Acarbose’s Impact on Glucose Metabolism, Gut Health, and Inflammation: The Potential in Colorectal Cancer Prevention

In recent years, as researchers continue to explore innovative approaches to preventing age-related diseases, the connection between health, lifestyle, and cancer risk has garnered significant attention.

Colorectal cancer (CRC) has become a focal point of concern due to a shifting pattern in incidence rates. While cases have been steadily declining in older populations, largely due to improved screening and early detection methods, there has been a troubling rise in CRC diagnoses among younger adults. This increase is particularly alarming, as it highlights the limitations of current preventative strategies and the need for more innovative approaches that address CRC risk from multiple angles.

One therapy that has emerged in this conversation is acarbose. Acarbose works by inhibiting α-glucosidase, an enzyme involved in carbohydrate digestion, thereby slowing glucose absorption and reducing postprandial spikes in blood sugar and insulin levels. This mechanism, long studied for its benefits in managing metabolic conditions, may also have far-reaching implications for cancer prevention, specifically in relation to CRC.

In this review, our Healthspan Research Review team will examine the potential of acarbose as a preventative agent for CRC. We will explore the drug’s impact on glucose metabolism, its ability to promote a healthy gut microbiome, and its anti-inflammatory properties—key factors in cancer development. Through this analysis, we aim to provide a deeper understanding of acarbose's emerging role in CRC prevention and its broader applications in the fight against age-related diseases.

Background

According to the Centers for Disease Control and Prevention (CDC), approximately 150,000 new cases of colorectal cancer (CRC) are diagnosed each year in the United States. Globally, CRC ranks as the third most commonly diagnosed cancer. In 2021, there were 141,902 new cases of CRC in the U.S., and 52,967 deaths were reported in 2022. While CRC is most commonly diagnosed in individuals over the age of 50, there has been a worrying rise in cases among younger populations. Since 1994, the incidence of CRC in individuals under 50 has been increasing by 2% per year. This alarming trend in younger adults contrasts with the overall decline in CRC rates. [1] 

The etiology of colorectal cancer (CRC) is complex, involving an interplay of genetic, lifestyle, and environmental factors. Genetic predispositions, particularly family history, play a significant role in increasing the risk of CRC. Individuals with a first-degree relative (parent, sibling, or child) who has had CRC are at a higher risk, and this risk increases with the number of affected relatives. Certain hereditary conditions, such as Lynch Syndrome, which involves mutations in DNA repair genes, and Familial Adenomatous Polyposis (FAP), characterized by mutations in the APC gene, further elevate this risk by causing the development of numerous polyps in the colon, some of which may become cancerous if untreated. [2]

It's important to note that 50% of young adults diagnosed with CRC have neither hereditary syndromes nor a family history of the disease, which presents a significant challenge for researchers in identifying other contributing factors. Understanding these risk factors is crucial for developing effective prevention strategies and reducing the incidence of CRC across all age groups. [1] [7]

While genetic factors are crucial, lifestyle choices significantly contribute to CRC risk. Diet plays a major role, with high consumption of red and processed meats and low intake of fruits, vegetables, and whole grains known to increase CRC risk. Physical inactivity is another key risk factor, as regular exercise helps maintain a healthy weight, improves digestion, and reduces inflammation, all of which lower CRC risk. Obesity, particularly abdominal obesity, is strongly associated with a higher risk of CRC. Excess body fat can lead to elevated insulin levels, promoting the growth of cancer cells. Smoking is also linked to an increased risk of CRC, as the carcinogens in tobacco smoke can cause mutations in the DNA of colon cells. Similarly, heavy alcohol consumption is associated with a higher CRC risk, as alcohol can irritate the colon lining, leading to inflammation and the production of acetaldehyde, a known carcinogen. [3]

Environmental factors further contribute to CRC risk. Certain occupations involve exposure to carcinogens, such as asbestos, arsenic, and polycyclic aromatic hydrocarbons (PAHs), which can increase the risk of various cancers, including CRC. Additionally, prolonged exposure to shift work, particularly night shifts, has been associated with a higher risk of CRC due to disruptions in circadian rhythms, which can affect hormone levels and immune function, contributing to cancer risk. Long-term exposure to air pollution is linked to an increased risk of CRC, as it can induce chronic inflammation, oxidative stress, and DNA damage. Moreover, living in urban environments, where access to recreational spaces may be limited, often correlates with sedentary lifestyles and dietary changes that further elevate CRC risk. [3]

Understanding these risk factors is vital for taking proactive measures to prevent CRC, especially given its progressive nature and the serious symptoms it can cause. 

