Dietary Fiber, Gut Microbiota, and Chronic Inflammation in Colorectal Cancer Prevention

1. Introduction

Colorectal cancer (CRC) remains one of the most prevalent and deadly malignancies worldwide. It ranks among the third most common cancer and the second leading cause of cancer related mortality. GLOBOCAN estimates that CRC accounts for approximately 9.3% of all new cancer cases. (1) CRC shows significant geographic disparity with higher incidence in developed countries and among men. CRC has markedly lower rates of incidence in developing regions such as Africa. (2) In Nepal, CRC ranks seventh most common cancer and fifth leading cause of cancer death. (3)

Chronic inflammation of colorectal region is widely recognized as a critical driver in colorectal carcinogenesis. Different inflammatory pathways like NF- κB, COX-2/PGE2, IL-6/STAT3, and IL-23/Th17 help create a tumor friendly microenvironment that promotes cellular proliferation, inhibits apoptosis, facilitates angiogenesis, and enhances metastatic potential. Patients with long standing inflammatory bowel disease (IBD) represent a high risk group and CRC risk increasing dramatically after 30 years of extensive colitis. (4)

Dietary fiber has emerged as a promising modifiable factor capable of interrupting this inflammatory cascade. Dietary fibers produce short-chain fatty acids (SCFAs) primarily butyrate, acetate, and propionate through fermentation by gut microbiota. They exert potent anti-inflammatory, anti-proliferative, and pro-apoptotic effects on colonic epithelial cells. These metabolites modulate key inflammatory pathways, reinforce intestinal barrier integrity, regulate immune responses, and influence epigenetic mechanisms, including microRNA expression and histone modifications. (5)

This review comprehensively studies the epidemiology of CRC, the link between chronic inflammation and colorectal tumorigenesis, the role of dietary fibers and their fermentation products (SCFAs) in modulating inflammatory signaling pathways, supporting gut barrier function and regulating epigenetics. It further discusses preclinical and clinical evidennce, existing challenges, potential synergies with probiotics and anti-inflammatory therapies, and future directions toward precision nutrition and fiber-based interventions for CRC prevention and management.

2. Epidemiology

According to GLOBOCAN 2022, colorectal carcinoma is the third most commonly diagnosed cancer globally comprising 9.3% of all cancer cases. Colorectal carcinoma is the most diagnosed cancer among men in nine of 185 countries worldwide. Colorectal carcinoma is more common among men than women and it is three to four times more common in developed than developing countries (1). Country with the highest incidence of CRC per 100,000 population is Hungary (70.6) among males and Norway (29.3) among female. CRC is the second most deadly cancer worldwide in 2013 . More than 50% of all cases occur in more developed countries with highest estimated rates are found in Oceania and the lowest in west Africa. (2) CRC has historically shown significant geographic disparities with high incidence in North America and Europe, lower rates in Asia, and very low rates in Africa. CRC is the seventh most common cancer in Nepal and fifth among the cancer death in the year 2018. (3) The age- standardized incidence and mortality rates of CRC in Nepal were 5.8 and 4.8 per 100,000 respectively in the year 2018. (6)

2.1. Risk Factors

The primary risk factor for colorectal cancer is age, past the fifth decade of life. A personal history of colorectal carcinoma or IBD also significantly increases the risk, the patients with ulcerative colitis face a 3.7% higher risk, while those with Crohn's disease have a increased risk of developed CRC. (7) Additional risk factors include longer disease duration, early onset, extensive disease, primary sclerosing cholangitis and a family history of sporadic colorectal cancer (8)

Epidemiological studies have estimated that up to 70-80% of CRC cases are attributable to modifiable dietary, environmental and life style factors. Dietary factors include low intake of fruits and vegetables or high consumption of red meat or saturated fats and exposure to caffeine or alcohol. Unhealthy lifestyle factors include lack of physical and smoking. (9)

Certain medical interventions that may increase the risk of CRC include pelvic irradiation, cholecystectomy, ureterocolic anastomosis. Comorbid medical conditions that are associated with increased risk of CRC include Barrett's oesophagus, HIV infection, acromegaly and inflammatory bowel disease. (10)

2.2. Dietary Fibres

According to the WHO, dietary fibers encompasses the non-digestible carbohydrates and lignin that are naturally present in plant based food and are not break down by human digestive enzymes. Dietary fiber is made up of carbohydrate polymers with three or more monomeric unit, which are neither digested nor absorbed in the human intestine. (11)

The main sources of various fibres are given below of sub-group classification:

Non-saturated Polysaccharides (monomeric unit ≥10) as outer layer of cereals, pulses, starchy endosperm, fruit and vegetable cell wall, outer layers of cereal groin, psylium, grain legumes, brown algae, red algae etc. Resistant oligosaccharides(MU<10) as pulses (bean, lentil) polymers derived from polysaccharides by hydrolyses, baked goods, dairy product, cake etc. Resistant starch (MU≥10) as whole or partially milled grains and legumes, green banana, high amylase starch. (12) The most common fibre source are bran from wheat, barley corn rice and oats, citrus fruits; grape, apple and sugar-beet fibre, soybean, peanut, pea and sunflower. (Soybean seeds and it's by-product okara as source of dietary fiber. Measurement by AoAc and Englyst methods). Marine algae appear to be good source of fibres presenting great chemied, physio-chemical and theological diversities. (13)

