Early-life Microbiota Exposure Prevents Colon Cancer in Adulthood

"It's been appreciated for quite some time that the microbiota can play an important role in the development of cancer and other diseases. However, the majority of these studies have been in adults. Our findings show that a key timing of exposure to the microbiota and microbiota metabolites may actually be very early in life. We think this makes sense because during development, whether it's in utero or early postnatal, there are so many changes going on that the contribution of the microbiota can be very impactful. That is the novelty of this finding."

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Studies have shown that gut microbiota are instrumental in fostering normal body function and a stable immune system in the host, but the research has been conducted in adult mice and humans because of the difficulty in studying microbiota in utero or in newborns. Humans and mice are initially exposed to microbiota when they are born, either by coming through the birth canal or being delivered through Cesarean section. The mother has microbiota which produce compounds called metabolites that can affect fetal development. In this study, the researchers investigated whether microbiota in this early period could influence disease in adulthood.

The study compared two groups of mice. The first group was mice born to germ-free mothers and raised under germ-free conditions (meaning no exposure to bacteria from their mother or in the environment outside the womb) until weaning. Then, they were transferred to normal conditions and exposed to normal microbiota. The second group was mice born to normal mothers and then bred under regular conditions with microbiota. At six weeks old, all of the mice had colon cancer induced.

"We found remarkable differences," Denning said. "The ex-germ-free mice had much larger and many more tumors in the colon."

The study found the absence of microbiota in early life resulted in enhanced pro-inflammatory gene expression and an accumulation of immune cells called myeloid-derived suppressor cells. These cells suppress other immune cells that can help to limit or kill tumors.

"When you have a tumor that starts to develop, you want your immune system to recognize that as abnormal and try to stop it," Denning said. "If it works perfectly, the tumor is killed off. But the tumor can start to hijack some of those immune cells for its own benefit, and one key example are myeloid-derived suppressor cells. They accumulate inside the tumor and suppress new, incoming immune cells that are trying to kill the tumor. That allows the tumor to grow bigger and for more tumors to grow. That's one of the consequences of the absence of microbiota in early life. To demonstrate this, we blocked a specific pathway that helps to recruit myeloid-derived suppressor cells, and we were able to completely reverse the enhanced size and number of tumors in ex-germ-free mice."

While humans are not germ-free, these results could provide insight into how the composition of microbiota in mothers and babies may control many inflammatory genes and susceptibility to diseases, including cancers, later in life. Gaining a better understanding of how microbiota and other factors are influential very early in life could lead to solutions, such as manipulating certain pathways.



Source: Eurekalert