The Microbiome and Colon Cancer: Dietary Influence on Incidence, Morbidity, and Mortality

The Microbiome and Colon Cancer |

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Over the past 15 years, colorectal cancer (CRC) diagnoses have risen among men and women aged 40 years and older, and even among younger individuals.¹ Currently, people born after 1990 are twice as likely to be diagnosed with CRC— and 4 times as likely to develop rectal cancer—as those born in 1950, according to the American Cancer Society (ACS). The ACS estimates about 107,000 new cases of colon cancer and 46,220 new cases of rectal cancer in the US in 2024. It is the third-leading cause of cancer-related deaths in men and fourth-leading cause in women; more than 53,000 deaths from colorectal cancer are expected this year (Figure 1).²

Figure 1. Colorectal Cancer Statistics and Predictions According to the American Cancer Society²

Although genetic drivers of CRC are sometimes inherited, more often they develop and accumulate over an individual’s lifetime. One of the prime risk factors for CRC is the consumption of a high-risk, Western-style diet high in processed foods, refined grains, red meat, and sugar, which increases the frequency of CRC nearly 10-fold.¹

Dietary modifications hold the promise of having a major impact on incidence, morbidity, and mortality of CRC. This has been supported by several studies on human populations, with rapid changes in tumor incidence in migrant populations. The historic data on migrants from Japan to Hawaii developing a higher incidence are particularly informative.³ These data suggest healthier dietary patterns may reduce CRC incidence in the US and other developed countries by more than 80% to 90%.

The gut microbiome, which includes naturally occurring microbes such as bacteria, viruses, and fungi, is a key player in the interplay between cancer and our diets. Although diet mediates the gut microbiome and an enormous diversity of chemical transformations, the microbiome/ diet interactions are a poorly understood component of CRC risk.

The Human Microbiome at Work

Bacteria in the gut have a symbiotic relationship with gut epithelial cells that absorb nutrients from food in the intestines and exchange information, keeping the system balanced and minimizing the probability of a tumor developing. This complex ecosystem is continuously modified by ongoing nutritional exposures, determining which cells dominate in either increasing or decreasing probability of a tumor developing.

The presence of genetic alterations in epithelial cells that will cause these cells to form tumors involves the interaction of the epithelial cells with many other cell types. This includes host immune and supporting cells, as well as the enormous and diverse population of bacteria in the gut that exceed the number of human cells in the body. Thus, the microbiome is a major influence on how many other cell types in the gut function.

The enormous impact of diet on the formation and growth of tumors also provides insight into the complex interplay of cell types and signals that determine probability of tumor development. The Augenlicht and Kelly labs at Montefiore Einstein Comprehensive Cancer Center and Albert Einstein College of Medicine have a strong collaboration that brings together complementary expertise of 8 investigators to provide unique insight into fundamental mechanisms of how the gut maintains its normal functions that are compromised in causing tumors to develop. Together, our labs are investigating how stem cells influence the maintenance of normal intestinal functions and how modulating the composition and biochemical functions of the intestinal microbiome influence normal functions that alter probability of disease (Figure 2).

Figure 2. Diet Alters Incidence of Colorectal Cancer in Mice

Feeding Mice the New Western Diet

Our research uses a mouse model system that reflects nutrient levels that humans are exposed to and helps us understand how dietary exposures alter probability of human tumor development. This is a simple idea, but it is rarely incorporated in scientific literature, leading to many observations in mice that may not be directly relevant to humans. The experimental system we use, termed new Western diet 1 (NWD1), is formulated to accurately reflect exposure to macronutrients, such as fat, vitamin D, fiber, and others, that are consumed by humans at higher risk for colon cancer.

