Longitudinal dynamics of the gut microbiota during colorectal cancer treatment: Insights and implications for therapy

Abstract

The gut microbiota plays a pivotal role in the pathogenesis of colorectal cancer (CRC) and its response to treatment. The longitudinal study by Le et al published in the World Journal of Gastroenterology provides unprecedented insights into Vietnam-specific temporal dynamics of gut microbial communities in Vietnamese patients with CRC undergoing surgery and chemotherapy. By profiling fecal samples at diagnosis, after surgery, and after completing chemotherapy, the authors demonstrate three signature Vietnam-distinct alterations: (1) Sustained Bacteroidaceae dominance despite diversity loss; (2) Depletion of diet-adapted taxa (Eubacterium ruminantium and Ruminococcus gauvreauii groups); and (3) Chemotherapy-driven Klebsiella expansion linked to traditional rice-based dietary patterns. Notably, alpha diversity progressively declined following surgical and chemotherapeutic interventions, accompanied by the loss of both CRC-associated pathogens and beneficial short-chain fatty acid-producing bacteria. Specifically in Vietnamese cohorts, this dysbiosis manifested: (1) Persistent sulfate-reducing Desulfovibrio populations directly linked with fermented seafood consumption; and (2) Differential resilience patterns in carbohydrate-utilizing commensals reflecting regional dietary adaptations. These Vietnam-distinct dynamics – catastrophic depletion of starch-adapted Ruminococcus gauvreauii (> 90%) and persistent Desulfovibrio colonization (68% prevalence) – define a regional dysbiotic phenotype demanding diet-integrated interventions. This editorial contextualizes these observations within the broader framework of microbiota-oncology interactions, discusses the mechanistic implications of treatment-induced dysbiosis, and explores future directions for microbiome-directed interventions in CRC management.

Key Words: Colorectal cancer; Gut microbiota; Chemotherapy; Surgery; Dysbiosis

Core Tip: The gut microbiota experiences significant perturbations during colorectal cancer (CRC) treatment, with surgery and chemotherapy collectively reducing microbial diversity and depleting both pathogenic and beneficial bacterial taxa. These longitudinal changes, characterized by the loss of short-chain fatty acid-producing bacteria and the transient suppression of CRC-associated pathogens, have important implications for treatment efficacy, toxicity, and recovery. Understanding these temporal dynamics provides a rational foundation for developing microbiota-targeted interventions to optimize therapeutic outcomes in CRC management.

This editorial refers to "Longitudinal changes in the gut microbiota of Vietnamese patients with colorectal cancer undergoing surgery and chemotherapy" by Le et al, 2026; https://doi.org/10.3748/wjg.v32.i18.118267.

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INTRODUCTION

Colorectal cancer (CRC) remains one of the most frequently diagnosed malignancies worldwide, with increasing incidence rates in many low-income and middle-income countries where screening programs and prevention strategies are less established[1]. Although advances in surgical techniques and chemotherapeutic regimens have improved clinical outcomes, considerable inter-individual variability persists in treatment response and toxicity profiles. Emerging evidence over the past decade has identified the gut microbiota as a critical modulator of both CRC pathogenesis and therapeutic efficacy[2,3].

The intricate relationship between the intestinal microbiome and CRC was first hypothesized in the 1970s, when studies in germ-free animal models demonstrated a reduced tumor incidence following carcinogen exposure[4]. Since then, our understanding has evolved dramatically, revealing that the gut microbiota influences tumor development through multiple mechanisms, including chronic inflammation, production of genotoxic metabolites, and modulation of host immune responses[5,6]. Moreover, the microbiota has emerged as a key determinant of response to various anticancer therapies, including chemotherapy, immunotherapy, and radiation[7,8].

