Colon Cancer, Nuts, and Early Onset

Dr. Daniel Rosenberg, professor of medicine, Health Net Inc. Chair in Cancer Biology, and investigator in UConn Health’s Center for Molecular Oncology, is on the trail of the connection between our digestive system’s microbiome and colon cancer. His research has shown how walnut consumption can impact gut bacteria in a way that seems to fight off inflammation in some people. He’s also investigating why colon cancers are turning up more in younger people, in their 40s and even 30s.

(March 2022, Daniel Rosenberg, Carolyn Pennington, Chris DeFrancesco)


Chris: Can the consumption of certain types of nuts protect you from colon cancer?

This is the UConn Health Pulse, a podcast to help you get to know UConn Health and its people a little better, and hopefully leave you with some health information. You’ll find useful.

With Carolyn Pennington, I’m Chris DeFrancesco. Colon cancer is known to be largely preventable with timely screening. Because it’s often relatively slow to develop, growths in the colon can be found and removed before they can develop into cancer.

Carolyn: But what if we could figure out a way to make the body less susceptible to these growths in the first place? Well, here to talk about that is Dr. Daniel Rosenberg from UConn Health’s Center for Molecular Oncology, and he’s also the Health Net Inc. Chair in Cancer Biology. Welcome. Now you’ve been studying environmental exposures and cancer risk for years. What got you interested in what’s going on in our gut and the possible development of cancer?

Dr. Rosenberg: This interest has evolved over the last decade or more, going back really to some work we had done with black raspberry and its effects on a very common disorder in the American population, which is ulcerative colitis. I was at conference on black raspberry, and I think I might’ve met someone from the California Walnut Commission at that meeting in California. And I think that’s when, it was at least a decade ago, when they asked me about possibly looking at walnut. And so I started becoming involved with California Walnut and they funded our first study, in a mouse model, of colon cancer. And back in 2016 Masako Nakanishi, who’s an assistant professor with me in the lab, Masako showed that giving walnut at around 7% of their caloric intake actually seemed to benefit male mice from getting colon cancer; it actually reduced the disease a lot. And Masako, in this paper, which was published, again in 2016, really started to focus on what’s going on with the walnut, why is the walnut affording this protection against colon cancer? And it was a very strong colon cancer model, where it’s pretty hard to interrupt it, so we were surprised that we had this effect. So Masako looked at every type of molecular genetic change you could think of, but nothing seemed to explain the effect. And then JAX moved in, and Dr. George Weinstock was one of the first hires. And somehow we started to connect the idea that perhaps the walnut’s affecting the microbiome. We did a number of studies with the Weinstock Lab that went into this paper, which shows the walnut was causing a powerful effect on the microbiome in terms of the community structure of the bugs, living in the gut in a way that seemed to be changing the microbiome of the walnut-consuming mice to a form that seemed to resist cancer initiation, or somehow help to suppress cancer growth. And that study in 2016 really led to all the subsequent clinical studies that we’ve been undertaking here at UConn Health ever since that first report that Masako published back in 2016 with the Weinstock Lab.

Carolyn: So you actually have tests now going on in people?

Dr. Rosenberg: Yes. So we, we recently completed a, what we call a pilot study. It was 39 patients that were — this study was funded from the American Institute of Cancer research and the California Walnut Commission, it was co-funded. And the study was designed to test the effects of three weeks of Walnut consumption: 56 grams a day, or about 2 ounces a day, for three weeks in people. And the idea was to find out what effects it would have on a number of different parameters. But what this study showed, the point of this study was — Walnuts are enriched in a number of important health benefit agents that are really important for your health. The walnuts have a lot of omega-3 fatty acids, walnuts have lots of fiber, they have a number of polyphenols, which are very important antioxidants that are found in nature, they have melatonin, and they have a lot of gamma and delta tocopherol from vitamin E.

And we decided to focus our interests on the polyphenol components in walnuts, primarily the ellagitannins. Ellagitannins are a complex molecule that, when ingested, the stomach pH causes the release from ellagitannin of something called ellagic acid. And ellagic acid has become very popular in the lay literature — You can actually buy it at GNC; there’s a lot of potential benefits to ellagic acid as an antioxidant. So walnuts have a lot of ellagic acid. What happens is the ellagic acid travels to your colon, and there your microbiome metabolizes the ellagic acid into urolithins. The urolithins are extremely potent antioxidants, and we’ve been routinely measuring nine different forms of urolithins in patients, before and after the three-week walnut interval. And what we found is that the ability of people to make urolithins from ellagic acid is entirely dependent on their microbiome. There’s people that can make lots and lots of urolithins, and there’s people that can make any. And because the urolithins have such powerful anti-cancer and anti-inflammatory properties, the whole goal of the study was to really figure out, why is it that there’s so much variability in the human population?

I want to mention, when we collect the urine specimens, we do metabolomics on them and the samples are all sent out to the CESE, which is a core facility in the Department of Chemistry in Storrs. And our collaborator in Storrs, Dr. Anthony Provatas, is a phenomenal metabolomics analytical chemist. He’s provided us with all of the metabolomics analysis for the urolithins in these patients.

So this pilot study brought us to that point, and we used that preliminary data from this pilot study, which we’re now writing up to get submitted for publication, to get our large new NIH grant, which was funded last year. That grant is a $3.5 million grant, which is — really the focus of that grant is, it was written in response to a request for applications on probiotics from NCI [National Cancer Institute]: How could modifying your gut microbiome prevent cancer? That was the real question that they were looking for. And with our data we had, we knew that we were in a really strong position to get funded. So we did get funded. The NCI study that was just funded is targeting patients at high risk for colon cancer. They don’t have it.