The Gut Microbiome and CRC:

The gut microbiome, consisting of trillions of microorganisms—including bacteria, viruses, fungi, and other microbes—resides primarily in the intestines and plays active roles in essential bodily functions such as digestion, metabolism, immune system regulation, and protection against harmful pathogens. The composition of the gut microbiome is unique to each individual and is shaped by various factors, including diet, lifestyle, genetics, and environmental exposures.

A healthy gut microbiome is characterized by a diverse range of beneficial bacteria that work harmoniously to maintain balance within the gut environment. These bacteria help break down complex carbohydrates and fibers, produce essential nutrients like short-chain fatty acids (SCFAs), and regulate immune responses. However, when this balance is disrupted—a condition known as dysbiosis—the composition of gut bacteria shifts in a way that can promote disease, including colorectal cancer (CRC). [8]

The correlation between CRC and the gut microbiome is well-established, with a growing body of epidemiological data highlighting the significant role that gut bacteria play in CRC development. One of the most important influences on the gut microbiome is diet. Diets high in fat and low in fiber, typical of a Western lifestyle, have been linked to an increased risk of CRC by altering the microbiome's composition. Research shows that individuals with CRC often exhibit reduced diversity in their gut bacteria. Beneficial bacteria, such as Roseburia and butyrate-producing species from the Lachnospiraceae family, tend to be less abundant in CRC patients. These bacteria are crucial because they produce butyrate, a type of SCFA with anti-inflammatory and anti-cancer properties that supports colon cell health and can induce apoptosis, or programmed cell death, in cancerous cells. [8

In contrast, CRC patients often have an overrepresentation of potentially harmful bacteria, such as Enterococcus and Escherichia/Shigella. These bacteria can contribute to CRC development and progression by creating an environment conducive to inflammation and disrupting the normal functions of the gut barrier. [8]

Dysbiosis, or the imbalance in gut microbiota, is a critical factor in CRC development. This imbalance can increase intestinal permeability, sometimes called "leaky gut," allowing harmful substances to pass into the bloodstream. This increased permeability, combined with a pro-inflammatory environment, can promote the growth and spread of cancer cells. For example, Fusobacterium nucleatum (F. nucleatum), a bacterium commonly found in higher concentrations in CRC patients, is known to exacerbate inflammation and interfere with the immune system's ability to combat tumor cells, thereby promoting tumor growth. [8]

However, certain bacteria within the gut microbiome offer significant protective benefits against CRC, highlighting the complex role that gut bacteria play in either promoting or preventing disease. Faecalibacterium prausnitzii is widely recognized for its potent anti-inflammatory properties. It produces molecules that specifically downregulate the NF-κB pathway in gut epithelial cells, a key pathway involved in the inflammatory response. By inhibiting this pathway, Faecalibacterium prausnitzii helps prevent the onset of colitis, a condition that can increase CRC risk and may directly reduce the likelihood of cancerous developments in the colon. [8]

In addition to Faecalibacterium prausnitzii, certain probiotic species such as Lactobacillus and Bifidobacterium have shown considerable potential in safeguarding against CRC. These probiotics contribute to gut health by enhancing gut barrier integrity, reducing inflammation, and inhibiting tumor growth. For instance, Lactobacillus rhamnosus GG strengthens gut barrier function and promotes the production of mucins, which protect the gut lining, while Bifidobacterium lactis Bb12 reduces epithelial proliferation—a process often associated with cancerous growth—thereby lowering CRC risk. [8]

