

Stem cells are located within tube-like crevices, called crypts, according to the authors. When cells at the end of the crypts are damaged, stem cells help repair the cells.

The authors found that pigs fed a high-calorie diet had stem cells that moved out of the crypt and became vulnerable to damage. The authors hypothesize that when human and pig cells are damaged, BMI-1 stem cells are likely activated and move up the crypt, according to the study.

"So, if we are studying colon crypts and looking at, for example, how cancer develops in mice, we are only taking one type of stem cells into the equation, not the interplay of both ASCL-2 and BMI-1," Dr Vanamala said. "We need to see how these stem cells are both working together to heal, or how they are damaged that leads to the development of colon cancer."

The investigators suggest that BMI-1 stem cells may become cancerous when they move up the crypt to repair damaged cells and sustain damage by inflammation and toxins from a high-calorie diet, according to the study.

"A high calorie diet means you may not be taking in a lot of fiber, which is an important food for the gut bacteria, and these gut bacteria devoid of any fiber may start eating away at the mucous and also start producing toxins, which causes inflammation to set in," Dr Vanamala said. "The stem cells that are working to repair this damage, then, are starting to move up the crypt toward the lumen where they may get exposed to toxins. Once they get damaged, the stem cell — because it lives a long time – can potentially become cancerous."

The authors also said that the advantages of having human-relevant animals model is that studies at of both agricultural and medical research can be strengthened to develop safe, affordable, and evidence-based food approaches to prevent chronic conditions, according to the study.

Previously, the team of researchers found that baked purple potatoes have compounds that suppress intestinal inflammation from a high-calorie diet and stem cell proliferation, which are linked to colitis and colon cancer.

The authors concluded these findings suggest that pigs could be a more accurate preclinical model compared with mice for drug development, as well as for developing food-based prevention approaches.