ON THE HUNT FOR CANCER’S MICROBIAL “PARTY” IN THE ANIMAL KINGDOM

Did you know that food, microbes, and cancer are often linked together? These links are well-studied in humans, but not as well-studied in other species. We wanted to ﬁnd out whether speciﬁc foods and/or microbes are linked with cancer across non-human species. So, we searched over a thousand articles reporting links between diet, microbes, and cancer. We found that some microbes, such as Helicobacter, papillomaviruses

Did you know that food, microbes, and cancer are often linked together?These links are well-studied in humans, but not as well-studied in other species.We wanted to find out whether specific foods and/or microbes are linked with cancer across non-human species.So, we searched over a thousand articles reporting links between diet, microbes, and cancer.We found that some microbes, such as Helicobacter, papillomaviruses, and Fusobacteria which are often found in carnivores, can promote tumor development in people as well as in other animals.Other microbes, such as the Lactobacillus found in milk products, can decrease tumor development in people and other animals.There is lots more to learn about these patterns across hundreds of species.Ultimately, these results have great potential to help researchers understand the variation in cancer They come from the things we eat and the people, animals, or objects we are exposed to during our lives.These microbes have been a part of human bodies since humans first evolved, and they a ect multiple aspects of our existence.Together, all of an animal's microbes are called its microbiome MICROBIOME A group of microorganisms living in a specific environment.
One of the things microbes a ect is the development of cancer and how it progresses as time goes on.There are cancer-inducing microbes that help cancer grow.Cancer-inducing microbes form

CANCER-INDUCING MICROBES
Microbes that increase the risk of developing cancer.a collection referred to as the oncobiome.These cancer-causing

ONCOBIOME
The collection of all cancer-inducing microbes in an animal.microbes are partly responsible for inducing cancer in . million people every year.On the bright side, there are also cancer-protective microbes that help our bodies fight cancer and reduce the risk

CANCER-PROTECTIVE MICROBES
Microbes that decrease the risk of developing cancer.
of getting it in the first place.These microbes usually come from healthy diets.

SEARCHING THE SCIENTIFIC LITERATURE
We looked for articles in the literature referring to associations between diet, microbes, and cancer in non-human animals.To find these articles, we used keywords and synonyms related to diet, microbes, the gut, cancer, and species.We also used specific keywords to specify that we wanted to exclude studies that focused on humans.We excluded those articles because there have been many discoveries on the associations between diet, microbes, and cancer in humans, but the new aspect of our research is that it is focused on non-human animals.We typed these keywords and synonyms into the Arizona State University library search engine and, after several rounds of reading and excluding irrelevant articles, we ended up with relevant articles [ ]. From these articles, we collected information about the standard diet of the animal(s), the way the microbes were added to the animals (with experimental tools or naturally found in the animals), the type of animal used in the experiment, and the e ects of diet and/or microbes on cancer in these animals (Figure ).
In general, we found that most of the articles described experiments in rodents, such as mice and rats.In most cases, the researchers experimentally inserted microbes through the mouths of these animals, and most of the researchers studied the e ect of these microbes on cancers of the gut.

LACTOBACILLI: MICROBES THAT HELP FIGHT CANCER
Some of the microbes that make up the microbiome fight cancer and protect the organism they live in.These cancer-protective microbes fight cancer by performing actions like preventing tumors from forming, reducing tumor size, and preventing cancer from spreading (a process called metastasis).One of these cancer-fighting microbes

METASTASIS
The spread of cancer cells to other parts of the body.
is called Lactobacillus, and it is mostly found in dairy products such as milk and cheese.Studies have found that Lactobacillus helps prevent breast cancer in mice by stopping the formation of tumors and cancer cells.It is incredible that microbes from the foods animals eat can help their bodies stay healthy in such microscopic yet remarkable ways.