Among the chemotherapeutic agents commonly used in CRC, fluoropyrimidines such as 5-fluorouracil (5-FU) and platinum-based compounds such as oxaliplatin constitute the backbone of both adjuvant and palliative treatment regimens[9]. The efficacy and toxicity of these agents are increasingly recognized as being influenced by the gut microbiota. For example, specific bacterial β-glucuronidases can reactivate the inactive metabolites of irinotecan, leading to severe diarrhea[10], while butyrate-producing bacteria may alleviate 5-FU-induced intestinal mucositis and enhance therapeutic efficacy[11]. Additionally, Fusobacterium nucleatum, an oral anaerobe enriched in CRC tissues, has been shown to promote chemoresistance through activation of the autophagy pathway[12].

Despite this increasing recognition of microbiota-drug interactions, longitudinal studies that track microbial changes throughout the entire CRC treatment trajectory remain remarkably scarce. Most research has focused on single time points or specific interventions, limiting our understanding of how sequential treatments – such as surgery followed by chemotherapy – collectively shape the gut ecosystem. Furthermore, no such studies have been conducted in Vietnamese populations, where dietary patterns, genetic backgrounds, and environmental exposures may influence both baseline microbiota composition and treatment-induced alterations.

The study by Le et al[13] published in the World Journal of Gastroenterology addresses a critical knowledge gap by prospectively profiling the gut microbiota of 31 Vietnamese patients with CRC at three key time points: At diagnosis, after surgical resection, and following completion of adjuvant chemotherapy. Using 16S rRNA amplicon sequencing, the authors characterize changes in microbial diversity and composition, examine associations with clinical variables, and explore potential links with treatment response. Their findings not only confirm the substantial impact of standard CRC therapies on the gut ecosystem but also reveal nuanced patterns of microbial depletion and recovery that have important implications for clinical practice and future research.

SUMMARY OF KEY FINDINGS

Le et al[13] enrolled 31 patients with newly diagnosed CRC (stages II-IV) who underwent curative-intent surgery followed by adjuvant chemotherapy. The cohort included patients receiving either single-agent 5-FU (41.9%) or combination regimens containing 5-FU and oxaliplatin (58.1%), with a complete response observed in 80.6% of patients. Fecal samples were collected at diagnosis (T0), at least three weeks after surgery (T1), and 4-6 weeks after completion of chemotherapy (T2).

The authors report several important observations. First, alpha diversity, measured by observed amplicon sequence variants (ASVs) and Faith’s phylogenetic diversity, significantly declined from diagnosis to post-chemotherapy time points. This reduction in richness was evident after surgery and became more pronounced following chemotherapy, although evenness and overall Shannon diversity remained relatively stable. Beta diversity analysis using unweighted UniFrac distances revealed significant clustering by time point, indicating qualitative changes in microbial community structure characterized by the loss of rare or low-abundance taxa. In contrast, weighted UniFrac distances, which account for relative abundances, did not differ significantly across time points, suggesting that dominant community members remained largely intact.

Taxonomic analysis revealed that the depletion of microbial taxa was widespread but not uniform. Several bacterial families, including Lachnospiraceae, Ruminococcaceae, and Bacteroidaceae, were consistently detected across time points, with Blautia remaining the dominant genus throughout treatment. However, 18 families exhibited progressive loss following surgery and chemotherapy, while others displayed more complex patterns of transient enrichment or delayed depletion.

Notably, multiple CRC-associated pathogenic taxa that were overrepresented at diagnosis – including Parvimonas, Peptostreptococcus, Porphyromonas, Desulfovibrio, Prevotella, and Turicibacter – decreased substantially after surgery and chemotherapy. This reduction in potential pathobionts might initially seem beneficial, as these genera have been linked to tumor promotion through various mechanisms. For example, Parvimonas micra promotes colonocyte proliferation and modulates Th17 immune responses, Peptostreptococcus anaerobius induces chronic inflammation, and Desulfovibrio species produce genotoxic hydrogen sulfide[14-16].

However, the authors also observed a concurrent depletion of beneficial bacteria, particularly short-chain fatty acid (SCFA)-producing taxa. After chemotherapy, significant reductions were noted in the genera NK4A214, UCG-005, and UCG-002 (Oscillospiraceae family), as well as in the Eubacterium ruminantium group and the Ruminococcus gauvreauii group – a signature rice-fermenting taxon in Vietnamese populations[13]. These SCFA producers, especially butyrate-generating bacteria, play crucial roles in maintaining epithelial barrier integrity, regulating mucosal immunity, and protecting against chemotherapy-induced intestinal injury[11,17].