Individual with high intakes of dietary fibre appear to be significantly lower risk for developing coronary and breast disease, stroke, hypertension, diabetes, obesity and certain gastrointestinal disease. (14) The protective effect of dietary fibre on obesity and Type 2 diabetes mellitus is due to increased mastication, calorie displacement and decreased absorption of macronutrients. (15) Regular consumption of dietary fibre, particularly fibre from cereals may improve CVD health through various mechanism as lipid reduction, body weight reduction, improved glucose metabolism, blood pressure control and reduction of chronic inflammation.(Cardiovascular benefit of dietary fibre). Clinical recommendation for dietary fibre are routinely provided to improve laxation and reduce diverticular disease. (16)

2.3. Role of Chronic Inflammation in CRC and Modulation of Dietary Fibers to it

Evidence increasingly suggests that individuals with chronic bowel inflammation face a higher risk of developing colorectal cancer (CRC). During prolonged inflammation, various immune cells and mediators activate molecular signaling pathways that create a tumor-supportive microenvironment. A key factor in this process is vascular endothelial growth factor (VEGF), which is upregulated by chronic inflammation and plays a crucial role in promoting tumor angiogenesis, growth, and metastasis. (17) Two key genes involved in inflammation—cyclo-oxygenase-2 (COX-2) and nuclear factor kappa-B (NF-κB)—serve as critical molecular links between chronic inflammation and cancer development. Pro-inflammatory cytokines such as TNF-α and IL-6 have also been shown to promote tumor growth in experimental models of colitis-associated cancer. Although patients with longstanding inflammatory bowel disease (IBD) account for only a small proportion (1–2%) of total colorectal cancer (CRC) cases, they represent a high-risk group. In individuals with extensive and prolonged colitis lasting over 30 years, the risk of developing CRC increases significantly, reaching up to 18%. (18)

3. Mechanism of Inflammation in CRC

Inflammation is the physiologic response of tissue healing that begins with secretion of biomolecules from damaged tissues, cellular migration to the injured site, and repair. Chronic inflammation occurs due to the activation of the signaling pathways without any stimulant injury. (19) Chronic inflammation has some role in the various steps involved in tumorigenesis like cellular transformation, survival, proliferation, invasion, angiogenesis, and metastasis. (20)Inflammation is considered to be an important driving factor of tumorigenesis in colorectal cancer. Evidences have shown that treatment with anti-inflammatory medications delays the development of colorectal cancer. (18)

Consensus molecularity subtypes (CMS) description has provided a basis for colorectal cancer subtyping. Subtypes CMS1 and CMS4 have been suggested to be inflammatory. Cms1 and cms4 exhibited worst post-relapse survival, and poorest relapse-free survival respectively, so this highlights the importance of understanding the mechanism of inflammation in colorectal cancer. (21)

Inflammation due to variety of risk factors like infection, environmental carcinogens like alcohol, tobacco, radiation exposure, cellular senescence etc. may lead to cancer. (22)

Innate immune system cells like neutrophils, macrophages, innate lymphoid cells, intraepithelial lymphocytes, myeloid-derived suppressor cells, natural killer cells, adaptive immune cells like B and T lymphocytes, intestinal epithelial cells including Paneth cells, and other stromal cells like fibroblasts, endothelial cells/pericytes, mesenchymal cells, adipocytes, and neurons are the important cell types associated with inflammation in colorectal cancer. (18)

Multiple genetic changes in the intestinal mucosal cells are found to be associated with the development of colorectal cancer from inflamed cells in patients with inflammatory bowel disease. (23)

3.1. Inflammatory Signaling Pathways in CRC

Two major mouse models have been devised to understand the pathogenesis of colorectal cancer.

First mouse model has features similar to colitis associated cancer (CAC). Induction of chronic inflammation in colon by treatment of mice with dextran sulfate sodium (DSS), has been found to be associated with the formation of tumor in the colon. Treatment with multiple rounds of DSS in drinking water induces sessile lesions and may undergo dysplastic changes as seen in those with ulcerative colitis. Addition of azoxymethane has been found to improve efficacy of dysplasia and development of adenocarcinoma. This occurs via nuclear translocation of beta-catenin by mutating exon 3 of ctnnb1 gene, and upregulation of COX-2, iNOS, and loss of p53. (24)

A second mouse model has features similar to that of sporadic colorectal cancer. The key pathogenetic feature is mutations in the adenomatous polyposis coli (Apc) gene. The APC gene mutation was first described in familial adenomatous polyposis, a hereditary form of colorectal cancer. Normally APC sequesters B-catenin in cytoplasm and prevents its nuclear translocation and the transcription of pro-proliferative genes of the wnt signaling pathways (eg. CCND1 and MYC). (25)

