Inflammatory markers as bridges to the mind in postoperative intestinal tumor recovery

Abstract

In the complex landscape of postoperative recovery following intestinal tumor surgery, the interplay between psychological distress and physiological responses emerges as a significant yet often overlooked factor influencing patient outcomes. This editorial examines the groundbreaking work of Wei et al published in the World Journal of Gastroenterology, which elucidates the temporal relationship between psychological distress and inflammatory markers, revealing that approximately 20%-40% of cancer patients, particularly those with gastrointestinal malignancies, are susceptible to heightened anxiety and depression during the vulnerable early postoperative phase. By employing a dynamic longitudinal design alongside innovative machine learning techniques, Wei et al identify critical inflammatory thresholds, such as the neutrophil-to-lymphocyte ratio and albumin-to-fibrinogen ratio, that serve as mediators in this relationship. Their findings underline the necessity of integrative rehabilitation models that combine psychological, nutritional, and physical interventions to enhance patient quality of life. This editorial advocates for a paradigm shift in postoperative care, urging the incorporation of psychological risk assessments alongside traditional methods to optimize recovery trajectories, ultimately bridging the gap between mind and body in cancer care. The challenges of translating these insights into routine practice and the imperative for future multicenter validation studies are also discussed, emphasizing the need for a holistic approach in addressing the multifaceted burdens faced by patients in the aftermath of surgery.

Key Words: Postoperative depression; Intestinal tumor surgery; Inflammatory markers; Neutrophil-to-lymphocyte ratio; Albumin-to-fibrinogen ratio; Quality of life; Precision oncology; Integrated care

Core Tip: Wei et al transform routine inflammatory markers into psychological risk stratification tools by demonstrating that neutrophil-to-lymphocyte ratio > 7.0 and albumin-to-fibrinogen ratio < 12.0 mechanistically predict postoperative depression and anxiety in intestinal tumor patients. This paradigm shift enables early identification of vulnerable patients using existing clinical infrastructure, facilitating integrated physical-mental rehabilitation that addresses the biological roots of postoperative psychological distress rather than treating mind and body as separate domains.

This editorial refers to "Postoperative depression and anxiety in patients undergoing intestinal tumor surgery: Incidence, predictors, and impact on quality of life" by Wei et al, 2025; https://dx.doi.org/10.3748/wjg.v31.i47.111599.

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INTRODUCTION

The psychological sequelae of cancer surgery have long been overshadowed by surgical success rates and tumor margins. In this editorial, we critically examine Wei et al’s prospective observational study[1] published in the World Journal of Gastroenterology, which illuminates a critical yet underappreciated dimension of postoperative care: The intricate relationship between psychological distress, inflammatory responses, and quality of life following intestinal tumor surgery. We argue that their findings suggest we should reconceptualize postoperative recovery not as merely a physiological process, but as an integrated mind-body phenomenon that may benefit from holistic intervention strategies, pending validation through interventional trials. However, significant methodological questions must be addressed before translating these observations into routine clinical protocols.

THE HIDDEN BURDEN OF PSYCHOLOGICAL DISTRESS

Approximately 20%-40% of cancer patients experience clinically significant depression and anxiety, with gastrointestinal cancer patients facing particularly elevated risks[2,3]. Wei et al’s study[1] adds crucial granularity to this understanding by demonstrating that psychological symptoms follow a predictable temporal pattern, with the highest burden occurring in the immediate postoperative period, with gradual improvement over 30 days. This timeline aligns with established literature showing that the acute surgical phase represents a vulnerable window for psychological intervention[4].

What distinguishes this manuscript is its systematic approach to dynamic monitoring. Rather than capturing psychological states at a single timepoint a limitation of many cross-sectional studies the authors tracked Hamilton Depression Scale and Self-Rating Anxiety Scale scores across three critical intervals. This longitudinal design reveals that while spontaneous improvement occurs, the early postoperative period warrants intensive psychological surveillance. Previous research has established that unaddressed psychological distress can precipitate non-adherence to adjuvant therapy, delayed wound healing, and increased healthcare utilization[5-7], making early identification paramount.