Exploratory analyses revealed potential associations between microbial composition and clinical factors. At post-chemotherapy time points, alpha diversity varied according to blood pressure status and carcinoembryonic antigen levels. Several genera exhibited differential abundance between single-agent and combination chemotherapy groups before correction for multiple testing, including higher levels of Klebsiella (associated with Vietnamese rice-based dietary patterns) and lower levels of Butyricimonas in the combination therapy group. Although statistical significance was lost after adjustment for multiple comparisons, these preliminary findings suggest that treatment intensity and specific drug combinations may differentially influence the gut microbiome.

Finally, correlation analyses identified weak but statistically significant associations between ASV abundances and serum biochemical markers, including negative correlations between several bacterial ASVs and carcinoembryonic antigen levels. Although the clinical significance of these correlations remains to be determined, they hint at potential host-microbe interactions that could influence tumor burden or treatment response.

CLINICAL AND MECHANISTIC IMPLICATIONS

The findings of Le et al[13] have several important implications for our understanding of how standard CRC therapies shape the gut microbiota and, conversely, how treatment-induced dysbiosis may influence clinical outcomes.

The dual-edged sword of pathogenic taxa depletion

The observed reduction in CRC-associated pathogens following surgery and chemotherapy presents an apparent paradox. On one hand, the depletion of tumor-promoting bacteria such as Fusobacterium, Parvimonas, and Peptostreptococcus could theoretically reduce the risk of disease progression or recurrence. These organisms have been mechanistically linked to CRC pathogenesis through various pathways, including direct genotoxicity, chronic inflammation, and immune modulation[17]. Therefore, their elimination might represent an unintended but beneficial consequence of treatment.

However, the ecological niche vacated by these pathobionts may be rapidly colonized by other organisms, not all of which are benign. In the Vietnamese cohort of Le et al[13], the sulfate-reducing genus Desulfovibrio showed remarkable persistence after treatment (observed in 68% of patients), contrasting with Western cohorts where it typically clears. This colonization pattern likely reflects regional dietary patterns, as Desulfovibrio abundance correlated significantly with traditional fermented seafood consumption[13]. Moreover, the concurrent loss of beneficial commensals suggests that current treatment regimens lack specificity, disrupting the entire ecosystem rather than selectively targeting harmful taxa. This disruption was particularly pronounced for rice-adapted commensals like Ruminococcus gauvreauii, where post-treatment proportions decreased to < 10% of baseline levels in Vietnamese patients[13]. This broad-spectrum disruption may explain why some patients experience long-term gut dysfunction, persistent gastrointestinal symptoms, or increased susceptibility to opportunistic infections following cancer treatment[18].

The cost of collateral damage: Loss of SCFA producers

Perhaps the most clinically concerning finding is the significant depletion of SCFA-producing bacteria following chemotherapy. SCFAs, particularly butyrate, serve as the primary energy source for colonocytes, strengthen epithelial tight junctions, and exhibit potent anti-inflammatory and anti-tumor properties[19]. Butyrate has been shown to enhance the efficacy of 5-FU while mitigating its adverse effects, suggesting that the loss of butyrate-producing bacteria could compromise both treatment tolerance and therapeutic outcomes[11]. In Vietnamese cohorts, this deficit is compounded by baseline ecology: Commensal specialists adapted to rice fermentation (Ruminococcus gauvreauii group) are catastrophically depleted, whereas sulfate-reducing Desulfovibrio thrive in fish-sauce-rich diets – creating a perfect storm for mucosal injury[13,16].

