The Interplay Between Obesity, Gut Microbiota and Early-onset Colorectal Cancer

Abstract

The global incidence of colorectal cancer (CRC) is rising at an alarming rate, particularly among individuals under the age of 50, referred to as early-onset CRC (EOCRC). While genetic predisposition accounts for approximately 20% of the total cases, the majority are influenced by environmental and lifestyle factors. Among these, the rising prevalence of obesity is a major modifiable contributor to EOCRC pathogenesis.This narrative review explores the multifaceted role of obesity in EOCRC, focusing on how diet-induced adiposity reshapes the gut microbiota and host metabolic signaling.We synthesize evidence on how obesity-associated dysbiosis, characterized by the depletion of protective, short-chain fatty acid (SCFA)-producing bacteria and the enrichment of genotoxic pathobionts, compromises intestinal barrier integrity and promotes a “leaky gut” phenotype. In addition, we explore the systemic consequences of obesity-driven inflammation, including M1-polarized macrophage infiltration into adipose tissue, dysregulated adipokine signaling, and the hyperactivation of the insulin-IGF-1 axis.By integrating epidemiological data with molecular mechanisms, this review highlights how the synergy between metabolic dysfunction and microbial alterations creates a fertile niche for early-onset carcinogenesis. These findings underscore the importance of targeting lifestyle interventions to mitigate the rising burden of obesity and reduce the risk of EOCRC progression.

Introduction

Colorectal cancer (CRC) is a cancer that occurs in the colon or rectum. It is the third most frequently diagnosed malignancy worldwide and the second leading cause of cancer-related mortality (1). According to a 2020 report by the American Cancer Society, CRC incidence declined by 3.3% annually and mortality by 3% annually among individuals aged 65 and older. However, in those under 50, the incidence of early-onset CRC (EOCRC) has increased by 2% per year, with a 1.3% annual rise in mortality (2, 3). This global increase in EOCRC appears largely independent of hereditary factors, suggesting a shift driven by environmental and lifestyle changes (2, 4, 5). The same trend is observed in Malaysia, a country in the Asia-Pacific region, where the rising incidence of EOCRC is a public health concern (6).

Risk factors for EOCRC include family history of CRC, personal history of diabetes, obesity, hypertension, prolonged sedentary behavior, higher consumption of sugary drinks, smoking, alcohol intake, and Westernized dietary patterns (7-9). Additionally, more frequent consumption of fast food and canned food is associated with a higher risk of EOCRC, while greater fiber intake is linked to a reduced risk (7, 9). Interestingly, obesity is highly prevalent among Malaysian adults, affecting approximately half of the population (10). Obesity results from a combination of genetic, epigenetic, and nutritional factors. Studies have found a strong correlation between obesity in early adulthood and an increased risk of developing EOCRC (11, 12). This association is likely mediated by complex biological mechanisms including dysregulated hormone metabolism, abnormal insulin and insulin-like growth factor (IGF) signaling, and activation of systemic inflammatory and adipokine pathways.

The critical role of gut microbiota in colorectal carcinogenesis is also undeniable. The human intestine harbors a complex ecosystem of trillions of microbes that regulate the immune system, maintain intestinal barrier integrity, and metabolize dietary substrates into bioactive compounds (13). In a state of dysbiosis, the loss of protective microbes allows for the expansion of opportunistic pathobionts (14). This will lead to disruption of intestinal barrier integrity and a compromised host immune system, promoting tumor progression. An unhealthy diet and a sedentary lifestyle are linked to alterations in gut microbiota composition, which may lead to obesity (13-15). This obesity-induced dysbiosis impairs the production of health-promoting metabolic products like SCFAs, while driving metabolic dysfunction and disruption of intestinal barrier integrity. The exact mechanistic interplay between obesity and gut microbiota in CRC development remains unclear.