Another crucial element in CRC prevention is the role of SCFAs, particularly butyrate, produced during the fermentation of dietary fiber by gut bacteria. Butyrate is a key metabolite that exerts a powerful influence on gut health by serving as the primary energy source for colonocytes (the cells lining the colon) and inducing apoptosis in tumor cells. Additionally, butyrate regulates immune responses by promoting the expansion of regulatory T cells (Tregs), which are essential for maintaining immune tolerance and suppressing chronic gut inflammation, another significant CRC risk factor. [8]

Given the protective roles of certain gut bacteria and their metabolites, microbiome modulation has emerged as a promising avenue for CRC prevention and treatment. One innovative approach in this field is fecal microbiota transplantation (FMT), which involves transplanting stool from healthy donors into patients with a disrupted gut microbiome. FMT aims to restore a balanced microbiome, enhancing immune responses and creating an environment less conducive to cancer. There is growing evidence that FMT may not only help prevent CRC but could also improve the effectiveness of existing cancer treatments, particularly in patients who have developed resistance to certain therapies. [8]

However, while the potential of microbiome modulation is vast, the field is still in its infancy, and further research is essential to fully understand the complex interactions between gut bacteria and CRC.

Acarbose and CRC:

Given the central role of the gut microbiome in colorectal cancer (CRC) prevention, there is growing interest in therapies that can beneficially modulate gut bacteria. One such promising therapy is acarbose, a medication traditionally used for managing diabetes.

Acarbose's primary action occurs by inhibiting α-glucosidase, an enzyme that breaks down complex carbohydrates into simpler sugars like glucose. This inhibition delays the conversion of carbohydrates into glucose, reducing the rate of glucose absorption in the small intestine. As a result, postprandial (after-meal) blood sugar spikes are diminished, leading to lower overall glucose levels throughout the day. Acarbose thus helps prevent the rapid insulin surges that typically accompany high glucose intake. Elevated insulin and glucose levels are known to fuel tumor growth by providing cancer cells with the necessary energy for proliferation. Acarbose's ability to dampen these spikes means fewer resources for potential cancer cells, effectively "starving" them of the energy they require for rapid growth. [4]

In addition to lowering blood glucose, acarbose helps reduce circulating insulin levels. This reduction in insulin has a cascade effect, particularly on Insulin-like Growth Factor 1 (IGF-1), a hormone that mirrors insulin's growth-promoting effects but primarily acts on cell proliferation and differentiation. High levels of IGF-1 have been linked to several cancers, including CRC, due to their role in stimulating cell division and inhibiting apoptosis (programmed cell death). Acarbose's ability to lower IGF-1 levels indirectly limits the promotion of cellular environments conducive to cancer development. [4]

Acarbose's Impact on the Gut Microbiome

Beyond glucose regulation, one of acarbose's most intriguing benefits lies in its effect on the gut microbiome. The undigested carbohydrates that reach the colon serve as substrates for fermentation by gut bacteria. Acarbose specifically encourages the growth of beneficial bacterial species such as Bifidobacteria and Lactobacilli, which play critical roles in maintaining gut health. These bacteria ferment carbohydrates into short-chain fatty acids (SCFAs), including acetate, propionate, and butyrate. [4]

Butyrate, in particular, stands out for its potent anti-cancer properties. It is the primary energy source for colonocytes (the cells lining the colon) and is pivotal in maintaining intestinal health. Mechanistically, butyrate promotes apoptosis in cancer cells while leaving healthy cells largely unaffected. It also inhibits cell proliferation, thereby preventing the growth of tumors. Butyrate's anti-inflammatory properties are equally important, as chronic inflammation in the gut is a known risk factor for CRC. By reducing inflammation, butyrate helps create an environment less favorable to cancer development. In fact, butyrate has been shown to inhibit histone deacetylases (HDACs), enzymes that are often overexpressed in cancerous cells and lead to unchecked cell growth. HDAC inhibition promotes the re-expression of tumor-suppressor genes, facilitating cancer cell death. [4]