3.1.1. NF-kB Pathway

NF-kB is a transcription factor family comprising of five members : p50, p52, p65, cRel, ReB. it is an integral promotor of inflammation in homeostasis and cancer. Loss of NF-kB signaling in gut leads to increased susceptibility to inflammation, although it provides protection from tumor development through increased apoptosis via Bcl-X_L pathway upregulation. NF-kB signaling in gut cells promotes tumorigenesis in colitis associated cancer, but not in spontaneous colorectal cancer. P53 mutation can prolong the activity of NF-kB, and drive colitis associated cancer via increasing the levels of IL-6 and IL-8. (26)

3.1.2. PGE2/COX Pathway

Cyclooxygenase signaling pathway has been found to be associated with tumor development. COX2 has been found to be associated with development of the colitis and the colitis associated cancer. (27)

Mice containing COX-2 mutations show reduced frequency of tumors. COX-2 induces BCL-2 expression and it thus decreases cellular apoptosis and proliferation of the tumor. PGE2 also directly increases the expression of CXCL1 in the endothelial cells, and thus activates and recruits neutrophils, and increases angiogenesis. (28)

3.1.3. IL-6/STAT Pathway

IL-6 regulates the survival and proliferation of intestinal epithelial cells through its production within the lamina propria in a NF-kB dependent manner. IL-6 is essential in the tissue homeostasis and the regeneration, and is also essential for T-cell survival and differentiation. (29)

IL-6 binds to membrane bound IL-6 receptor, thus interacts with gp-130, triggers the activation of the janus kinase (JAK) and downstream signaling pathway, signal transducer and activator of transcription-3 (STAT3), and phosphatidyl inositol 3′ kinase (PI3K)-Akt. STAT3 regulates the transcription of regulators of cellular proliferation (cyclin D1, proliferating cell nuclear antigen), survival (BCL-xL, surviving), and angiogenesis (VEGF) via binding to specific DNA sequences. (30)

IL-11 (a type of IL-6) is found to promote tumorigenesis. Mutein, a potent IL-11 antagonist is found to reduce the tumor number and size by limiting STAT3 activation. Inhibition of STAT-3 signaling via NT157, an IGFR-1R also reduces the tumor burden. IL-22 induces epithelial activation of STAT3 and promote tumorigenesis. All these multiple convergence pathways depicts the critical role of STAT3 in colorectal cancer progression. (31)

3.1.4. IL23/Th17 Pathway

IL-23 is a member of IL-12 family of cytokines, produced by dendritic cells and other antigen presenting cells. and is composed of two subunits p19 and p40, whereas its receptor is comprised of two subunits: IL-12RB1 and IL-23Ralfa. IL-23 increases level of PGE2 and enhances IL-17 function. IL23/Th17 are strongly implicated in the pathogenesis of IBD and colitis associated cancer. Those with IL23 deficiency are found to be associated with decreased expression of proinflammatory cytokines in the colon mucosa, and reduced cancerous growth. (32)

Administering anti-IL-17A antibodies has been found to suppress the development of CAC in 1,2-dimethylhydrazine/DSS-treated mice, and AOM/DSS-treated IL-17A-deficient mice with CAC show reduced tumor development, suggesting the involvement of IL23/IL17 signaling pathway in the colon cancer development. (33)

Understanding the mechanism of inflammation in the gut in IBD and tumorigenesis is essential for knowing the exact mechanism of development of colorectal cancer. Cytokine related signaling mechanism have been found to have role in tumorigenesis. Understanding the molecular and signaing mechanism can be helpful for developing new techniques for the prevention as well the therapeutic targets of colorectal cancer. (34)

4. Role of Dietary Fibers in Modulating Inflammatory Pathways

4.1. Anti-inflammatory Effects of Butyrate, Acetate and Propionate:

SCFAs like butyrate, acetate and propionate are the main sources of energy for colorectal epithelial cells and inhibit inflammation and tumor formation(1). (35) They inhibit the proliferation and induce apoptosis in colorectal cancer (CRC) cells by interacting with the Wnt/β-catenin signaling pathway modulating the composition of the gut microbiota(1). (35)They also enable cell cycle arrest, differentiation and apoptosis at physiological concentrations via HDAC inhibition(1). Dietary fibers via SCFAs production, influence the gastrointestinal function by providing energy-yielding substrates to the colonocytes, increasing or modifying intestinal mucosal growth, increasing colonic blood flow, and promoting sodium and water absorption, thus maintaining the gut hemostasis and its epithelial integrity(2). (36) Butyrate induces the release of IL-18 from colon epithelial cells by activating GPR109A, thereby participating in the regulation of colitis and colon cancer, thus preventing inflammation and inducing autophagy in colon cancer cell lines(3). Furthermore, SCFAs directly or indirectly regulate T cell differentiation and participate in specific cellular immunity, by inhibiting HDACs and regulating the mTOR S6K pathway to induce the production of effector T cells and regulatory T cells, resulting in protection from ongoing inflammation(3). (37)