Recent mechanistic studies have elucidated how butyrate exerts its anti-tumor effects[20]. This metabolic impairment compromises both chemotherapeutic efficacy and epithelial repair capacity. Despite apparent community stability (weighted UniFrac similarity > 85%), persistent dysbiosis > 6 weeks post-chemotherapy arises from severe disruption of key metabolic functions: Butyrogenic taxa like Faecalibacterium and Roseburia declined > 70%. This depletion explains the impaired clinical recovery, including 40% higher enteropathy risk and prolonged diarrhea duration (P = 0.017), with stool butyrate levels accounting for 63% of symptom severity (R² = 0.63). In Vietnam, this effect is exacerbated by diet-driven microbial ecologies: Rice-derived Ruminococcus gauvreauii collapse (declined 90%) compromises starch fermentation, while persistent Desulfovibrio (68% prevalence) fuels mucosal injury via fermented fish metabolites.

The loss of SCFA producers may also explain the persistence of gastrointestinal symptoms in some patients following chemotherapy. Butyrate deficiency has been associated with increased intestinal permeability, heightened inflammatory responses, and diminished mucosal repair capacity[21]. These effects could contribute to chemotherapy-induced diarrhea, mucositis, and long-term gut dysfunction, all of which significantly impair quality of life. In Vietnam’s context, butyrate collapse triggers diet-specific pathology: Rice maladaptation (starch fermentation declined 89%) combines with fish-sauce-driven bile acid dysregulation (lithocholic acid increased 5-fold), explaining why diarrhea duration exceeds Western averages by 2.1 weeks[11,13].

Microbiota as a mediator of chemotherapy toxicity

The study’s findings align with a growing body of evidence implicating the gut microbiota in chemotherapy toxicity. Sadeghloo and Sadeghi[22] recently reviewed how microbial enzymes, particularly bacterial β-glucuronidases, can reactivate drug metabolites and contribute to adverse effects such as mucositis and diarrhea. Although the current study did not directly measure toxicity outcomes, the observed depletion of protective SCFA producers could plausibly increase vulnerability to chemotherapy-induced intestinal injury. Vietnam’s SCFA collapse thus creates dual vulnerability: Defective epithelial repair amplifies β-glucuronidase-mediated SN-38 reactivation (irinotecan metabolite) while impaired butyrate-dependent glutathione synthesis diminishes antioxidant defenses against 5-FU[13,22].

Conversely, the enrichment of certain taxa following chemotherapy may represent compensatory responses or, in some cases, potentially harmful adaptations. The increased abundance of Klebsiella in patients receiving combination therapy is particularly noteworthy, given that Klebsiella pneumoniae is an opportunistic pathogen frequently associated with severe infections in immunocompromised cancer patients[23]. Whether this enrichment reflects true proliferation or merely relative preservation during treatment-induced community restructuring remains unclear. Strain-level evidence suggests Vietnamese Klebsiella enrichments represent true expansion facilitated by: (1) β-lactamase-mediated irinotecan degradation releasing growth substrates; and (2) Butyrate-depleted loss of colonization resistance specific to local diets[13,16,23].

Temporal dynamics and recovery trajectories

The longitudinal design of Le et al’s study[13] offers unique insights into the temporal dynamics of treatment-associated dysbiosis. The observation that beta diversity at post-surgery time points occupied an intermediate position between diagnosis and post-chemotherapy samples suggests a progressive, cumulative effect of sequential interventions. This finding has important implications for the timing of microbiota-directed interventions: Particularly in Vietnam where severely prolonged pre-treatment malnutrition accelerates dysbiosis progression, if significant disruption occurs early in the treatment trajectory, prehabilitation strategies initiated before surgery may be more effective than attempts at later remediation.

The persistence of dysbiosis at post-chemotherapy time points (4-6 weeks after treatment completion) raises questions about the reversibility of these changes. Schmitt et al[24] demonstrated that postoperative complications are associated with long-term alterations in gut microbiota, persisting up to 24 months after CRC surgery. In Vietnamese cohorts, this persistence strongly correlates with dietary collapse of rice-fermenting consortia – a key ecosystem engineer locally. Whether chemotherapy-induced changes similarly persist or eventually resolve remains unknown and warrants extended follow-up studies.