Feeding mice NWD1 yields important results. NWD1 causes sporadic tumors in mice, meaning they have no genetic predisposition; such tumors are, by far, the major form of human CRC.^4-14 Additionally, in mice that harbor gene mutations that can cause tumors, feeding NWD1 always causes much earlier appearance of tumors.15-19 This reflects a major clinical problem that has become alarming over the last decade: Development of CRC at a younger age in the US and other industrialized countries coincides with greater consumption of unhealthy Western-style diets that are likely the underlying cause of this shift. The Augenlicht lab has shown that the NWD1 causes numerous alterations in the function of cells in normal-appearing intestinal tissue long before tumors are detected.^{5,7,9-11,14,16,20-23,25,26}

As a result of these findings, our research is now focused on understanding how the higher-risk diet alters the function of intestinal stem cells, the cells in the gut tissue that are responsible for producing all the other cells that maintain intestinal functions and that also form tumors when their DNA mutates.^4,12,24 Surprisingly, we found that alternate stem cells in the intestine are recruited to function in mice fed NWD1, but with the caveat that these cells, and all the daughter cells they produce, are reprogrammed to cause tumors to develop over time. Moreover, these reprogrammed stem cells and the differentiated cells they produce are also involved in many of the fundamental alterations that occur during aging or in patients with inflammatory bowel disease—2 other conditions that have been shown to elevate the risk for CRC.

Collaborative Findings

The Kelly and Augenlicht labs recently discovered that metabolism of xenobiotics—foreign compounds in the gut that are ingested—can be driven by microbial community production of sulfide (H₂S), a highly reactive chemical compound that reduces structurally diverse azo compounds, including drugs and other xenobiotics.²⁵ This novel, nonenzymatic mechanism of drug metabolism in the gut overturns the standard enzymatic paradigm for how microbes interact with xenobiotics. It also indicates that gut chemistry, derived from microbial community function, has been a missing component that shapes metabolism in the gut.²⁵ The team found that H₂S production is a core feature of human gut microbiomes and showed that H₂S concentrations in the gut are adjustable by diet in mouse models. As a highly reactive molecule that chemically reduces many molecules that are either produced in the gut or ingested, H₂S can be toxic, and diets containing a high level of sulfur, in particular sulfur containing amino acids, have been associated with CRC risk.²⁶

The NWD1 high-risk diet increases H₂S levels in the gut by 2 mechanisms: by providing higher levels of sulfur-containing amino acids and by increasing the number of bacteria capable of producing H₂S.²⁵ Further, the human stem cells of the gut sense this increased production of H₂S, elevating the activity of a pathway that can eliminate H₂S. This is of major interest, since this pathway exists in the mitochondria of the human cells—a subcellular organelle—and disruption of the structure and function of the mitochondria has been identified by the Augenlicht lab as a key to how the NWD1 diet alters the stem cells, causing the recruitment of alternate stem cells that increases risk for tumors to form.⁴ Recent data from our collaboration have shown that this mediated biochemical alteration may precede the appearance of tumors. Thus, these changes in the microbiome can be a marker to indicate elevated tumor risk and a signal for intervention to reduce risk.

Building on our research findings that highlight the complex biology of the gut, several research goals remain. First, we must understand details of the biochemistry and alterations in gene and cell function that tie the effects of the diet on the intestinal bacteria and the intestinal stem cells that determine the chance of tumor development. A second goal is to identify dietary patterns, or individual nutrient interventions, that can reduce the detrimental impact of bacteria-epithelial cell interaction. A third goal is to harness the detailed understanding of this ecosystem to identify individuals who are at elevated risk for tumor development and to closely monitor those at higher risk for tumors in earlier stages when tumors can be readily removed for cure, and, better yet, perhaps motivate those identified to be at risk to alter their lifestyle so that the tumors never arise.

Leonard Augenlicht, PhD, is a professor of medicine and cell biology; Ziv Cohen, PhD, is part of the Department of Systems and Computational Biology; Sarah Wolfson, PhD, is a staff scientisit in the Department of Systems and Computational Biology; Jiahn Choi, PhD, is an instructor in cell biology; and Libusha Kelly, PhD, is an associate professor of Systems and Computational Biology, all at the Montefiore Einstein Cancer Center.

References

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