4.2. SCFAs with Histone Deacetylase (HDAC) Inhibitor to Suppress Inflammation:

Short chain fatty acids (SCFAs) are organic acids produced in the intestinal lumen by the bacterial fermentation of undigested dietary carbohydrates, dietary or endogenous proteins, such as mucous and sloughed epithelial cells(1). (35) Bacteria of the phylum Bacteroidetes are known to produce high levels of acetate and propionate, whereas bacteria of the phylum Bacillota are known to produce high amounts of butyrate(1).(35) Acetate (C2), propionate (C3) and butyrate (C4) account for more than 95% of the SCFAs in the gut, with an estimated ratio of about 3:1:1 in the gut(1). (35)HDACs are the group of enzymes needed for gene expression, and the level of enzymes are increased in tumor cells and differ according to the type of cancer. HDAC1 is highly expressed in prostate, gastric, lung, esophagus, and breast cancers. Colon, cervical and gastric cancers express high levels of HDAC2. Furthermore, HDAC3 is expressed in breast and colon tumors, while HDAC6 is highly expressed in neuroblastoma cells(2). (36) HDACs, especially HDAC3 are involved in maintaining the intestinal hemostasis. SCFAs via inhibition of HDACs are known to alter the expression of several genes involved in various processes like cell proliferation, apoptosis, and cell differentiation, thus maintaining the normal colonic epithelium. SCFAs via HDACs inhibition induce cell death by various process like changes in gene expression, histone modifications, and epigenetic post- translational alterations. Studies have shown that butyrate, via the inhibition of HDACs epigenetically silence genes in cancer cells, by inducing cell cycle arrest and apoptosis, decreases HIF-1α expression and angiogenesis, and also attenuates tumor aggressiveness. These implications have shown its use in colorectal cancer therapy and prevention(2). (37)

4.3. Dietary Fibers and Gut Barrier Integrity:

A healthy gut barrier consists of mucus layer and tight junctions controlling paracellular transport(4). (38) The mucus layer is made up of butyrate, mucins, immunoglobulins, and glycoproteins(5). (39) The mucus layer acts as a barrier and limits the contact and harmful effects of luminal bacteria and other noxious stimuli on the colonic epithelium. It comprises the outer layer which is in contact with the gut microbiome and noxious stimuli, and the inner layer which is in contact with the epithelial cells. Both the inner and the outer layers allow access of metabolites to epithelial cells(4). (38) The colonic barrier is further reinforced by the intercellular tight junctions that regulate the paracellular flux of ions and water(6). (40) The major components of tight junctions include transmembrane proteins called claudins, tight- junction-associated marvel proteins (TAMPs) such as occludins, junctional adhesion molecules (JAMs), and cytosolic proteins such as zonula occludens(7). (41) These proteins prevent the translocation of luminal contents beyond the epithelial layer and into the systemic circulation. Studies have shown that the occludins, zonula occludens 1 (ZO-1), claudin-1, claudin-3, claudin-4, and claudin-5 have been shown to promote barrier integrity, whereas claudin-2, claudin-7, claudin-10, and claudin-12 have the opposite effect(6,8). (40,42) SCFAs (mainly butyrate), produced by the bacterial fermentation of dietary fibers, is associated with maintenance of gut integrity via mucus layer and tight junction proteins. In-vitro studies have shown that, butyrate was associated with an increase in claudin-1, claudin-3, and claudin-4, and a concomitant reduction of claudin-2, resulting in augmented tight junction(9). (43) Furthermore, it has been found that, butyrate increases the expression of the MUC2 gene, which increases the production of mucin, thus protecting the epithelial cells from luminal toxins(5). (39)

4.4. Role of Dietary Fibers in Maintaining Epithelial Health and Reducing Bacterial Translocation:

Intestinal microflora and intestinal epithelial cells stay in symbiotic relationship to maintain the normal gut epithelium. This harmony may be disturbed by any abrupt change in food and environmental conditions, which can switch the beneficial microflora into pathogenic by modifying the production of their metabolites, a process called as dysbiosis, which plays a critical role in the progression of colorectal cancer. Dysbiosis in gut microflora has a greater chance of producing dysplasia, inflammation, and ultimately CRC. Thus, dietary fiber supplementation is crucial for maintaining the normal symbiotic relation in the gut, which prevents the progression of CRC (10). (44) SCFAs produced by the fermentation of dietary fibers have immunomodulatory properties, promoting the regeneration of the intestinal epithelium, lower the pH of the colon and inhibit the growth of pathogens(11). (45) SCFAs particularly, acetate and butyrate, balances mucus production and secretion to prevent microbial invasion and susceptibility to infection. A diet low in fiber produces less SFCAs and results in an increase in harmful metabolites that increases susceptibility of infections by deterioration of the mucus layer and contribute to the development of chronic disease and CRC(11). (45)

Furthermore, insoluble dietary fibers bulk the luminal content and accelerate transit colon, minimizing colonic epithelium exposure to ingested carcinogens, such as nitrosamines(2). (36)