To address the limitations in the current understanding of the rise in EOCRC, this review examines the role of obesity in creating a pro-tumorigenic colonic microenvironment. We synthesize existing literature to highlight the interplay between metabolic dysregulation, shifts in gut microbiota, and compromised barrier function. This review aims to provide an evidence-based perspective on the biological mechanisms of early-onset carcinogenesis and the urgent need for tailored intervention strategies.

Obesity-associated Colorectal Cancer

Obesity is widely recognized as a major environmental risk factor in the pathogenesis of CRC (16, 17). Beyond the colon, obesity is a well-established risk factor for numerous malignancies, with at least 12 distinct cancer types including esophageal, pancreatic, hepatic, breast, and uterine cancers, demonstrating increased incidence among individuals with excess adiposity (18). According to the World Health Organization, the prevalence of obesity has escalated significantly over recent decades, with global rates more than doubling since 1990. This upward trend in obesity rates parallels the rising global incidence of CRC, particularly in countries undergoing rapid socioeconomic and lifestyle transitions (12, 19, 20). Notably, the burden of overweight and obesity continues to escalate in middle- and lower-income countries, including Malaysia (10). Data from the National Health and Morbidity Survey (NHMS) Malaysia indicates that more than half of the adult population is overweight or obese (50.1%), a concerning trend given that nearly 80% of affected individuals are under 60 years of age (10, 21).

Epidemiological evidence consistently demonstrates that excess body weight, particularly central adiposity, is associated with an increased risk of CRC. Each 5 kg/m² increase in body mass index (BMI) is linked to a significant rise in CRC risk (22, 23). Notably, women with obesity (BMI ≥30) have been shown to have nearly double the risk of EOCRC compared with women whose BMI ranges from 18.5 to 22.9 (24). A recent population-based cohort study reported that men in all age groups had an increased risk of CRC with higher BMI, with the strongest association observed for right-sided colon cancer (23). Importantly, accumulating evidence suggests that adiposity during early life plays a critical role in the development of EOCRC. Meta-analyses have shown that elevated BMI in early life is associated with a 39% increased risk of CRC in adult men and a 19% increased risk in adult women (25-27). Supporting this, genomic studies in mouse models of diet-induced obesity demonstrate that obesity-related metabolic reprogramming of colonic epithelial cells at a young age may act as an initiating event, expanding the pool of cells with tumorigenic potential and promoting subsequent tumor development (28).

There are conflicting findings regarding BMI and EOCRC risk. A population-based study by Chang et al. (2021) unexpectedly reported an inverse association between BMI and EOCRC. This could be due to reverse causality driven by tumor-induced weight loss, commonly seen in aggressive early-onset malignancies (7). Furthermore, BMI lacks the resolution to differentiate between lean muscle mass and visceral adiposity (7). In contrast, central obesity characterized by excess abdominal fat has been shown to be more strongly associated with metabolic disorders such as diabetes, cardiovascular disease and overall mortality, even among individuals with a normal BMI (29). Growing evidence suggests that central obesity may account for a substantial proportion of the CRC risk attributed to obesity (30, 31). Measures of central adiposity, including waist-to-hip ratio (WHR) and waist circumference (WC), more accurately reflect visceral fat accumulation than BMI and are associated with increased metabolic risk even in normal-weight individuals. This highlights their potential superiority as indicators of obesity-related CRC risk. Indeed, association studies evaluating BMI, WHR, and WC have demonstrated that WHR exhibits a strong and statistically significant relationship with CRC risk across all BMI categories, in both sexes, and for both colon and rectal cancers, even after adjustment for BMI (31).

