NEWPORT INTERNATIONAL JOURNAL OF SCIENTIFIC AND EXPERIMENTAL SCIENCES

(NIJSES)
Volume 6 Issue 3 Page 122-129, 2025
©NIJSES PUBLICATIONS ONLINE ISSN:2992-5819
Open Access PRINT ISSN:2992-6149 Page | 122

https://doi.org/10.59298/NIJSES/2025/63.122129

Gut Microbiota-Derived Natural Metabolites in Obesity-

ABSTRACT
The rising global prevalence of obesity has significantly increased the burden of colorectal cancer (CRC), now
recognized as one of the leading causes of cancer-related morbidity and mortality worldwide. Recent advances
in microbiome research have highlighted the intricate interplay between obesity, gut microbiota, and colorectal
carcinogenesis. Obesity-induced dysbiosis not only perturbs intestinal homeostasis but also alters the
production of gut microbiota-derived natural metabolites, many of which possess critical bioactive properties.
These microbial metabolites such as short-chain fatty acids (SCFAs), secondary bile acids, indole derivatives,
and polyphenol catabolites, play pivotal roles in modulating host immunity, inflammation, cell proliferation, and
apoptosis. While certain metabolites may exacerbate tumorigenesis, others demonstrate protective or
chemopreventive effects, thereby representing a novel frontier for therapeutic exploration. This review provides
an integrated overview of how obesity reshapes gut microbial ecology and the metabolic landscape, examines
the roles of specific microbial-derived metabolites in colorectal cancer development, and evaluates current and
emerging therapeutic strategies that harness these metabolites for cancer prevention and treatment.
Understanding the mechanistic underpinnings of these host-microbe interactions offers promising opportunities
for precision medicine, including microbiota-targeted dietary interventions, probiotic formulations, and
metabolite-based drug development to mitigate the dual burden of obesity and colorectal cancer.
Keywords: Gut microbiota, Obesity, Colorectal cancer, Microbial metabolites, Therapeutic strategies

INTRODUCTION
Colorectal cancer (CRC) represents a significant global health burden, ranking among the top three most
commonly diagnosed cancers and a leading cause of cancer-related mortality worldwide[1, 2]. A myriad of
genetic, environmental, and lifestyle factors contribute to CRC development, with obesity emerging as one of
the most prominent and modifiable risk factors[3, 4]. The global prevalence of obesity has escalated in recent
decades, coinciding with a parallel rise in CRC incidence, particularly in younger populations[4]. Obesity-
induced carcinogenesis is a multifactorial process involving chronic low-grade inflammation, insulin resistance,
dyslipidemia, adipokine imbalance, and, importantly, metabolic reprogramming of host tissues[5–7]. These
metabolic alterations not only foster a microenvironment conducive to tumor initiation and progression but also
interact with gut-resident microbial populations to modulate cancer risk.
The gut microbiota, a complex and dynamic community of trillions of microorganisms including bacteria,
archaea, fungi, and viruses, plays a pivotal role in maintaining host metabolic homeostasis, immune regulation,
and gastrointestinal health. Recent advances in high-throughput sequencing and metabolomics have deepened
our understanding of the intricate relationship between the gut microbiome and host physiology[8–10]. In the
context of obesity and CRC, gut microbial dysbiosis, characterized by a reduction in microbial diversity, a decline
in beneficial bacteria, and an overrepresentation of pathogenic species has been consistently observed[11, 12].
This dysbiotic state contributes to the disruption of intestinal barrier integrity, systemic inflammation, altered
bile acid metabolism, and the generation of carcinogenic compounds, thereby promoting colorectal
tumorigenesis.

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Among the most compelling avenues through which the gut microbiota impacts CRC development is the
production of natural bioactive metabolites[10, 12, 13]. These small-molecule compounds, derived from
microbial fermentation of dietary fibers, amino acids, bile acids, and other host- or microbe-derived substrates,
act as crucial signaling molecules that influence host cellular pathways. Metabolites such as short-chain fatty
acids (SCFAs), secondary bile acids, tryptophan derivatives, polyamines, and microbial-derived vitamins exert
diverse effects on epithelial cell proliferation, immune modulation, apoptosis, angiogenesis, and epigenetic
modifications[10, 14]. While some of these metabolites, notably butyrate and other SCFAs, are known for their
protective effects against inflammation and cancer, others like deoxycholic acid (a secondary bile acid) have been Page | 123
implicated in promoting DNA damage and oncogenic signaling.