THE INFLAMMATORY-PSYCHOLOGICAL INTERFACE

Wei et al’s most compelling contribution lies in demonstrating that elevated neutrophil-to-lymphocyte ratio (NLR) and decreased albumin-to-fibrinogen ratio (AFR) are strongly associated with the relationship between postoperative psychological distress and quality of life, suggesting potential mediating pathways that require experimental validation[1]. This aligns with psychoneuroimmunology evidence showing that surgical trauma triggers inflammatory cytokine release (interleukin-6, tumor necrosis factor-α, C-reaction protein) that are associated with alterations in neurotransmitter metabolism and hypothalamic-pituitar-adrenal axis function, which may contribute to depressive symptoms[8-12].

The identification of specific intervention thresholds (NLR > 7.0, AFR < 12.0) represents a translational advance. While NLR is established as an oncological prognostic marker[13,14], its application to psychological risk stratification in postoperative intestinal tumor patients is novel. The AFR, reflecting both inflammatory activation and nutritional status, may prove particularly relevant given malnutrition’s high prevalence in gastrointestinal cancer[15,16]. However, whether these thresholds apply across diverse populations and surgical contexts requires validation. Table 1 summarizes key findings linking these markers to psychological outcomes.

Table 1 Psychological distress and inflammatory marker thresholds in postoperative intestinal tumor patients.

Parameter	Threshold value	Clinical implication
Neutrophil-to-lymphocyte ratio	> 7.0	Predicts tightened risk of depression/anxiety
Albumin-to-fibrinogen ratio	< 12.0	Indicates vulnerability due to inflammation and malnutrition
Intraoperative mean arterial pressure	< 90 mmHg	Associated with increased psychological distress

MACHINE LEARNING MEETS CLINICAL PREDICTION

Artificial intelligence is revolutionizing the diagnosis and management of numerous diseases in gastroenterology, including those that have historically been challenging and elusive[17-19]. The authors’ application of the eXtreme Gradient Boosting algorithm to identify key predictors demonstrates methodological sophistication. Machine learning approaches offer advantages over traditional regression models in handling non-linear relationships and complex interactions among variables[20]. With an area under the curve of 0.873 and external validation area under the curve of 0.826, the model demonstrates robust discriminative ability for clinical utility thresholds.

The identification of intraoperative hypotension as a strong correlate adds an intriguing dimension. Perioperative hemodynamic instability has been associated with adverse surgical outcomes[21,22], but its connection to psychological sequelae deserves further mechanistic exploration. Potential pathways may include cerebral hypoperfusion that could affect mood-regulating circuits, or hypotension may serve as a proxy for surgical complexity and physiological stress burden. However, these remain speculative hypotheses requiring mechanistic investigation. This finding underscores the importance of meticulous intraoperative management extending beyond immediate surgical concerns. Figure 1 summarizes the key findings from the study.

Figure 1 Mind-body bridge: Bridging inflammation and psychology in postoperative recovery. This infographic illustrates the bidirectional relationship between psychological distress and inflammatory markers in patients recovering from intestinal tumor surgery. The bridge metaphor connects psychological symptoms (anxiety, depression) with biological mediators (neutrophil-to-lymphocyte ratio, albumin-to-fibrinogen ratio, cytokines, nutrition), emphasizing the role of integrated care models in optimizing recovery outcomes. NLR: Neutrophil-to-lymphocyte ratio; AFR: Albumin-to-fibrinogen ratio.

METHODOLOGICAL CONSIDERATIONS AND INTERPRETIVE CAUTION

While Wei et al’s study offers valuable insights into the inflammation-psychology axis[1], several methodological limitations warrant careful consideration before clinical implementation. First, the sample size of 120 patients, though adequate for exploratory analyses, raises concerns about statistical power for the multiple correlations examined. The study reports numerous associations between inflammatory markers, psychological scores, and quality of life measures across three timepoints without clearly addressing correction for multiple comparisons. Without Bonferroni or false discovery rate adjustments, the risk of type I error (identifying spurious associations) increases substantially, potentially inflating the significance of some findings.

The single-center design from a specialized tertiary hospital introduces important selection biases. Patients treated at high-volume oncology centers differ systematically from general surgical populations in terms of disease complexity, socioeconomic status, baseline health literacy, and access to perioperative support all factors that independently influence both inflammatory responses and psychological outcomes. The extent to which these findings generalize to community hospitals or resource-limited settings remains uncertain and requires multicenter validation.