In addition, obesity is closely associated with other lifestyle-related risk factors, including dietary patterns, physical inactivity, and alcohol consumption, which together amplify CRC risk (32). Birth cohort analyses further indicate that the rising burden of EOCRC is largely driven by early-life environmental and lifestyle exposures, such as increased consumption of processed foods, sedentary behavior, antibiotic use and gut microbiota alterations, all of which can disrupt metabolic and inflammatory homeostasis and promote a pro-tumorigenic environment from an early age (33). Diets associated with obesity are often characterized by higher intake of red and processed meats and lower consumption of plant-based foods, patterns shown to increase key indicators of adiposity such as BMI and WC (34). High consumption of red and processed meats has been classified as carcinogenic, mainly due to the formation of genotoxic and mutagenic compounds, thereby contributing to increased CRC risk (34, 35). Furthermore, individuals with obesity are more likely to exhibit lower levels of physical activity and increased sedentary behavior, which promote insulin resistance and chronic inflammation, both fundamental mechanisms in colorectal carcinogenesis (32, 36). Alcohol consumption further exacerbates this risk by disrupting lipid and mitochondrial metabolism, contributing to weight gain and central adiposity, and inducing inflammation and unbalanced oxidative stress, which are key mechanisms that promote tumor development (37). Collectively, these interrelated lifestyle factors interact with obesity to create a pro-tumorigenic environment, highlighting the importance of integrated lifestyle modification in reducing CRC risk.

Diet and Obesity

The fundamental driver of obesity is a sustained energy imbalance, whereby caloric intake through overnutrition exceeds energy expenditure (38). Human epidemiological studies indicate that, in the modern era, this imbalance is exacerbated by rapid urbanization and the global expansion of fast-food chains offering hyperpalatable, high-fat, high-sugar, energy-dense foods (38, 39). Central to this dietary pattern is the excessive consumption of free sugars, specifically fructose and sucrose. Indeed, high consumption of ultra-processed foods, including sugar-sweetened beverages, has been associated with an increased risk of CRC in men generally, and with a 16% and 32% higher risk of EOCRC in adult and adolescent women, respectively (40-42). Projections suggest that fructose consumption now exceeds recommended daily allowances by up to three times in certain demographics, correlating strongly with increased body weight and a heightened risk of endocrine-metabolic disturbances, including colorectal carcinogenesis (38).

The pathogenesis of diet-induced obesity involves complex adaptations of the gastrointestinal tract to maximize nutrient uptake. Experimental animal studies, particularly high-fat diet (HFD) mouse models, have shown that chronic HFD consumption significantly alters lipid absorption rates by upregulating key jejunal fatty acid transporters, such as FATP-4, CD36, and FABP-1 (38). These animal studies further demonstrate reduced intestinal interleukin-25 (IL-25) production, facilitating glucose uptake through increased expression of SGLT-1 and GLUT-2. These physiological changes promote enlargement of cytoplasmic lipid droplets (CLDs) and enhance lipid repackaging into chylomicrons. This hyper-absorptive state is often accompanied by acute endoplasmic reticulum stress in Paneth cells and a loss of protective commensals such as Lactobacillus, thereby further accelerating systemic lipid delivery (38).

Mechanistic studies in animal models suggest that these intestinal alterations subsequently remodel the adipose tissue microenvironment. Adipose tissue comprises a complex landscape of adipocytes, stromal cells, and immune cells, particularly adipose tissue macrophages (ATMs). In mouse models, although ATMs constitute approximately 5% of the stromal vascular fraction in the lean state, this proportion can rise to nearly 50% in obesity (43). Diet-induced obesity triggers a phenotypic shift from anti-inflammatory M2-polarized macrophages to pro-inflammatory M1-polarized macrophages (43, 44). These M1 macrophages promote systemic insulin resistance and chronic inflammation by upregulating a specific set of pro-inflammatory and pro-coagulant mediators, including TNF-α, IL-6, iNOS, MCP-1, and plasminogen activator (43).