MICROBES THAT CONTRIBUTE TO CANCER
Some microbes seem to be associated with cancer not only in people, but in other animals as well.For example, particles over a million times smaller than the tip of a human finger, such as papillomaviruses, are associated with skin cancer in people and dogs.These viruses enter animal cells and can damage the cellular machinery that fixes DNA damage and/or controls the cells' response to stress.Two types of bacteria, Bacteroides fragilis and Fusobacterium nucleatum, are also associated with cancer in people and mice.These microbes produce toxins that can damage the DNA, changing the way the cells connect to neighboring cells.This change in the way cells attach may trigger the metastasis of cancer cells to other parts of the body.Another bacterium, Helicobacter, is associated with cancer development in humans, mice, gerbils, and cats.Helicobacter leading to cell death, and the remaining gut cells adapt by dividing more.These microbes also produce toxins that increase the risk of these animals developing kids.frontiersin.orgcancer in the gut.Given that Helicobacter bacteria are associated with cancer in both a predator (cat) and its prey (mouse), it could be interesting to test whether these germs are transmitted from prey to predator.
The germs associated with cancers in various animals may actually come from their diets.It seems that a group of meat-eating species (Carnivora) have a higher prevalence of tumors than other groups of mammals that eat mostly plants [ -].This is also true when we compare feeding levels on the food pyramid [ ] (Figure ).Could certain cancer-associated microbes thrive in specific diets?We do not know for sure yet whether this is true across species, but there is evidence that the microbes Fusobacteria and Peptostreptococcus are associated with tumor formation in humans and mice, and these germs are most often found in animals that eat meat [ ].

Figure Figure
The prevalence of tumors across tissues is higher in animals of higher trophic (feeding) levels.For example, secondary carnivores have higher tumor prevalence than plant-eating animals (herbivores) and boneless-eating animals (invertivores).The P-value shows the feeding categories that are significantly di erent in their tumor prevalence.N shows the number of dots (i.e., species) in each feeding category, and the horizontal lines show the median number of tumor prevalence in each feeding category.Sometimes the development of cancer might not be related to specific microbes, but might have to do with the diversity of DIVERSITY Consisting of a variety of di erent elements.microbes.Macaques and humans that ate a Western-type diet (which consists of a lot of red/processed meat, fried foods, butter, eggs, refined sugars, and salt, and is associated with cancer) had a lower diversity of microbes compared to macaques and humans that ate a Mediterranean-type diet (consisting of many plant-based products) [ ].

THE EFFECTS OF MICROBES ON CANCER ARE COMPLEX
Microbes such as Bacteroides and Clostridium have been found to have both cancer-protective and cancer-inducing e ects.These microbes can either promote or protect from gut cancer (colorectal cancer) and skin cancer (melanoma), depending on an animal's genetic background and the type of food it eats.The genetic backgrounds of laboratory mice are very well-characterized, and each background has a separate name.For example, Clostridium promotes tumor formation in the guts of mice with a genetic background called FVB/N, whereas the same microbe inhibits the growth of colorectal cancer cells and melanoma cells in mice with a C BL/ genetic background.In terms of diet, Bacteroides can cause tumor formation in the guts of mice, but may also protect them from cancer if the mice have eaten foods that contain soluble fiber, which has anti-inflammatory properties [ ].

A SURVIVAL GAME BETWEEN THREE PLAYERS
There are three di erent players in cancer formation: the animal, the microbes, and the cancer cells.First, animals rarely benefit from having cancer.Second, certain microbes can gain a survival and reproductive advantage from using some of the resources that cancer cells tend to hoard, like cell-free DNA.The benefit that microbes can attain from cancer cells varies based on the function of the microbes.Third, the cancer cells benefit from interacting with Helicobacter pylori as this microbe promotes cancer in the stomach.As H. pylori attaches to animal cells and divides, it also triggers those cells to divide.The cancer cells are a burden to the animal, since they develop the ability to steal more resources from the body and migrate to di erent organs and tissues when they use up the resources from one place [ ].

CONCLUSION
In humans, cancer kills almost million people every year.Some microbes, such as the Lactobacillus often found in milk products, are beneficial in terms of lowering the chances of tumor formation in people and other animals, whereas other microbes, such as the papillomaviruses, Helicobacter, and Fusobacteria often found in meat-eating species, have the opposite e ect and often increase the likelihood of tumor formation.Although these links between diet, microbes, and cancer are only known for a few animals so far, we hope that future studies will find such links across many more animal species.This can be a di cult task given the complexity of the microbiome in the gut; the interactions of these microbes with the animals' genes, age, sex, and environment; and the di culty of growing and studying almost % of these microbes in the lab.Many of these problems can potentially be solved with recent technological advances that allow the analysis of thousands of gut microbes from fecal (poop) samples, for example.
Understanding the links between food, microbes, and cancer across species may improve the ways medical doctors and vets detect and treat cancers.For example, healthcare providers may be able to adjust an animal's food, track the presence of potentially harmful microbes in its body, and potentially transplant cancer-protective microbes into the gut.Together, such therapies could be life-saving for many animals su ering from cancer. .doi: ./frym. .

CONFLICT OF INTEREST:
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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