Obesity significantly alters the composition and metabolic function of the gut microbiota, leading to shifts in the
production profiles of these key metabolites[15, 16]. For example, obese individuals often exhibit reduced levels
of SCFA-producing bacteria such as Faecalibacterium prausnitzii and Roseburia spp., which correlates with
decreased butyrate levels and a weakened anti-inflammatory gut environment[17]. Conversely, there is often
an enrichment of bile-tolerant, pro-inflammatory species such as Bilophila wadsworthia and Bacteroides spp., which
contribute to the increased production of tumor-promoting metabolites[17]. These obesity-induced changes in
microbial ecology and function not only exacerbate intestinal inflammation and metabolic stress but also create
a tumor-permissive environment conducive to CRC development[17].
Moreover, the bidirectional relationship between host metabolism and the gut microbiota suggests a synergistic
interaction in the context of obesity and CRC[13]. Host metabolic cues, such as elevated insulin and glucose
levels, can influence microbial composition and behavior, while microbial metabolites can in turn affect host gene
expression, immune responses, and metabolic pathways[18]. This dynamic crosstalk underscores the
importance of considering both host and microbial factors in understanding CRC pathogenesis[18].
Given the pivotal role of microbial metabolites in mediating the obesity-CRC axis, they have garnered
significant interest as potential therapeutic targets and biomarkers. Modulating the gut microbiota through
dietary interventions, prebiotics, probiotics, postbiotics, or even fecal microbiota transplantation (FMT) offers
promising strategies for restoring microbial balance and favorably altering metabolite profiles[19].
Additionally, harnessing the beneficial effects of specific metabolites, such as butyrate, indolepropionic acid, or
urolithins, may provide novel avenues for chemoprevention and adjuvant therapy in CRC[19]. This review aims
to provide a comprehensive overview of the mechanistic interplay between obesity-induced gut microbial
dysbiosis, natural microbial metabolite production, and colorectal cancer pathogenesis. It highlights major
classes of microbial-derived metabolites, elucidates their functional roles in modulating tumorigenic processes,
and explores their therapeutic potential in CRC prevention and treatment. By unraveling the complex metabolic
dialogue between the gut microbiota and the host, this review seeks to shed light on novel, microbiota-targeted
approaches to mitigate the rising burden of obesity-associated colorectal cancer.
2. Obesity, Gut Microbiota, and Colorectal Carcinogenesis
Obesity is a multifactorial condition that significantly reshapes the gut microbial ecosystem and contributes to
colorectal cancer (CRC) development through various interrelated mechanisms[7, 19, 20]. The gut microbiota,
a dense and diverse microbial community, plays a pivotal role in maintaining gastrointestinal homeostasis[12,
13]. In obese individuals, this balance is disrupted, leading to a state of dysbiosis—a reduction in beneficial
commensal microbes and an overgrowth of pathogenic species. Notably, obesity often results in a decreased
Bacteroidetes-to-Firmicutes ratio and diminished populations of Akkermansia muciniphila, Bifidobacterium, and
Faecalibacterium prausnitzii, species known for their anti-inflammatory and barrier-protective roles[21, 22].
This microbial imbalance compromises the intestinal epithelial barrier, increasing gut permeability and
facilitating the translocation of bacterial products such as lipopolysaccharide (LPS) into the systemic
circulation[23]. This condition, termed "metabolic endotoxemia," triggers chronic low-grade inflammation a
hallmark of obesity. Adipose tissue in this inflamed state becomes metabolically active, secreting pro-
inflammatory cytokines (e.g., TNF-α, IL-1β, IL-6) and adipokines (e.g., leptin, resistin) that further amplify
systemic and local inflammation within the colonic mucosa[23]. These factors drive epithelial cell proliferation,
suppress apoptosis, and create a pro-tumorigenic niche conducive to DNA damage and malignant
transformation.