Interestingly, recent mechanistic evidence from animal studies suggests that the body attempts to counter this energy imbalance through a Piezo1-dependent mechanosensory pathway within ATMs (43). As obesity develops, Piezo1-activated macrophages induce the secretion of Slit3, which binds to ROBO1 receptors on sympathetic neurons. This signaling cascade promotes norepinephrine release, facilitating lipolysis and thermogenesis as a negative feedback mechanism to limit obesity progression (43). However, disruption of this pathway may result in chronic metabolic and inflammatory signaling, thereby creating a fertile environment for tumorigenesis. These findings have increased interest in dietary herbal bioactive compounds, including polysaccharides, polyphenols, and saponins, as potential adjunctive strategies for obesity management. These compounds may inhibit digestive enzymes such as lipase and α-amylase, thereby mitigating the initial stages of weight gain (39, 45). Cumulative investigation further reinforce the role of obesity and increased adiposity as critical drivers of EOCRC development (46, 47, 49, 50). Concurrently, associated lifestyle behaviors such as unhealthy dietary habits, physical inactivity, and inadequate sleep, may substantially contribute to CRC development (47, 48, 51).

Gut Dysbiosis in Obesity

In the context of obesity, gut dysbiosis is characterized by reduced microbial diversity and a structural reconfiguration of the taxonomic landscape. Table I summarizes studies highlighting obesity in association with gut microbial alterations and CRC. High-fat and high-carbohydrate diets program the microbiota toward a profile dominated by Firmicutes, Prevotella, and Methanobrevibacter, while inducing a deficiency in beneficial genera such as Bacteroides, Bifidobacterium, Lactobacillus, and Akkermansia (13, 52). A hallmark of this shift is an elevation of the Firmicutes/Bacteroidetes (F/B) ratio, a taxonomic imbalance that correlates strongly with weight gain and impaired insulin sensitivity (53). This altered composition results in decreased production of SCFAs, which are essential for maintaining intestinal epithelial barrier integrity. The loss of these metabolites facilitates bacterial translocation and the onset of metabolic endotoxemia, a state of low-grade chronic inflammation that culminates in obesity and its metabolic comorbidities (13).

Table I. Summary of epidemiological and clinical observational studies evaluating the association between obesity indices, gut microbial shifts, and colorectal cancer risk.

BMI: Body mass index; BRI: body roundness index; CCFR: Colon Cancer Family Registry; CRC: colorectal cancer; EOCRC: early-onset colorectal cancer; LOCRC: late-onset colorectal cancer; GECCO: Genetics and Epidemiology of Colorectal Cancer Consortium; HDL: high-density lipoprotein.

The obese microbiome fundamentally reconfigures the dynamic interaction networks within the gut. Using generalized Lotka-Volterra models, recent evidence inferred via computational modelling shows that the obese gut environment is characterized by a greater number of predicted microbial interactions, with a shift towards competitive dynamics (54, 55). These mathematical simulations indicate that while the inhibitory effect of Bacteroidetes on Firmicutes is intensified in obese individuals, Firmicutes and Proteobacteria consistently exhibit higher carrying capacities, reflecting an in silico environment that selectively favors the expansion of these potentially pro-inflammatory taxa (54). This aggressive, high-interaction environment modelled computationally provides a niche that conceptually harbors opportunistic pathobionts that may directly drive colorectal carcinogenesis. Fusobacterium nucleatum expresses the FadA adhesin, which activates oncogenic β-catenin signaling and inhibits T-cell-mediated immunity (56). Notably, fadA levels in colonic tissues from patients with adenomas and adenocarcinomas are 10-100 times higher than those in healthy individuals, and this elevated expression is associated with upregulation of oncogenic and pro-inflammatory genes, further promoting tumor development (57). Simultaneously, strains of Escherichia coli harboring the polyketide synthase (pks) island produce colibactin, a genotoxin that induces double-stranded DNA damage. Colibactin-associated mutational signatures (SBS88 and ID18) are more prevalent in countries with higher CRC incidence and occur at a 3.3-fold higher frequency in EOCRC (58). Combined with elevated microbial metabolites such as hydrogen sulphide (H2S) and secondary bile acids, these shifts create a highly carcinogenic niche (59, 60). Furthermore, the depletion of beneficial microorganisms such as Clostridia (specifically within the Lachnospiraceae and Oscillospiraceae families) inhibits fasting-induced adipocyte factor (FIAF) expression, leading to dyslipidemia and increased adiposity (13, 61).