4.5. Dietary Fibers and Cytokine Modulation:

Evidences suggest that, inflammation and cancer promotion of the colonic epithelium are caused by the involvement of various pro- inflammatory cytokines [like tumor necrosis factor (TNF), interleukins (IL), chemokines], inflammation-inducing enzymes [like cyclooxygenase- 2 (COX-2) and matrix metalloproteinase-9 (MMP-9)], adhesion molecules, and transcription factor activation [such as nuclear factor-κB (NF-κB) and hypoxia-inducing factor 1α (HIF-1α)] that results in inflammatory gene products. These gene products are mainly controlled by NF-κB, which are strictly linked with carcinogenic process, since they are related with tumor cell survival, antiapoptotic signaling pathways, proliferation, invasion, and angiogenesis. NF-κB activation was reported in about 40 % of the colorectal cancers(2). (36) Dietary fibers via formation of butyrates play a role in inhibition of inflammation by inhibition of transcription factor NF-κB(2). SCFAs, mainly butyrate reduces the Lipopolysaccharides (LPS) and cytokine stimulated production of pro-inflammatory mediators such as TNF-α, IL-6, IFN-γ and NO while increase the release of the anti-inflammatory cytokine IL- 10, thus leading to inhibition of inflammatory pathways. These activities are thought to be due to inhibition of HDACs via SCFAs(12). (46)

SCFAs also modulate the expression and secretion of cell adhesion molecules and chemokines like selectins, integrins, vascular cell adhesion molecule-1, and intercellular adhesion molecule-1 are critical for recruitment, adhesion and trans-endothelial migration of leukocytes needed for inflammatory pathways(12). (46) SCFAs are also known to increase the expression of peroxisome proliferator-activated receptor-γ (PPAR-γ), thus eliciting the antiproliferative and proapoptotic actions in epithelial cells, which may decrease the risk for inflammation-induced CRC(13). (47)

4.6. Prebiotic Effects

Colorectal cancer can be easily prevented by a balanced diet, regular physical activity and appropriate weight management. Probiotics/live microorganisms has antimicrobial activity which support gut health by modulating the immune system, reducing colitis, lowering of blood cholesterol level, lowering intestinal PH, reducing colitis, modulation of apoptosis and cell differentiation and influencing cell signaling pathways (1). (48) Prebiotics, such as: inulin, FOS, GOS, and XOS, are non-digestible, selectively fermentable food components that stimulate composition and/or activity of beneficial gut microbiota (Bifidobacterium) to produce short-chain fatty acids (SCFAs) like butyrate, enhance nutrient absorption, and have anticarcinogenic effects (2,3) (36,37) while reducing pro-inflammatory microbes, also improving immune markers pre- and post-surgery (1,2,4). (35,36,38) Synbiotics are the combination of probiotics and prebiotics, which also contributes in SCFA production, immune activation, apoptosis, and suppressing carcinogenic enzymes, while also positively modifying the gut microbiota (3). (37)

Short-chain fatty acids (SCFAs) are result of fermentation of dietary fibers (DF) executed by intestinal anaerobic bacteria, such as Bifidobacterium spp. and Lactobacillus spp., using various enzymes. These SCFAs are carboxylic acids with aliphatic tails containing less than 6 carbon atoms, majorly including acetate (C2), propionate (C3), and butyrate (C4) (5). (39) In the human gut, acetate and propionate are mainly produced by Bacteroidetes, while Firmicutes produce butyrate. Additionally, acetate, lactate, amino acids, and carbohydrates contribute to butyrate production via glycolysis (6). (40) Highest level of SCFAs are present in colon at molar ratio of approximately 60:20:20 for acetate: propionate: butyrate, respectively (5). (39) These SCFAs are transported into the intestine and colon through transporters such as MCT1, SMCT1, and SLC26A3 (6). (40)

4.7. Mechanisms Linking SCFAs to Immune Modulation

SCFAs acts as a source of energy for intestinal epithelial cells and has a major role in defensive mechanisms of intestinal epithelial barrier and in regulation of function of innate immune cells to participate in immune system. Also, it has crucial function in T cells and B cells differentiation. (7). (41) There are two known mechanisms: GPCRs (GPR41 and GPR43) activation and histone deacetylase (HDAC) inhibition, by which SCFAs act on leukocytes which then migrate to the site inflammation and destroy offending microorganisms (8). (42) SCFAs helps in production of chemokine and inflammatory mediators via macrophages and expression of adhesion molecules in neutrophils and endothelial cells which in turn attract and activate more leukocytes. Suppression of lipopolysaccharide (LPS)- induced NF-KB activation is mediated by butyrate. Along with this stimulation of potassium efflux and hyperpolarization in HT-29 and NMC460 colonic cells is mediated by acetate/GPR43 pathway resulting in NLRP3 inflammation activation. (9) (43)

5. Epigenetics and microRNA Regulation in Colon Cancer

Epigenetic modifications, particularly DNA methylation and histone modifications, play a crucial role in regulating microRNA (miRNA) expression during colon cancer progression. Several studies have identified that specific miRNAs are either silenced or activated through epigenetic mechanisms, directly influencing cancer cell behavior.