The gut microbiota contributes to CRC pathogenesis through multiple biological pathways. Immune
modulation is a key mechanism—dysbiosis disrupts mucosal immune balance by impairing dendritic cell
function, altering antigen presentation, and skewing the balance of T helper and regulatory T cells[24]. This
facilitates immune evasion by neoplastic cells. Microbial metabolism also plays a role; harmful metabolites like
secondary bile acids and trimethylamine-N-oxide (TMAO) increase, while protective metabolites such as short-
chain fatty acids (SCFAs) decrease. Epigenetic modifications induced by microbial metabolites (e.g., butyrate,
folate, polyamines) can alter gene expression profiles, influencing tumor suppressor gene activity[24, 25].
Given this complex interplay, modulating the gut microbiota presents a promising strategy for CRC prevention
in obese individuals. Targeted interventions using prebiotics, probiotics, synbiotics, and dietary modifications
may restore microbial balance, improve intestinal barrier integrity, and reduce inflammation, thereby mitigating
CRC risk in this vulnerable population.
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 3. Key Gut Microbiota-Derived Metabolites in Obesity-Associated CRC
3.1 Short-Chain Fatty Acids (SCFAs)
SCFAs as primarily acetate, propionate, and butyrate, are metabolic end-products generated by the anaerobic
fermentation of dietary fibers by commensal gut bacteria, such as Roseburia, Eubacterium, and Faecalibacterium
prausnitzii[26]. Butyrate, in particular, plays a central role in colonic health. It is a primary energy source for
colonocytes and serves as a signaling molecule that regulates various cellular processes. Butyrate exerts anti-
inflammatory effects by inhibiting the activation of nuclear factor kappa-light-chain-enhancer of activated B
cells (NF-κB) and reducing the expression of pro-inflammatory cytokines.[26, 27] Furthermore, it modulates Page | 124
gene expression through inhibition of histone deacetylases (HDACs), promoting cell cycle arrest, differentiation,
and apoptosis in colorectal cancer cells.
Butyrate also enhances epithelial barrier function by upregulating tight junction proteins such as claudins and
occludins[28]. It influences immune function by promoting regulatory T cell differentiation and suppressing
inflammatory macrophage activity. However, in the context of obesity, SCFA production is markedly reduced
due to several factors, including diminished fiber intake and depletion of SCFA-producing microbial species[28].
This reduction compromises mucosal immunity, promotes chronic inflammation, and increases susceptibility to
CRC.
Therapeutic strategies aimed at restoring SCFA levels include increased consumption of fermentable fibers (e.g.,
inulin, resistant starch), administration of SCFA-producing probiotics, and supplementation with SCFA
analogs[28]. Clinical studies have demonstrated that dietary interventions that increase butyrate production
can improve epithelial health and reduce inflammatory markers in obese individuals[29]. These findings
underscore the potential of SCFAs as therapeutic agents in CRC prevention and treatment, especially in
metabolically compromised individuals.
3.2 Secondary Bile Acids
Secondary bile acids (SBAs) are microbial metabolites produced through the biotransformation of primary bile
acids (PBAs) synthesized in the liver. In the gut, bacteria primarily from the Clostridium and Eubacterium genera
convert PBAs such as cholic acid and chenodeoxycholic acid into SBAs like deoxycholic acid (DCA) and
lithocholic acid (LCA)[30]. While bile acids are essential for lipid digestion and absorption, the excessive
accumulation of SBAs, particularly in the colon, has been strongly associated with colorectal carcinogenesis.
DCA has been implicated in inducing oxidative stress, DNA damage, and genomic instability[31]. It promotes
the generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS), which directly damage
cellular DNA, proteins, and lipids. Moreover, DCA activates pro-inflammatory signaling cascades such as
nuclear factor kappa B (NF-κB) and mitogen-activated protein kinases (MAPKs), both of which enhance the
expression of pro-tumorigenic cytokines and anti-apoptotic proteins[31]. DCA can also induce cellular
proliferation via the Wnt/β-catenin and epidermal growth factor receptor (EGFR) pathways, thereby
promoting tumor initiation and progression.