The clinical implications of Oscillospira-related taxa remain debated. Although their abundance is often reduced in inflammatory bowel disease (IBD) and non-alcoholic fatty liver disease (NAFLD), suggesting a protective role, it is elevated in patients with gallstones and chronic constipation (62, 63). This suggests that these bacteria may thrive under conditions of slowed intestinal transit and altered bile acid metabolism (64). However, the plasticity of this microbial network offers a route for intervention. Nutritional strategies, such as the administration of prebiotics or specialized bioactive compounds (e.g., L-PPRS), can restore eubiosis, reduce the F/B ratio, and modulate the expression of lipid-metabolic genes (53). Tailored dietary interventions based on microbiota dynamics known as Optibiomics represent a promising future direction for mitigating the systemic and genotoxic drivers of EOCRC (54).

Obesity-associated Colorectal Cancer Pathway

Obesity promotes colorectal carcinogenesis through a complex interplay of metabolic, inflammatory, hormonal, and microbial pathways that drive tumor initiation and progression (Figure 1). A key underlying mechanism is chronic low-grade inflammation, characterized by sustained increases in adipokines, interleukins, and other pro-inflammatory cytokines (17, 65, 66). These mediators activate oncogenic signaling pathways, including NF-κB, Wnt/β-catenin, and JAK/STAT3, which collectively promote cellular proliferation, inhibit apoptosis, and facilitate tumor progression (67, 68).

Figure 1.

Integrated systemic and local pathophysiological pathways linking adiposity to early-onset colorectal cancer (EOCRC). The systemic adipose-inflammatory and metabolic pathway: Expansion of visceral fat triggers an influx of M1 macrophages and a systemic pro-inflammatory baseline that induces local endothelial dysfunction at the intestinal epithelial cell (IEC) lining, characterized by microvascular vasoconstriction, elevated cellular permeability, active leukocyte recruitment, and local micro-thrombosis. At the same time, obesity-induced insulin resistance leads to compensatory hyperinsulinemia and pancreatic β-cell strain, driving a downstream surge in reactive oxygen species (ROS). This metabolic cascade may induce DNA damage and genomic instability. In cells with an intact DNA-damage response, such damage normally activates DNA repair, cell-cycle arrest, senescence, or apoptosis. However, when checkpoint control or apoptotic signaling is impaired and pro-survival pathways remain active, damaged epithelial cells may survive, accumulate additional mutations, and undergo clonal expansion, thereby contributing to colorectal tumorigenesis. The gut microbiota dysbiosis pathway: Visceral adiposity and related dietary and metabolic changes may disrupt the gut microbiota, reducing short-chain fatty acid-producing commensals and promoting pathobionts such as pks+ Escherichia coli and Fusobacterium nucleatum. Reduced butyrate may impair mucosal barrier integrity, allowing bacterial translocation and lipopolysaccharide leakage, which promote metabolic endotoxemia, chronic inflammation, and a pro-tumorigenic colonic environment conducive to EOCRC.

Adipocytes, particularly those in white adipose tissue (WAT), play a central role in the initiation and regulation of inflammatory processes (69). In obesity, WAT undergoes phenotypic and functional alterations, leading to adipocyte dysfunction and increased infiltration of immune cells. This dysregulated adipose tissue environment promotes chronic inflammation, characterized by excessive release of pro-inflammatory mediators, including tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and interleukin-1β (IL-1β) (70). These inflammatory mediators actively contribute to colorectal tumorigenesis. For example, obesity-induced IL-6 has been shown to accelerate colitis-associated cancer, a subtype of CRC, by promoting macrophage polarization towards a tumor-supportive phenotype. These macrophages then secrete chemokines such as CC-chemokine ligand-20 (CCL-20), which further enhances a pro-tumorigenic microenvironment (71).