A study developed a cellular model of colon cancer progression that mimicked the epithelial–mesenchymal transition (EMT) and mesenchymal–epithelial transition (MET) cycles observed during metastasis. (49) They discovered that global DNA hypomethylation and specific histone modifications accompanied the metastatic process. Notably, miR-99a, miR-100, and miR-125b were upregulated in mesenchymal-like cells, promoting migration and invasion, correlating with poor patient survival. Promoter demethylation also led to elevated expression of the H19 long non-coding RNA (lncRNA), which was associated with metastasis and worse outcomes¹. Another demonstrated that miR-137, a tumor-suppressive miRNA, is frequently silenced by promoter hypermethylation even at the adenoma stage, making it an early event in colorectal carcinogenesis. Restoration of miR-137 expression inhibited colon cancer cell proliferation, with LSD1, a histone demethylase, validated as a direct target of miR-137, suggesting its potential utility as an early detection biomarker. (50)

A similar research focused on miR-373, finding that it is significantly downregulated through promoter methylation in colon cancers. Re-expression of miR-373 suppressed cell proliferation by targeting the oncogene RAB22A, and treatment with demethylating agents restored its expression, indicating that epigenetic silencing of miR-373 is a critical mechanism in colorectal tumor development . (51)

Complementing these findings, Suzuki et al.conducted genome-wide chromatin profiling in colorectal cancer cells, revealing that hypermethylation of CpG islands at miRNA promoters silences key tumor-suppressive miRNAs such as miR-1-1. Their study showed that DNA demethylation restores active chromatin marks and miRNA expression, highlighting potential applications in epigenetic therapy. (52)

Similarly, a review demonstrated that aberrant miRNA expression patterns, along with DNA methylation and histone modifications, represent major epigenetic changes in colorectal cancer. They underscored the reversible nature of these changes and the role of miRNAs as promising diagnostic and therapeutic targets. (53)

Menigatti et al. demonstrated that miRNAs such as miR-195 and miR-497 undergo monoallelic methylation in normal colorectal mucosa and biallelic hypermethylation in precancerous adenomas⁶. They also reported frequent loss of imprinting (LOI) at miRNA-coding loci like MEG3 and GNAS-AS1, suggesting that epigenetic silencing of miRNAs is an early and critical step in colorectal tumorigenesis . (54)

These studies collectively underscore that epigenetic regulation of miRNAs through DNA methylation and histone modification is central to colon cancer progression, metastasis, and early tumorigenesis, offering valuable avenues for early detection, prognosis, and therapeutic intervention.

6. Clinical and Preclinical Evidence

High-fiber diets have garnered significant attention for their potential role in modulating colorectal cancer (CRC) development and progression as evidenced by both preclinical and clinical investigations. (55) Animal models like CRC mouse models have been instrumental in dissecting the intricate mechanisms through which dietary fiber exerts its effects. Looking at the preclinical evidence, animal studies which are using murine models of colorectal cancer (CRC) have provided detailed insights into the potential mechanisms underlying the effects of high-fiber diets. (55)Findings from a study that investigated the impact of different fiber types on tumor development in Apc-mutant mice, suggested that supplementation with fermentable fibers such as inulin led to a significant reduction in tumor multiplicity and size compared to a cellulose-based non-fermentable fiber or a fiber-free diet. (56) This reduction was associated with alterations in the gut microbiota composition by increase in butyrate producing bacteria and enhanced anti-tumor immune responses within the tumor microenvironment. (56)

Another study utilized a gnotobiotic mouse model where the gut microbiota composition could be precisely controlled. It is demonstrated that the protective effects of a high-fiber diet against CRC tumorigenesis were dependent on the presence of a specific gut microbial community capable of fermenting the fiber and producing butyrate. In the absence of this specific microbiota or with low production of substance like butyrates the high-fiber diet no longer conferred protection against tumor development. (57) Different studies have explored the impact of fiber on inflammation in animal models. For example, a study by β-glucan on DSS-induced colitis, a model of inflammatory bowel disease often linked to increased CRC risk, showed that β-glucan supplementation could attenuate colonic inflammation by modulating the production of pro-inflammatory cytokines and altering immune cell infiltration. (58)

Extending these observations to human populations, a wealth of epidemiological data from large-scale prospective studies consistently demonstrates a robust association between higher dietary fiber intake and a reduced risk of CRC. (59,60) This protective effect arise from a confluence of factors including the physical bulking of stool which limits the exposure by diluting potential carcinogens and accelerates their transit through the colon. The fermentation of dietary fiber by the gut microbiota yields short-chain fatty acids such as butyrate which serve as an energy source for colonocytes and have been shown to possess anti-inflammatory and anti-neoplastic properties. (57) Human intervention studies have also provided evidence that increased dietary fiber consumption can lead to a measurable reduction in systemic inflammatory markers including C-reactive protein (CRP) and interleukin-6 (IL-6), both of which are implicated in the chronic inflammation that is increasingly recognized as a critical driver of CRC pathogenesis. (61) These suggestive findings warrant future research to fully elucidate the optimal types and amounts of fiber for CRC prevention and to understand the inter-individual variability in response based on genetic and microbial factors.