In obesity, bile acid homeostasis is profoundly disrupted. Increased dietary fat intake and insulin resistance
stimulate hepatic bile acid synthesis via the classical CYP7A1 pathway[32]. At the same time, obesity-associated
dysbiosis favors bacterial species with enhanced bile salt hydrolase and 7α-dehydroxylase activity, which
accelerate the conversion of PBAs into carcinogenic SBAs. The cumulative effect is an elevated colonic
concentration of DCA and LCA, contributing to mucosal injury, inflammation, and carcinogenesis[32].
Targeting bile acid metabolism has therapeutic potential in mitigating CRC risk. Dietary interventions such as
reducing saturated fat intake and increasing fiber consumption can restore bile acid balance[33]. Certain
probiotics like Lactobacillus and Bifidobacterium species have been shown to deconjugate and detoxify bile acids,
reducing their carcinogenic potential. Additionally, pharmacologic agents such as bile acid sequestrants and
farnesoid X receptor (FXR) agonists are under investigation for their ability to modulate bile acid signaling and
reduce CRC progression[33]. Understanding the complex interplay between obesity, bile acid metabolism, and
microbiota remains crucial for developing targeted CRC preventive strategies.
3.3 Indole Derivatives
Indole derivatives are a diverse group of microbial metabolites derived from the catabolism of the essential amino
acid tryptophan by gut microbiota. Bacteria such as Clostridium, Bacteroides, and Lactobacillus convert tryptophan
into bioactive compounds, including indole, indole-3-acetic acid (IAA), indole-3-aldehyde (IAld), and indole-3-
propionic acid (IPA)[34]. These metabolites serve as important signaling molecules, particularly through their
interaction with the aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor expressed
throughout the gastrointestinal tract. Activation of AhR by indole derivatives promotes intestinal homeostasis
by regulating epithelial cell proliferation, enhancing tight junction integrity, and suppressing pro-inflammatory
responses[34]. IPA, for example, possesses potent antioxidant properties and protects against oxidative DNA
damage in colonic epithelial cells. It also reduces the expression of inflammatory cytokines such as IL-6 and
TNF-α, which are elevated in both obesity and CRC[35–37]. Moreover, indole derivatives support mucosal
barrier function by stimulating mucin production and modulating immune responses, thereby preventing
bacterial translocation and systemic inflammation.
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In obesity, tryptophan metabolism is dysregulated due to altered gut microbiota composition. The abundance
of beneficial tryptophan-metabolizing bacteria is reduced, leading to a decline in protective indole
derivatives[38]. This shift contributes to increased intestinal permeability, chronic inflammation, and oxidative
stress—factors that drive colorectal carcinogenesis. Additionally, metabolic syndrome and insulin resistance
influence tryptophan catabolism through the kynurenine pathway, diverting it from microbial metabolism and
exacerbating immune dysregulation[38]. Therapeutically, restoring indole derivative production holds
significant promise. Strategies such as probiotic supplementation (e.g., Lactobacillus reuteri), dietary inclusion of
tryptophan-rich or fiber-rich foods, and modulation of AhR signaling are being explored[39]. Additionally, Page | 125
emerging research highlights the role of microbial-host co-metabolism in the bioavailability and function of
these compounds, suggesting personalized interventions based on individual microbiota profiles[39].
Understanding the mechanisms through which indole derivatives mediate gut-immune interactions provides a
valuable framework for CRC prevention and therapy, particularly in the context of obesity-induced dysbiosis
and inflammation.
3.4 Polyphenol Metabolites
Polyphenols are plant-derived compounds widely recognized for their antioxidant, anti-inflammatory, and
anticancer properties[9, 40]. Major dietary sources include fruits, vegetables, tea, coffee, and wine. However,
polyphenols are poorly absorbed in the small intestine; up to 90–95% reach the colon, where they are extensively
metabolized by gut microbiota into smaller, bioactive phenolic metabolites[41, 42]. These metabolites,
including urolithins, phenylpropionic acids, and hydroxycinnamic acids, exert potent biological effects relevant
to colorectal cancer (CRC) prevention and management[43].
