The hidden partnership: how gut bacteria and obesity shape colorectal cancer risk

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Introduction

Colorectal cancer (CRC) is a malignancy that originates in the colon or rectum, both of which are part of the large intestine. Millions of people globally are diagnosed with this disease, leading to approximately one million deaths each year. While CRC traditionally affected older individuals, it is now increasingly being diagnosed in people under the age of 50, with men being more affected than women [1]. In the absence of effective therapies, CRC is a major public concern. A number of risk factors contributing to the development of CRC that have been identified so far, include genetic predisposition, gut bacteria, lifestyle-related factors such as diets rich in red and processed meats, alcohol consumption, and obesity [2]. To understand how these risk factors contribute to disease onset, it is essential to first understand how this disease develops.

How colorectal cancer develops in the colon

Colorectal cancer is known to develop gradually from tiny noncancerous growths in the lining of the intestine called adenomas. This process is believed to be influenced by an unhealthy lifestyle and environmental factors. A small proportion of CRC cases arise from inherited conditions, while a large proportion are sporadic, resulting from a combination of genetic and environmental factors. The development of sporadic CRC follows a well-established sequence known as the adenoma–carcinoma sequence. This process begins with genetic changes in the intestinal epithelium, involving mutations in cancer-causing genes. These changes are thought to induce the formation of small non-cancerous growths known as benign adenomatous polyps. Over time, the accumulation of additional mutations leads to the development of abnormal cells, which eventually transform into cancerous cells [3]. With this stepwise progression in mind, attention is now directed towards key modifiable factors that influence and accelerate this process.

Obesity as a driving factor for colorectal cancer

Obesity, defined as a body mass index (BMI) of 30 or more, is a well-established risk factor for colorectal cancer (CRC). Its role in this malignancy is understood as an active mediator rather than just a passive risk factor. Obesity is also a recognized risk factor for other cancer types such as breast, liver, pancreas, and kidney cancers. The positive association between excess body weight and CRC risk was first reported by Bergström and colleagues in 2000. Their study showed that each unit increase in BMI was associated with a 3% increase in cancer risk, with most of the cases being that of CRC [4]. Since these findings were derived from studies in the Western world, the study demonstrates the role of obesity as a modifiable risk factor in CRC development.

Excess body fat in obese individuals secretes chemical signals (pro-inflammatory cytokines) that create a chronic inflammatory environment. This inflammation can potentially damage DNA, promote cell proliferation, and suppress apoptosis (cell death), thereby supporting the development of early stages of CRC [5]. In addition, obesity is commonly associated with insulin resistance and elevated insulin levels, which increase circulating levels of insulin and insulin-like growth factor-1 in the blood [6]. These factors can promote the growth and survival of pre-cancerous and cancerous cells in the colon. Although obesity plays a crucial role in colorectal cancer risk, it is not the only factor at play. Gut bacteria have also been shown to play a crucial role in the development of this disease.

The role of gut microbiota

Besides obesity, gut bacteria is another risk factor for CRC. The human gastrointestinal tract harbors diverse microorganisms that play a role in maintaining intestinal microbial balance, nutrient metabolism, and regulating the host immune system. However, when this delicate balance is disturbed, harmful bacteria can proliferate in the intestine. This imbalance can lead to chronic inflammation, damage to the intestinal barrier, and the generation of bacterial substances (toxins and metabolites) that contribute to the development of colorectal cancer [7]. Considering the pivotal role of obesity and gut bacteria, it is important to understand how these two factors interact to drive CRC progression.

How obesity and gut microbiota work together

Colorectal cancer is increasingly understood to be influenced by a complex interaction between gut bacteria and obesity. At the center of this interaction is the disruption of the delicate balance of the gut microbiota, where harmful bacteria and their byproducts build up while beneficial bacteria decrease. 

This imbalance has been linked to cancer development through various mechanisms. For instance, bacteria named Escherichia coli produces colibactin, a toxin that damages DNA and induces genetic changes in intestinal epithelial cells. Other bacterial strains such as Bacteroides fragilis and Fusobacterium nucleatum, promote inflammation by activating the immune response, creating a favorable cancer environment while suppressing anti-cancer immune responses [8].