Most critically, the observational design fundamentally limits causal inference. While elevated NLR correlates with higher depression scores, we cannot determine directionality: Does inflammation drive psychological distress, does pre-existing anxiety elevate inflammatory markers through stress-induced immune activation, or do both phenomena arise from unmeasured confounders? Potential confounding variables inadequately addressed include: Postoperative complications (infections, anastomotic leaks, ileus), pain medication regimens (particularly opioids with known mood effects), tumor stage and burden, adjuvant chemotherapy timing, pre-existing psychiatric diagnoses, and social support availability. Each could independently explain the observed associations without requiring a direct inflammatory-psychological mechanism. The 3-month follow-up period, while capturing acute recovery, may miss crucial long-term trajectories. Depression following cancer surgery frequently exhibits delayed onset (4-6 months post-surgery) or may resolve spontaneously as physical function improves. Without extended follow-up (12-24 months), we cannot determine whether inflammatory markers predict sustained psychological morbidity requiring intervention, or merely transient distress that resolves naturally. This temporal limitation is particularly relevant for clinical implementation decisions. Finally, the study does not test interventions. The proposed thresholds (NLR > 7.0, AFR < 12.0) identify high-risk patients, but whether targeting these inflammatory markers through pharmacological anti-inflammatory agents, nutritional support, or early psychological intervention actually improves outcomes remains speculative. Randomized controlled trials are essential to establish whether the observed associations represent modifiable pathways vs epiphenomena of unmeasured disease severity.

QUALITY OF LIFE: THE ULTIMATE OUTCOME

Wei et al’s documentation of quality of life improvements paralleling psychological and inflammatory recovery suggests potential interconnections among these domains[1], though temporal correlation does not establish causal direction. The 36-item short-form improvements, particularly in physiological and social functioning dimensions, suggest that addressing psychological distress may yield broad benefits beyond mood symptoms themselves. Previous research has established bidirectional relationships between depression and functional impairment in cancer survivors[23,24], with psychological interventions demonstrating improvements in quality of life comparable to some medical treatments[25].

The complication rate reduction observed over time likely reflects natural healing processes. Whether improving psychological states causally influence immune function and self-care behaviors, thereby contributing to complication reduction, remains an open question requiring interventional studies to test. Studies have demonstrated associations between depression and impaired wound healing, potentially mediated by dysregulated inflammatory responses and hypothalamic-pituitary-adrenal axis dysfunction[26], though the extent to which this represents a causal relationship vs shared underlying pathophysiology remains debated.

STUDY LIMITATIONS

Several methodological constraints limit the immediate clinical applicability of Wei et al’s findings[1]. The modest sample size (n = 120) provides adequate power for primary correlation analyses but may be underpowered for subgroup analyses and interaction testing. Single-center recruitment from a tertiary oncology hospital raises concerns about selection bias patients at specialized centers may differ systematically from community hospital populations in disease severity, comorbidity burden, socioeconomic resources, and baseline psychological resilience. Multicenter validation across diverse healthcare settings (academic vs community, urban vs rural, varying resource levels) and patient populations (different ethnic groups, age ranges, tumor locations) is essential before recommending widespread implementation of inflammatory marker screening protocols.

The observational design, while valuable for hypothesis generation, cannot establish causality. We cannot determine from these data whether elevated inflammatory markers directly cause psychological distress, whether pre-existing anxiety elevates inflammatory markers through stress-induced immune activation, or whether both arise from unmeasured confounders such as disease severity, surgical complications, or nutritional status. Critical confounding variables inadequately addressed include: (1) Postoperative complications: Infections, anastomotic leaks, and delayed recovery independently affect both inflammation and mood; (2) Pain management: Opioid use has direct effects on mood and may confound psychological assessments; (3) Tumor characteristics: Stage, grade, and completeness of resection may influence both inflammatory responses and psychological distress through prognostic concerns; (4) Pre-existing mental health: Baseline psychiatric diagnoses or prior psychological treatment were not systematically assessed; (5) Social support: Family structure, caregiver availability, and socioeconomic factors strongly influence postoperative psychological outcomes; and (6) Adjuvant therapy timing: Chemotherapy initiation during the follow-up period could affect both inflammatory markers and psychological well-being.