Moreover, the endocrine system plays a crucial role in modulating NF-κB signaling in obesity through the actions of metabolic and inflammatory hormones. Specifically, adipokines such as leptin and resistin, which are elevated in obesity, act as pro-inflammatory mediators that activate the NF-κB pathway, leading to increased cytokine production and the perpetuation of inflammation and insulin resistance, thereby accelerating CRC progression (72, 73). In vitro studies further support the oncogenic role of leptin, demonstrating its ability to enhance cell invasion, migration, and adhesion in various cancer types, including CRC (74). Mechanistically, leptin has been shown to activate the JAK and ERK signaling pathways in CRC cell lines such as HCT116, promoting the growth, survival, and stemness of cancer cells, which are critical for colorectal tumorigenesis (75). In contrast, adiponectin, an anti-inflammatory and insulin-sensitizing adipokine, is generally reduced in obesity and appears to exert protective effects against CRC (76). Numerous studies have consistently reported lower adiponectin levels in CRC patients compared to healthy individuals or other adipokines (76-78). Moreover, adiponectin levels have been shown to correlate with tumor differentiation grade, with lower levels observed in poorly differentiated tumors compared to well-differentiated tumors. Adiponectin mediates its effects through the receptors AdipoR1, AdipoR2, and T-cadherin, regulating inflammation and cellular proliferation. Activation of adiponectin receptors suppresses colorectal cancer progression, highlighting their tumor-inhibitory potential (79). Interestingly, differential expression of these receptors has been reported in CRC, with AdipoR1 often overexpressed in tumor tissues, whereas AdipoR2 expression is reduced, suggesting distinct and potentially context-dependent roles in colorectal carcinogenesis (77).

Apart from that, obesity acts as a highly relevant metabolic contributor that may exacerbate CRC by inducing insulin resistance, which leads to chronic hyperinsulinemia and increased levels of insulin-like growth factor-1 (IGF-1) (80). Both insulin and IGF-1 bind to their respective receptors on colorectal epithelial cells, which are often overexpressed in CRC, thereby activating key oncogenic signaling pathways, including PI3K/Akt and MAPK/ERK. Activation of these pathways promotes cellular proliferation, inhibits apoptosis, and enhances angiogenesis, collectively facilitating tumor development and progression (16, 32). Additionally, genetic evidence supports the role of IGF-1 in CRC susceptibility. A mutational analysis study reported that the IGF-1 rs6214 polymorphism (CT or TT genotypes) is associated with an increased risk of CRC, regardless of BMI, highlighting the importance of IGF-1 signaling beyond obesity-related metabolic effects (81).

Furthermore, obesity is closely associated with increased oxidative stress and lipid peroxidation, leading to the generation of reactive aldehydes such as malondialdehyde (MDA) and 4-hydroxy-2-nonenal (4-HNE). These reactive species can form DNA adducts and induce mutagenic alterations in tumor suppressor genes, including TP53 (82). Dysregulation of TP53 has been shown to further amplify inflammatory signaling by upregulating pro-inflammatory adipokines through the NF-κB pathway, thereby contributing to adipose tissue inflammation, insulin resistance, and metabolic dysfunction in both murine models and obese individuals (83-86).

In parallel, the expansion of visceral adipose tissue in obesity often results in local hypoxia due to inadequate vascularization (86). This hypoxic state severely impairs the surrounding vascular network, triggering local endothelial dysfunction characterized by increased cellular permeability, microvascular constriction, and active leukocyte recruitment (87). At the same time, the dysfunctional endothelium shifts into a localized hypercoagulable state. Recent clinical and biomarker evidence has confirmed that colorectal malignancies are linked to thromboembolic mechanisms and systemic hypercoagulability at the tissue level (88), which may lead to persistent microthrombosis within the mucosal capillaries. This localized microthrombosis restricts blood flow, exacerbates tissue ischemia, and disrupts the integrity of the intestinal epithelial barrier. Furthermore, this hypoxic and damaged vascular environment stimulates the production of chemotactic factors, such as monocyte chemoattractant protein-1 (MCP-1), which drives the recruitment and accumulation of macrophages within adipose tissue (89, 90). These infiltrating macrophages, together with dysfunctional adipocytes, secrete elevated levels of pro-inflammatory cytokines, including TNF-α and IL-6, as well as reactive oxygen species (ROS). Collectively, these factors activate key oncogenic signaling pathways, such as NF-κB, STAT3, and PI3K/Akt, thereby sustaining chronic inflammation and establishing a pro-tumorigenic microenvironment that promotes colorectal carcinogenesis (91, 92).