The production of SCFAs, particularly butyrate, also has systemic effects beyond the gut. SCFAs are absorbed into the bloodstream, modulating immune function and reducing systemic inflammation. SCFAs have been shown to inhibit pro-inflammatory cytokines like IL-6 and TNF-alpha, both of which are implicated in chronic inflammation and cancer progression. IL-6 is known to activate the JAK/STAT3 pathway, which promotes cancer cell survival and proliferation. TNF-alpha, on the other hand, can induce oxidative stress and DNA damage, further increasing cancer risk. By lowering levels of these pro-inflammatory molecules, acarbose indirectly helps suppress cancer-promoting pathways. [4]

Acarbose's Modulation of Inflammatory Pathways

Acarbose's influence on inflammation is not limited to its effects on SCFA production. By stabilizing blood glucose levels, acarbose reduces the inflammatory response triggered by hyperglycemia. High blood sugar levels are known to induce oxidative stress and inflammation, both of which contribute to cancer development. Hyperglycemia leads to the generation of reactive oxygen species (ROS), highly reactive molecules that can damage cellular components, including DNA, proteins, and lipids. DNA damage caused by ROS is a significant driver of cancer initiation and progression. Acarbose reduces the formation of ROS by lowering blood glucose and insulin levels, thereby decreasing oxidative stress

In experimental studies, acarbose has been shown to reduce oxidative stress markers, such as malondialdehyde (MDA) and 8-hydroxy-2'-deoxyguanosine (8-OHdG). MDA is a byproduct of lipid peroxidation, a process in which free radicals attack the lipids in cell membranes, causing cell damage. Elevated levels of MDA are often found in cancerous tissues. Similarly, 8-OHdG is a marker of oxidative DNA damage and is frequently used as a biomarker for cancer risk. By reducing these oxidative stress markers, acarbose helps protect cells from the DNA damage that can lead to cancer development. 

Furthermore, acarbose's role in reducing insulin resistance and hyperinsulinemia also contributes to its anti-inflammatory effects. Insulin resistance, a hallmark of metabolic disorders like T2D, is associated with chronic low-grade inflammation. This inflammatory state is thought to play a significant role in cancer progression, as it creates an environment where pro-inflammatory cytokines, growth factors, and immune cells can promote tumor growth. Acarbose reduces this inflammatory burden by improving insulin sensitivity and lowering circulating insulin levels, attenuating the chronic inflammatory signals contributing to cancer development. [4][5][6]

Acarbose's Influence on Tumor Growth and Cancer Metabolism

The metabolic reprogramming of cancer cells, known as the Warburg effect, is characterized by an increased reliance on glucose for energy production, even in the presence of oxygen. This metabolic shift allows cancer cells to rapidly generate the energy and biosynthetic precursors needed for proliferation. Acarbose disrupts this process by reducing glucose availability, effectively starving cancer cells of their primary energy source. Animal studies have demonstrated that acarbose slows tumor growth by reducing glucose metabolism and lowering circulating insulin and IGF-1 levels, which are critical for cancer cell survival and growth. [6]

By limiting glucose availability, acarbose also affects cancer cells' ability to produce the building blocks necessary for DNA, RNA, and protein synthesis. Without these essential components, cancer cells cannot replicate as efficiently, slowing tumor growth. Moreover, reduced insulin signaling inhibits the PI3K/AKT/mTOR pathway, a key regulator of cell growth and survival that is often hyperactivated in cancer. The inhibition of this pathway further limits cancer cell proliferation and enhances apoptosis. [6]

Recent Research on Acarbose and CRC:

Acarbose's effects on glucose metabolism, gut microbiota, inflammation, and oxidative stress collectively create a less favorable environment for cancer development, especially in the colon. By lowering blood glucose and insulin levels, acarbose directly disrupts metabolic pathways that cancer cells rely on for growth. Its ability to promote the growth of short-chain fatty acid (SCFA)-producing bacteria while reducing pro-inflammatory cytokines strengthens its potential in colorectal cancer (CRC) prevention. [9] [10]

Recent research into acarbose's role in cancer has yielded promising insights. Studies in this area typically focus on two types of research: (1) experimental studies using animal models (in vivo) and cancer cells (in vitro) and (2) clinical trials in human patients. 