Bacteria can also produce substances that influence the development of colorectal cancer. For example, short-chain fatty acid-producing bacteria, particularly those that produce Butyrate, support epithelial layer integrity, regulate the immune system, and induce apoptosis (cancer cell death). However, imbalances in the gut microbiota or changes in metabolism can cause certain bacterial byproducts to promote inflammation and cancer progression. [9]. To gain insights into this interaction, recent studies have begun to uncover the mechanisms linking obesity, gut microbiota, and colorectal cancer risk.

A recent study by Yates and colleagues examined the connection between obesity and gut microbiota in colorectal cancer. The study shows that genetically predicted obesity increases the risk of cancer, partly due to its effect on the composition of gut microbes. Using a Mendelian randomization approach, Yates and colleagues identified Actinobacteria as a key mediator in this relationship. These bacteria, which are linked to an increased risk of colorectal cancer and are positively associated with obesity, provide a mechanistic link between obesity and cancer development. Indeed, the changes in gut bacteria identified in this study may explain up to approximately half of the total effect of BMI (a measure of obesity) on colorectal cancer risk, indicating that these changes are not just a secondary occurrence but an important link between obesity and cancer [10]. These findings not only strengthen our understanding of disease mechanisms but also suggest new opportunities for diagnosis and possible therapy.

Conclusion

Colorectal cancer, one of the leading causes of cancer-related deaths, is influenced by genetic susceptibility, lifestyle choices, and environmental factors. Recent research has established a connection between obesity and gut bacteria in the development of colorectal cancer. An imbalance between harmful and beneficial bacteria can lead to the accumulation of harmful bacteria, triggering inflammation, DNA damage, and weakening host immunity. Therefore, early changes in gut bacteria can be explored as possible diagnostic biomarkers to detect precancerous lesions or early-stage disease. Additionally, interventions such as dietary changes, probiotics, and targeted microbial therapies show promise in the prevention and treatment of colorectal cancer.

References

1.            WHO: Colorectal cancer. wwwwhoint/news-room/fact-sheets/detail/colorectal-cancer  2026.

2.            Laskar RS, Murphy N, Ferrari P, Brennan P, Cross AJ, Guevara M, Pala V, Smith-Byrne K, Tjønneland A, Fortner RT et al: A prospective investigation of early-onset colorectal cancer risk factors–pooled analysis of three large-scale European cohorts. British Journal of Cancer 2026, 134(5):781-789.

3.            Simon K: Colorectal cancer development and advances in screening. Clinical interventions in aging 2016, 11:967-976.

4.            Bergström A, Pisani P, Tenet V, Wolk A, Adami H-O: Overweight as an avoidable cause of cancer in Europe. International Journal of Cancer 2001, 91(3):421-430.

5.            Miranda BC, Tustumi F, Nakamura ET, Shimanoe VH, Kikawa D, Waisberg J: Obesity and Colorectal Cancer: A Narrative Review. In: Medicina. vol. 60; 2024: 1218.

6.            Aleksandrova K, Nimptsch K, Pischon T: Influence of Obesity and Related Metabolic Alterations on Colorectal Cancer Risk. Current Nutrition Reports 2013, 2(1):1-9.

7.            Campillo-Gimenez L, Yang Y, De Los Reyes-Gavilan CG, Izumi T: Editorial: "The Host-Microbiome Interplay in Colorectal Cancer". Frontiers in cellular and infection microbiology 2022, 12:906719.

8.            Bautista J, Lamas-Maceiras M, Hidalgo-Tinoco C, Guerra-Guerrero A, Betancourt-Velarde A, López-Cortés A: Gut microbiome-driven colorectal cancer via immune, metabolic, neural, and endocrine axes reprogramming. NPJ biofilms and microbiomes 2026, 12(1):21.

9.            Liu Y, Lau HC, Yu J: Microbial metabolites in colorectal tumorigenesis and cancer therapy. Gut microbes 2023, 15(1):2203968.

10.          Yates T, Went M, Mills C, Law P, Gockel I, Maj C, Schumacher J, Palles C, Houlston R: Mendelian randomisation analysis to discover plasma metabolites mediating the effect of obesity on cancer risk. Br J Cancer 2025, 133(9):1344-1353.

Authored by

Micah Sagini

Assessed and Endorsed by the MedReport Medical Review Board