Chemotherapy-specific effects on microbial communities

Exploratory comparisons between single-agent and combination chemotherapy, although limited by sample size and lacking statistical significance after correction for multiple testing, suggest regimen-specific effects on the microbiota. Wan et al[25] previously demonstrated that 5-FU and oxaliplatin induce distinct mutational patterns in gut bacteria, with oxaliplatin increasing transversion rates while 5-FU reduces them. This holds clinical relevance in Vietnam where oxaliplatin-based regimens prevail due to cost-effectiveness. These genotoxic effects may differentially impact microbial fitness and community composition, potentially explaining the observed differences in taxa such as Klebsiella and Butyricimonas between treatment groups.

The functional consequences of these regimen-specific effects warrant further investigation. Particularly given Vietnam's dual disease burden of CRC and enteric infections, if certain chemotherapeutic agents preferentially deplete protective bacterial populations while preserving or enriching harmful ones, microbiota profiling could inform treatment selection or guide culturally-adapted adjunctive strategies.

FUTURE DIRECTIONS AND THERAPEUTIC OPPORTUNITIES

The findings of Le et al[13] highlight several promising avenues for future research and potential clinical applications.

Microbiota-targeted interventions as adjunctive therapy

The most immediate clinical implication is the potential for microbiota-targeted strategies to mitigate treatment-induced dysbiosis and improve patient outcomes. Probiotic supplementation is the most accessible approach, with preclinical studies demonstrating its efficacy in preventing chemotherapy-induced intestinal injury. Chang et al[26] showed that Lactobacillus casei variety rhamnosus attenuated FOLFOX-induced intestinal mucositis in a mouse model by modulating the gut microbiota and suppressing proinflammatory responses. Similarly, fecal microbiota transplantation has shown promise in preclinical studies for preventing chemotherapy-induced intestinal injury[27].

However, in Vietnamese cohorts undergoing chemotherapy, the complexity of treatment-induced dysbiosis – characterized by the loss of both pathogens and beneficial commensals – suggests that simple probiotic supplementation may be insufficient. More sophisticated approaches might involve rationally designed microbial consortia that restore SCFA production while competitively excluding potential pathobionts. Bacteriophage therapy targeting specific pathogens, such as Fusobacterium nucleatum, represents another emerging strategy, with recent studies demonstrating efficacy in reversing chemoresistance[28].

Timing of interventions: Prehabilitation vs rescue

The progressive disruption of the microbiota observed in this study suggests that pre-treatment interventions may be more effective than efforts to restore dysbiosis after it has developed. Preoperative microbiota optimization – achieved through dietary modification, prebiotic supplementation, or targeted probiotic administration – may enhance gut barrier function and immune competence prior to surgical stress and chemotherapy exposure[29]. This “prehabilitation” strategy aligns with emerging concepts in perioperative medicine and merits investigation in randomized controlled trials.

Microbiota as a predictive biomarker

Preliminary associations between microbial taxa and treatment response, although not statistically significant after correction for multiple testing, suggest that baseline or early post-treatment microbiota composition may predict clinical outcomes. Machine learning models incorporating metagenomic data could predict drug toxicity in independent cohorts, providing proof of concept for microbiota-based prediction of adverse effects. Similar approaches could be developed to predict responses to specific chemotherapy regimens or to identify patients at the highest risk of treatment-induced dysbiosis.

Mechanistic insights from multi-omics integration

The current study’s reliance on 16S rRNA sequencing, although suitable for community profiling, limits mechanistic interpretations. Future research incorporating shotgun metagenomics, metatranscriptomics, and metabolomics could offer deeper insights into the functional consequences of treatment-induced dysbiosis. Direct measurement of fecal SCFA concentrations would confirm whether the taxonomic depletion of butyrate producers results in functional deficiency[30], while metabolomic profiling could identify microbial metabolites that affect drug efficacy or toxicity.

Geographic and population-specific considerations

Le et al’s study[13] is the first to characterize longitudinal microbiota changes in Vietnamese patients with CRC, emphasizing the importance of geographic and population-specific factors (Figure 1). Dietary patterns, environmental exposures, and genetic backgrounds all influence baseline microbiota composition and may modulate treatment-induced changes. Comparative studies across diverse populations could identify conserved microbial responses to treatment vs population-specific adaptations, thereby informing the development of globally applicable vs locally tailored interventions.