7. Challenges and Gaps in Colorectal Cancer Research

7.1. Variability in Fiber Types and Sources

Dietary fiber's role in colorectal cancer (CRC) prevention is complicated by the diversity of fiber types (soluble vs. insoluble) and sources (fruits, vegetables, cereals). Cereal fiber and whole grains consistently show stronger protective effects than fruit or vegetable fibers. (62,63) While poorly fermentable fibers like wheat bran may be more effective than soluble fibers. (64) However, inconsistencies persist, with some studies finding no association or even increased risk from certain sources. (65) This variability underscores the need for precise classification of fiber types and sources. (66,67)

7.2. Individual Differences in Microbiota Composition

Gut microbiota composition significantly influences fiber metabolism and CRC outcomes. Variations in microbial populations affect the production of short-chain fatty acids (SCFAs) like butyrate, which have anti-inflammatory and anti-cancer properties. (36,68) Individuals with fiber-fermenting bacteria may derive greater benefits, whereas others with dysbiotic microbiota might not. (69,70) Standardizing dietary recommendations remains challenging due to this variability. (71)

7.3. Lack of Large-Scale, Long-Term Clinical Trials

Most evidence comes from observational studies or short-term trials, which are prone to confounding factors. For instance, randomized controlled trials (RCTs) on recurrent adenomas found no consistent fiber benefits due to short durations and high dropout rates. (72) Large, long-term trials are needed to clarify fiber’s preventive vs. therapeutic roles (73,74)

8. Synergies and Combinations with Probiotics

8.1. Combined Effects of Fiber and Probiotics in Modulating Inflammation

Both dietary fibers and probiotics have been shown to modulate inflammation, a key factor in colorectal cancer development. When consumed together, fibers can serve as prebiotics, providing substrates for beneficial gut bacteria, which, in turn, may enhance the anti-inflammatory effects of probiotics. Some studies suggest that the combination of specific fibers, such as inulin or pectin, with probiotics like Lactobacillus or Bifidobacterium, can reduce inflammatory markers in the gut and help maintain a healthier colon. This synergistic effect may offer an innovative approach to modulating the inflammatory environment associated with colorectal cancer. (68,69)

8.2. Enhancing Efficacy of Anti-Inflammatory Drugs Through Dietary Fibers

One of the promising directions in colorectal cancer research is enhancing the efficacy of anti-inflammatory drugs through dietary fibers. The mechanism behind this involves fiber's ability to affect the microbiota and modulate the production of SCFAs, which have anti-inflammatory properties. This could potentially complement the effects of pharmaceutical anti-inflammatory drugs. For example, dietary fibers may improve the bioavailability of certain medications or enhance their anti-inflammatory effects, leading to better therapeutic outcomes. (75)

8.3. Ongoing Medications and the Role of Fiber

In the context of ongoing colorectal cancer treatments, dietary fibers might play an adjunctive role. While patients undergoing chemotherapy or immunotherapy often experience gut dysbiosis or digestive disturbances, fibers could help restore the balance of gut microbiota and improve the gut barrier function, mitigating some of the adverse effects of treatment. (69) Furthermore, fibers may interact with current medications, enhancing their therapeutic effects or reducing side effects, thereby improving patients' overall quality of life. (67)

Numerous studies have explored the link between dietary fiber and colorectal cancer (CRC), emphasizing the influence of fiber sources, gut microbiota interactions, and its potential synergy with probiotics and NSAIDs. The Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial suggests that different fiber sources may have varying protective effects but lacks an in-depth analysis of fiber variability and microbiota differences. (76) Likewise, Encarnação’s study emphasizes butyrate’s role in CRC prevention but lacks an in-depth analysis of fiber-probiotic interactions or its influence on NSAIDs. (36) Le Marchand distinguishes between fiber types, highlighting vegetable fiber as the most protective. (77) The Multiethnic Cohort Study indicates that lifestyle, ethnicity, and dietary habits shape fiber’s effectiveness, while NSAIDs and hormone therapy may alter its impact on CRC risk. (66) Yang’s review of Eastern Asian populations finds no clear consensus on fiber’s protective effects, highlighting the need for long-term controlled trials. (73) Biswas explores fiber’s mechanistic role in gut microbiota modulation, particularly through SCFA production, and suggests that prebiotic-probiotic synergies may help reduce CRC risk. (69) Park’s pooled analysis and Aune’s meta-analysis reveal inconsistent findings on fiber’s effects, with cereal fiber showing the strongest protective link. (62,63) Reviews stress the need for more controlled trials, as case-control studies and observational data remain inconclusive. (72,78,79)Celiberto presents molecular evidence supporting fiber’s protective role and its synergy with probiotics, NSAIDs, and chemotherapy, while Goodlad cautions that some fiber types may promote cell proliferation, raising concerns about potential adverse effects. Overall, these studies indicate that while fiber likely contributes to CRC prevention, its effectiveness depends on fiber type, microbiota composition, and interactions with dietary and pharmacological factors, highlighting the need for extensive long-term research. (68)