Microbial metabolism of polyphenols enhances their bioavailability and modulates their physiological activity.
For instance, ellagitannins from pomegranates and berries are converted into urolithins, particularly urolithin
A, which demonstrates anti-proliferative, pro-apoptotic, and anti-inflammatory effects in colon cancer cells[44].
Urolithin A also activates autophagy and improves mitochondrial function mechanisms that contribute to the
elimination of damaged cells and the suppression of tumor initiation. Similarly, catechins from green tea and
flavonoids from citrus fruits are transformed into phenolic acids that modulate signaling pathways such as NF-
κB, PI3K/Akt, and MAPK, resulting in reduced inflammation and enhanced DNA repair[44].
In obesity, the metabolic capacity of the gut microbiota to transform polyphenols is compromised due to the
depletion of key bacterial taxa such as Gordonibacter, Slackia, and Eggerthella. This alteration results in reduced
production of beneficial metabolites and a diminished chemoprotective effect[45]. Additionally, increased
oxidative stress and systemic inflammation in obese individuals may further attenuate the biological activity of
polyphenol metabolites.
Interventions aimed at enhancing polyphenol metabolism include dietary diversification with polyphenol-rich
foods, co-administration of specific probiotics, and development of polyphenol–microbiome synergy
supplements[46]. Personalized nutrition strategies that consider the individual’s microbiota profile can
optimize the generation of bioactive metabolites and enhance CRC prevention [47]. Furthermore, synthetic
biology approaches are being explored to engineer bacteria capable of efficient polyphenol bioconversion[46].
Altogether, gut microbial metabolism of dietary polyphenols represents a promising avenue for mitigating
obesity-associated CRC risk, offering a natural and diet-based strategy to enhance mucosal defense, modulate
inflammatory pathways, and prevent tumorigenesis.
4. Therapeutic Implications and Strategies
4.1 Microbiota-Modulating Interventions: Restoring gut eubiosis defined as a balanced and health-promoting
microbial community, is an increasingly promising approach to reducing colorectal cancer (CRC) risk,
particularly in obese individuals whose microbiota is often dysbiotic[48]. Several interventions are being
explored to modulate the gut microbiota effectively. Prebiotics, such as inulin, fructooligosaccharides, and
resistant starch, are non-digestible dietary fibers that selectively stimulate the growth of beneficial bacteria like
Faecalibacterium prausnitzii and Bifidobacterium spp[49]. These bacteria enhance the production of short-chain
fatty acids (SCFAs), especially butyrate, which has known anti-inflammatory and anti-carcinogenic properties.
Probiotics, comprising live microorganisms such as Lactobacillus and Bifidobacterium, can competitively inhibit
pathogenic bacteria, reinforce the intestinal barrier, and promote mucosal immune homeostasis[49]. Their
administration has been associated with reduced tumor burden and improved gut integrity in preclinical models
of CRC. Fecal Microbiota Transplantation (FMT) offers a more direct route by transferring stool from a healthy
donor to a recipient with disrupted microbiota [50]. FMT has shown promise in treating Clostridioides difficile
infections and is currently being evaluated for efficacy in CRC prevention[49]. By re-establishing microbial
balance, FMT can reintroduce beneficial metabolic functions and reduce inflammation-driven tumorigenesis.
Although still under investigation, these microbiota-modulating strategies underscore the therapeutic potential
of targeting the gut ecosystem as a preventive and adjunctive approach in obesity-associated colorectal cancer.