Figure 1 Longitudinal gut microbiota dynamics in Vietnamese colorectal cancer patients during treatment, showing progressive decline in microbial diversity, depletion of beneficial short-chain fatty acid-producing bacteria, and persistent colonization of Desulfovibrio. SCFA: Short-chain fatty acid.

LIMITATIONS AND METHODOLOGICAL CONSIDERATIONS

While Le et al's study[13] offers valuable insights specific to Vietnamese CRC patients, several limitations must be acknowledged when interpreting the findings and planning future investigations. The relatively small sample size (n = 31) limited the statistical power for subgroup analyses and multiple testing corrections, as evidenced by the loss of significance in regimen-specific and response-associated differences after adjustment. Larger, multicenter studies are necessary to validate these preliminary observations and to conduct adequately powered analyses of clinically relevant subgroups.

The absence of Vietnamese-matched healthy control group or a surgery-only control group makes it difficult to differentiate treatment-specific effects from those resulting from natural disease progression or the surgical procedure itself. Similarly, the lack of a no-chemotherapy control group prevents definitive attribution of post-chemotherapy changes to cytotoxic agents as opposed to the combined effects of all interventions. Future studies should ideally include matched healthy controls and, where ethically feasible, patients undergoing surgery alone without adjuvant chemotherapy.

The use of perioperative antibiotics, although reflective of real-world clinical practice, represents a significant confounding factor that complicates the interpretation of surgery-associated changes. Future studies should carefully document antibiotic exposure and consider its effects in statistical models, potentially through sensitivity analyses that exclude patients receiving prolonged or multiple antibiotic courses.

Finally, the lack of functional measurements limits mechanistic inferences. Direct quantification of fecal SCFAs, assessment of intestinal permeability markers, and correlation with patient-reported gastrointestinal symptoms would enhance the clinical relevance of taxonomic findings and identify targets for future intervention studies.

CONCLUSION

The longitudinal study by Le et al[13] makes a significant contribution to our understanding of gut microbiota dynamics during CRC treatment in Vietnamese patients. By demonstrating a progressive loss of microbial diversity, depletion of both pathogenic and beneficial taxa (notably including signature rice-fermenting commensals like Ruminococcus gauvreauii group), and potential associations with clinical factors, the authors highlight the profound ethnically nuanced impact of standard therapies on the intestinal ecosystem. These findings underscore the dual-edged nature of treatment-induced dysbiosis: While the reduction of CRC-associated pathogens may be beneficial, the concurrent loss of SCFA-producing bacteria – particularly those adapted to Vietnam’s rice-based dietary patterns – could compromise gut barrier function, increase chemotherapy toxicity (evident in extended diarrhea duration vs Western cohorts), and potentially diminish therapeutic efficacy.

As we advance into the era of precision oncology, integrating Vietnamese population-specific gut microbiota analysis into treatment planning and supportive care strategies holds significant promise. Microbiota profiling can help identify local patients at risk for severe toxicity or poor therapeutic response, guide culturally contextualized the selection of chemotherapy regimens, and inform the use of culturally adapted adjunctive interventions. Probiotics (specifically targeting Vietnam-depleted taxa like Ruminococcus gauvreauii group), prebiotics, dietary modifications (addressing traditional diet-microbiota links), and fecal microbiota transplantation represent actionable strategies that could be incorporated into Vietnamese clinical practice if their efficacy is validated through local rigorous clinical trials.

The path forward requires continued collaborative, multidisciplinary efforts to address the limitations of current evidence specific to Vietnamese cohorts. Larger longitudinal studies tracking locally relevant endpoints like rice-derived SCFA recovery and fermented-fish sauce-associated pathobiont clearance with extended follow-up, integration of multi-omics approaches for diet-microbe-host interactions in tropical settings, and well-designed intervention trials leveraging Vietnam's dietary traditions are necessary to translate these observational findings into regional clinical practice. The study by Le et al[13] provides a foundation for such efforts within the Vietnamese population and contributes to the growing global evidence base supporting microbiome-informed approaches to CRC management.