So here, we’re trying now to target patients at elevated risk for colon cancer and we’ve increased the numbers quite a lot. We’re hoping to recruit a total of 200 patients. The way we’ve broken it down by prediction, is that about, I think maybe it’s a third, third and third, clean colon, a small polyp or a more advanced polyp, it’s roughly like that. So it’s essentially the same design as the pilot study. Only the difference is that we’re now targeting high-risk patients.

This grant has a lot of people on it. Dr. Ock Chun, who’s a professor of nutrition in Storrs, she’s working on all of the dietary information now. She’s doing it for the pilot study and she’s now doing all the diet analysis for the, for the new NIH grant. All the food frequency questionnaires and all the diet recall information, everything’s going through Dr. Chung.

Chris: I wanted to talk with you about some of the work you’re doing in the world of early-onset colon cancer. But before we do that, while we’re talking about nuts, you’re also doing a study involving peanuts?

Dr. Rosenberg: Yes. So we received funding from the Peanut Foundation, and there it’s a simpler design where we’re trying to recruit a total of 30 patients. Fifteen will be non-peanut and 15 will be peanut. There’s really no complicated inclusion criteria or exclusion criteria, really. Right now, we’re looking for people 50 to 65, but we’re going to expand that to 50 to 75. They get a small stipend and all they have to do is eat peanut for three weeks. We collect a stool sample before and after, and a colonoscopy at the end, where we will look at their tissues, if they have polyps, and measure some different inflammatory markers in their colons. So the peanut study is really to see what effect does your diet and do peanuts have on the composition of the microbiome.

Chris: Now early-onset, one of the things we wanted to talk about, people are getting colon cancer at an earlier age? What are you seeing and what are you hoping to find out?

Dr. Rosenberg: We recently received funding from NCI to look at the question of early-onset, colon cancer. It’s something I’ve been interested in for a long time, actually. And the reason I became interested in it was there a colorectal surgeon at Waterbury hospital named John Zhang. And John, a number of years ago, had told me during some meetings we were having with that group that he was seeing more and more very young people coming in with colorectal cancer at ages that you shouldn’t see it. So over the last few years, that question has become really important in the United States. Even though the overall risk of colon cancer in the United States has fallen, largely due to diet, exercise, and colonoscopies, the incidence of colorectal cancer in people under 50 is actually increasing a lot. And the question is why, why is that? It really piqued my interest, and I said, you know, we should really think about this. So we finally put in a NIH grant, which was funded, and the purpose of this grant is to try to get at the mechanism of what’s different about these early-onset cases when compared to more traditional cases that might be in a 60-to 75-year-old colon.

And so far we’ve collected a total of five early-onset and five-late onset colon cancers from Dr. Zhang’s practice. When the sample comes in, someone in my, my lab — it was Dr. Nakanishi, now it’s Dr. [Yuichiro] Hatano, who’s a postdoc. He’s actually a pathologist from Gifu, Japan. Dr. Hatano isolates fibroblast cultures and makes colon organoids from these colon tumors. We’ve made so far a total of five early-onset and five-late onset, and we’ve established this pretty impressive collection of samples that we’re now gearing up the start studying to try to understand what is it that’s different in those two populations of tumors. We think the answer might lie in the fibroblast, and we think that there’s some sort of inappropriate, perhaps environmentally stimulated activation of fibroblasts that releases a number of different inflammatory cytokines that shouldn’t really be present at such high levels in a healthy colon, and somehow this all ends up collaborating to affect your tumor immune response. So that’s where we’re working on this project right now. And some of the work will be done out in Storrs with my collaborator, Dr. Charles Giardina, he and I have worked together on dozens of publications and studies, and we have a number of grants together, including this early-onset one.

Chris: Can you just briefly explain what you mean by “organoid”?

Dr. Rosenberg: Organoids are in a simple way, mini guts. They were developed probably seven or eight years ago. The idea is that if you take a small piece of colon tissue, and under the right conditions with the right sets of buffers and the right media, you actually can isolate stem cells. And everything else will die away except for the colon stem cell, and over time, over a week or two, those colon stem cells start to actually reform a little mini gut in a dish. It doesn’t really look like a mini gut, but it’s, it’s got many of the characteristics of an intestine. And so they’re becoming a very important model for studying a person’s colon and how that colon might respond to different treatments or therapies.

We’re making these little mini guts, not only from the early-onset colon cancer patients, but also from our ulcerative colitis patients that we’re getting from Dr. [Haleh] Vaziri here at UConn Health. So really the, the organoid is a first attempt to kind of create the ecosystem of your colon, but there’s many other things that need to be added in order to really make it model what it’s coming from.

Chris: Right, OK. Dr. Daniel Rosenberg, the Health Net Inc. Chair in Cancer Biology, and part of UConn Health’s Center for Molecular Oncology, thank you so much for joining us. We’re going to get the information on those studies you mentioned, the walnut study and the peanut study, we’ll have that information in the show notes. That is our time for today. For Dr. Daniel Rosenberg and Carolyn Pennington. I’m Chris DeFrancesco. Thank you for listening to the UConn Health Pulse. Be sure to subscribe so you can catch us next time, and please share with a friend.