4.2 Metabolite-Based Therapies: Targeting microbial metabolites represents a novel and potentially
transformative therapeutic avenue in obesity-associated colorectal cancer (CRC). Certain microbial-derived
compounds possess immunomodulatory, anti-inflammatory, and anti-tumor properties that can be leveraged to
counteract the carcinogenic effects associated with dysbiosis[51]. One of the most studied metabolites is
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(http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the
original work is properly cited
butyrate, a short-chain fatty acid (SCFA) produced predominantly by Faecalibacterium and Roseburia species
through the fermentation of dietary fiber[52]. Butyrate acts as a histone deacetylase (HDAC) inhibitor,
promoting apoptosis and inhibiting the proliferation of colon cancer cells. Butyrate enemas have demonstrated
chemopreventive effects in experimental models of colitis-associated CRC by restoring epithelial barrier
function and dampening pro-inflammatory cytokine production. Another promising class of metabolites includes
indole derivatives produced from dietary tryptophan by gut microbiota[52]. These compounds activate the aryl
hydrocarbon receptor (AhR), a transcription factor involved in maintaining mucosal homeostasis and regulating
immune responses. AhR agonists such as indole-3-aldehyde and indole-3-propionic acid exhibit anti- Page | 126
inflammatory effects and are under investigation for their ability to modulate T-cell responses and suppress
tumor-promoting inflammation. Additional compounds under study include secondary bile acids, polyamines,
and conjugated linoleic acids, although their dual roles in cancer promotion and suppression necessitate precise
modulation. Metabolite-based therapies thus offer a precision-medicine approach to CRC prevention and
treatment, allowing the use of naturally occurring or synthetically derived analogs to restore microbial
functionality, modulate immunity, and directly affect tumor biology without the need for systemic antibiotics or
major dietary overhauls[52].
4.3 Diet and Lifestyle Modifications
Dietary and lifestyle interventions represent foundational strategies for modulating the gut microbiota and
reducing the risk of obesity-associated colorectal cancer (CRC). Diets high in fiber, polyphenols, and fermented
foods have been shown to favor the proliferation of beneficial gut bacteria and the production of protective
microbial metabolites such as short-chain fatty acids (SCFAs)[53]. Fiber-rich diets, especially those containing
whole grains, legumes, fruits, and vegetables, enhance butyrate production, which in turn supports colonic
epithelial health and exerts anti-inflammatory and anti-carcinogenic effects[53]. Polyphenol-rich foods, such as
berries, green tea, cocoa, and olive oil, act as prebiotics and antimicrobial agents, shaping microbial composition
while simultaneously modulating redox status and inflammatory pathways. Fermented foods like yogurt, kefir,
kimchi, and sauerkraut are natural sources of probiotics that contribute to microbial diversity and
gastrointestinal resilience[54]. Dietary patterns such as the Mediterranean and plant-based diets offer a
composite benefit by integrating these elements into a sustainable lifestyle model[54]. These diets are
consistently associated with reduced systemic inflammation, improved metabolic health, and lower cancer
incidence through favorable shifts in the microbiota-metabolite axis. Beyond diet, physical activity, sleep
hygiene, and stress reduction also influence gut microbial diversity and systemic immune function[55].
Sedentary lifestyles and chronic stress are linked to dysbiosis and increased CRC risk, whereas regular physical
activity has been shown to enrich microbial diversity and enhance SCFA levels[55]. Taken together,
comprehensive diet and lifestyle modifications offer a non-invasive, cost-effective, and holistic approach to CRC
prevention by targeting both metabolic and microbial pathways involved in obesity-related carcinogenesis.
5. Conclusion and Future Directions
The gut microbiota and its natural metabolites serve as a critical nexus linking obesity and colorectal cancer.
Understanding the metabolic outputs of gut microbes and how they interact with host pathways opens up new
frontiers for personalized medicine. Therapeutic strategies targeting microbiota-derived metabolites, whether
through diet, probiotics, or direct metabolite supplementation, represent promising adjuncts in preventing and
treating CRC, particularly in the context of obesity.
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CITE AS: Mutebi Mark (2025). Gut Microbiota-Derived Natural Metabolites in Obesity-Associated
Colorectal Cancer: A Therapeutic Perspective. NEWPORT INTERNATIONAL JOURNAL OF
SCIENTIFIC AND EXPERIMENTAL SCIENCES 6(3):122-129
https://doi.org/10.59298/NIJSES/2025/63.122129

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original work is properly cited