For example, a study by Zhan et al. (2022) investigated the combined effects of acarbose and anti-PD1 immunotherapy on colon cancer in mouse models. Anti-PD1 therapies are a type of immunotherapy that blocks PD1 proteins in immune cells, preventing cancer cells from evading immune detection. This allows the immune system to better target and destroy cancer cells. [9] 

In Zhan et al.'s study, acarbose and anti-PD1 monotherapies were effective in slowing tumor growth, but combining the two treatments yielded even stronger results. Tumor size and weight were significantly reduced in mice treated with both acarbose and anti-PD1 compared to those treated with monotherapies or placebo. Microscopic analysis showed increased CD8+ T cells—a type of immune cell that directly kills cancerous cells—within the tumors treated with combination therapy. The highest CD8+ T cell infiltration levels were observed in the combination therapy group, suggesting a synergistic interaction between acarbose and anti-PD1 immunotherapy. [9] 

In addition to animal studies, large-scale clinical trials have also examined the potential cancer-preventive effects of acarbose. One notable example is a Nationwide Population-Based Cohort Study (2015) published in Diabetes Care, which analyzed data from over 1.3 million newly diagnosed diabetic patients using the Taiwan National Health Insurance Research Database. This study found that acarbose use was associated with a 27% reduction in CRC risk. The protective effect appeared to be dose-dependent, with higher cumulative doses of acarbose linked to a greater reduction in CRC risk. This large-scale study highlights acarbose's potential for cancer prevention, particularly among individuals with diabetes. [10] 

While results of recent studies have been promising, they represent only an initial step toward fully understanding acarbose's role in cancer prevention and treatment. More research is necessary to clarify how acarbose impacts tumor biology, its long-term effects on cancer patients, and how it might be integrated into broader cancer treatment protocols. [9] 

Further studies should aim to explore the broader immunological effects of acarbose, including its potential to modulate other immune cell populations, as well as its interaction with different cancer types. Additionally, human clinical trials will be essential to confirm whether the synergistic effects observed in animal models translate to similar benefits in cancer patients. Given its ability to impact glucose metabolism, gut microbiota, inflammation, and immune responses, acarbose could become an important adjunct to existing cancer therapies.

Future Directions in Acarbose and CRC Prevention

The potential of acarbose as a therapeutic agent in colorectal cancer (CRC) prevention and management is promising, but there are significant gaps in current research that need to be addressed for a comprehensive understanding of its efficacy. One major gap is the need for clinical trials specifically designed to assess the impact of acarbose on CRC progression in human populations. While preclinical studies and observational data have shown encouraging results, robust randomized controlled trials (RCTs) are necessary to establish causality. These trials are critical for determining acarbose's appropriate dosing, safety, and long-term efficacy in CRC prevention and treatment.

Additionally, there is limited research exploring the exact mechanisms by which acarbose exerts its effects on CRC. While we can infer potential mechanisms based on acarbose's role in diabetes management—such as its modulation of blood glucose and insulin levels—these mechanisms must be specifically validated in CRC-focused studies. Detailed mechanistic research will help clarify how acarbose interacts with cancer cells, immune responses, and the gut microbiome to inhibit CRC development or progression.

Moreover, most existing studies on acarbose in cancer contexts have been preclinical or observational, underscoring the need for longitudinal cohort studies. Long-term clinical trials tracking patients over several years are essential to observe the lasting effects of acarbose on CRC incidence and recurrence. This is particularly important since cancer prevention and progression are often slow processes, and short-term studies may miss critical outcomes. These trials would provide a clearer understanding of acarbose's potential role in reducing CRC risk over time.

Currently, acarbose is not a standard treatment for CRC, but its use in longevity therapies could position it as a potential protective factor against CRC development. One known effect of acarbose is its ability to modulate the gut microbiome, which is increasingly recognized as a critical factor in cancer prevention. A deeper understanding of how acarbose influences the gut microbiota, particularly in relation to SCFA production and inflammation modulation, could further elucidate its role in CRC prevention.

While the current research on acarbose and CRC is promising, there are significant opportunities to expand our understanding through well-designed clinical trials, mechanistic studies, and investigations into combination therapies. Acarbose's role in gut microbiome modulation, glucose metabolism, and inflammation control makes it a compelling candidate for further study in cancer prevention, particularly in high-risk and aging populations.