Thus, these interconnected mechanisms illustrate how obesity can act as a highly permissive and complex network of metabolic, inflammatory, and molecular alterations that may converge on key oncogenic signaling pathways, including NF-κB, JAK/STAT3, PI3K/Akt/mTOR, MAPK/ERK, and Wnt/β-catenin. The integration of these pathways drives aberrant cellular proliferation, inhibits apoptosis, and sustains a pro-tumorigenic microenvironment, thereby promoting the initiation and progression of colorectal cancer. This highlights obesity as a highly relevant and modifiable factor in CRC pathogenesis.

Study limitations. As this review is based on previously published literature, it is inherently affected by potential selection bias and heterogeneity in study designs, populations, and methodologies. In addition, variability in study populations, definitions of early-onset CRC, and methods for assessing microbiota composition and metabolic pathways may limit direct comparability across studies. Finally, because research in microbiome and metabolic oncology is rapidly evolving, some emerging mechanisms may not be fully captured in this review.

Conclusion

In summary, the rising tide of EOCRC is a multifaceted challenge in which obesity is a key modifiable contributor to a pro-tumorigenic microenvironment. Through a synergistic combination of dietary overnutrition and chronic adipocyte dysfunction, obesity may drive a cascade of systemic inflammation and gut dysbiosis. The resulting depletion of protective, SCFA-producing microbes, coupled with the recruitment of M1-polarized macrophages and genotoxic pathobionts, forges a suitable colonic niche for the molecular initiation and development of EOCRC. Moving forward, research and clinical strategies should move beyond BMI-centric models to prioritize central adiposity and the modulation of gut microbiota. It is essential to emphasize early lifestyle modifications to improve the metabolic trajectory of this malignancy in younger populations.

Conflicts of Interest

The Authors declare that they have no known competing financial interests or personal relationships that could have influenced the work reported in this paper.

Authors’ Contributions

Conceptualization: S.M.A.K., N.N.R. and A.A.H.; resources: S.M.A.K., N.N.R., M.S.B. and M.S.; data curation: S.M.A.K. and N.N.R.; writing-original draft preparation: S.M.A.K., N.N.R., M.S.B. and M.S.; writing-review and editing: S.M.A.K., N.N.R., M.H.M. and A.A.H.; visualization: S.M.A.K., N.N.R., M.H.M. and A.A.H.; funding acquisition: M.H.M. and A.A.H. All Authors have read and agreed to the published version of the manuscript.

Acknowledgements

The Authors thank Universiti Kebangsaan Malaysia (UKM) and Universiti Malaysia Sarawak (UNIMAS) for providing guidance and support.

Funding

This research was funded by Universiti Kebangsaan Malaysia (GUP-2023-038).

Artificial Intelligence (AI) Disclosure

The Authors declare that a generative artificial intelligence (AI) tool (Gemini 3.5 Flash) was utilized during the preparation of this manuscript. The tool was employed strictly for language polishing, grammatical optimization, and editing assistance to enhance the structural clarity and readability of the text. The conceptual framework, literature synthesis, and final textual validation were executed solely by the authors.

In addition, the Gemini 3.5 Flash AI was used to convert the authors’ original drawings into digital figures (Figure 1). The structural pathway configurations and figure concept were designed and sketched by the authors.