The link between dietary fiber intake and colorectal cancer (CRC) risk remains complex, with studies yielding mixed results. Heilbrun attributes inconsistencies in fiber’s protective effects to variations in fiber types and individual gut microbiota composition. (70) Similarly, Nucci highlights the challenge of standardizing dietary fiber due to its structural diversity, calling for more controlled studies. (74) Fuchs suggests that fiber sources like cereal, fruit, and vegetable may impact cancer risk differently, though a 16-year study found no significant association. (80) Gianfredi emphasizes that fiber’s protective role in rectal cancer depends on fermentation rate and microbiota composition. (81) Otani finds no strong link between fiber intake and CRC risk in a large Japanese cohort but notes that extremely low fiber consumption may be harmful. (82) Łęcka suggests fiber’s benefits depend on type and source, affecting bile acid metabolism and potentially enhancing NSAID effects. (71) Sengupta reports that poorly fermentable fibers may offer greater protection, especially when combined with probiotics to boost SCFA production, such as butyrate, which lowers colonic pH and promotes apoptosis in cancer cells. (64) Ji shows that fiber-probiotic combinations reduce inflammation and enhance immune markers in CRC patients, potentially complementing NSAIDs.(83) Mwaura indicates that fiber may help prevent CRC recurrence by strengthening the gut barrier and lowering systemic inflammation. (83) Uchida reports no general correlation between fiber and CRC risk but identifies rice as a potentially protective source. (65) Zhong adds that vegetable and fruit fibers appear to offer protective benefits, while soy fiber does not.(67) Although some studies suggest that dietary fiber may enhance chemotherapy effectiveness, many emphasize the need for long-term, large-scale trials to draw definitive conclusions.

9. Future Directions

The evolving perception of the complex interplay between dietary fiber, gut microbiota, and colorectal cancer (CRC) pathogenesis opens up a number of promising avenues for future research as well as clinical practice. One of the more salient areas is the development of precision nutrition, where dietary advice, in terms of fiber quantity as well as type, can be tailored to an individual's distinct gut microbiota. Future research will likely seek to identify key microbial signatures for responsiveness to various fiber interventions, making it feasible to have tailored dietary interventions to optimize CRC prevention or treatment efficacy. (84) This can include advanced analysis of the microbiome along with controlled dietary interventions to fine-tune the gut ecosystem to achieve anti-tumorigenicity. (85)

One promising potential direction includes designing new fibers or new prebiotics to target central pathways in CRC development. This can involve developing new fibers that selectively stimulate beneficial bacteria to produce anti-inflammatory metabolites such as butyrate, or to increase anti-tumor immune reactions (85) Research can also involve modifying currently available fibers to increase their fermentability or to introduce specific functional groups that directly interfere with growth or survival of CRC cells. Ultimately, a key direction for the future encompasses integrating fiber interventions into programs of CRC prevention. This will require taking robust epidemiologic and mechanistic evidence to practical public health advice and developing appropriate strategies to promote fiber intake in populations. Clinical trials to determine whether targeted fiber interventions have a benefit in high-risk persons or as adjunct therapies in patients with CRC will be essential in moving to a complete utilization of dietary fiber in the control of this malignancy. (86)

10. Conclusions

In conclusion, colorectal cancer continues to impose a substantial global health burden, driven significantly by chronic inflammation and modifiable lifestyle factors. Emerging evidence strongly supports the protective role of dietary fiber against CRC development and progression. By serving as substrates for beneficial gut bacteria, dietary fibers promote the production of short-chain fatty acids (SCFAs), particularly butyrate, which exert multifaceted beneficial effects: suppressing pro-inflammatory pathways (NF-κB, COX-2, IL-6/STAT3), enhancing intestinal epithelial barrier integrity, promoting apoptosis, inhibiting cell proliferation, and modulating both innate and adaptive immune responses. These actions collectively disrupt the tumor-promoting inflammatory microenvironment and may favorably influence epigenetic regulation, including miRNA expression patterns critical to colorectal carcinogenesis.

Preclinical studies in murine models and numerous epidemiological investigations consistently demonstrate an inverse association between high dietary fiber intake—especially from cereals and whole grains—and CRC risk. The protective effects appear to be mediated through microbiota-dependent mechanisms, highlighting the importance of individual gut microbiome composition in determining responsiveness to fiber interventions. Synergistic interactions between dietary fibers (as prebiotics), probiotics, and conventional anti-inflammatory or chemotherapeutic agents further suggest potential for integrated therapeutic strategies.

However, several challenges persist, including variability in fiber types and sources, inter-individual differences in microbiota composition, and the scarcity of large-scale, long-term randomized controlled trials. These gaps underscore the need for precision nutrition approaches that tailor fiber recommendations based on microbial profiles and genetic background.

Moving forward, future research should focus on developing targeted prebiotic fibers, conducting well-designed interventional trials in high-risk populations, and integrating dietary fiber strategies into comprehensive CRC prevention and survivorship programs. With continued advances in understanding the intricate interplay between diet, microbiota, inflammation, and epigenetics, dietary fiber holds considerable promise as a safe, accessible, and cost-effective modality for reducing the global burden of colorectal cancer.