CULTURAL CONSIDERATIONS

An important consideration for generalizability involves cultural factors in psychological assessment and expression. Wei et al[1] employed the Hamilton Depression Scale and Self-Rating Anxiety Scale tools with validated Chinese versions demonstrating acceptable psychometric properties. However, cultural dimensions specific to Chinese populations, including collectivistic values, family-centered medical decision-making, and mental health stigma, may influence both the experience and reporting of psychological symptoms. Symptom expression varies across cultures; for example, somatic manifestations of depression may be more prominent than affective symptoms in some Asian populations. Before implementing inflammatory marker-based psychological screening globally, cross-cultural validation is essential. The cutoff thresholds (NLR > 7.0, AFR < 12.0) identified in this Chinese cohort may not predict psychological distress equivalently in Western, African, or other Asian populations due to genetic variation in inflammatory responses, dietary differences affecting baseline inflammatory markers, and cultural variation in psychological resilience and coping mechanisms. International multicenter studies with culturally adapted assessment tools are necessary to establish whether the inflammation-psychology axis operates consistently across diverse populations.

PRIORITY RESEARCH DIRECTIONS

Priority research directions include: (1) Interventional trials: Randomized controlled trials testing whether inflammatory marker-guided interventions (anti-inflammatory agents, nutritional support, early cognitive-behavioral therapy) can improve psychological outcomes compared to standard care to establish causal relationships; (2) Mechanistic studies: Prospective cohorts with detailed inflammatory cytokine profiling, neuroimaging, and neurotransmitter assessments to establish biological plausibility of the inflammation-psychology pathway; (3) Multicenter validation: External validation of the proposed thresholds across diverse populations and healthcare settings to establish generalizability; (4) Long-term follow-up: Extended observation (≥ 12 months) to determine whether inflammatory markers predict sustained psychological morbidity vs transient distress; (5) Integrated rehabilitation trials: Testing comprehensive programs combining nutritional support, exercise, psychological therapy, and anti-inflammatory approaches, compared to component interventions alone to determine optimal care models; and (6) Cost-effectiveness analyses: Economic evaluations of inflammatory marker screening programs to inform resource allocation decisions in diverse healthcare systems.

The role of nutritional rehabilitation deserves explicit attention. Given that AFR encompasses albumin a marker of nutritional status and the high prevalence of malnutrition in gastrointestinal cancer patients[27-29], integrating registered dietitian expertise into postoperative care pathways may prove beneficial. Furthermore, exploring how emerging treatments like enhanced recovery after surgery protocols affect the inflammatory-psychological nexus could optimize perioperative care[30]. Table 2 summarizes a pathway towards better post operative integrated care.

Table 2 Integrated rehabilitation model components.

Domain	Intervention example	Expected outcome
Psychological	Cognitive-behavioral therapy, counseling	Reduced anxiety/depression, improved adherence
Nutritional	Dietitian guided nutritional supplementation, micronutrient support	Improved AFR, enhanced wound healing
Physical	Early mobilization, structure exercise rehab	Better immune function, Improved quality of life
Medical monitoring	NLR/AFR surveillance, hemodynamic stability	Early detection of risk, proactive intervention

NLR: Neutrophil-to-lymphocyte ratio; AFR: Albumin-to-fibrinogen ratio.

CONCLUSION

Wei et al’s study represents a meaningful step toward precision medicine in postoperative psychological care by demonstrating that specific inflammatory thresholds (NLR > 7.0, AFR < 12.0) may identify patients at elevated risk for depression and anxiety[1]. Their framework for evidence-based screening offers clinical promise, yet critical questions remain. The observational design cannot establish causality, the single-center sample limits generalizability, and the 3-month follow-up may miss delayed or resolving psychological trajectories. Most importantly, whether targeting these inflammatory markers through anti-inflammatory interventions, nutritional support, or early psychological therapy actually improves outcomes remains untested. The priority for future research is clear: Multicenter randomized controlled trials testing whether inflammatory marker-guided interventions can break the proposed inflammatory-psychological cycle. Only such evidence can justify implementing routine postoperative NLR/AFR screening and threshold-based interventions. As oncology moves toward increasingly personalized care, Wei et al’s work provides a hypothesis-generating foundation but the hard work of intervention testing and implementation science lies ahead before we can confidently integrate biological markers of psychological risk into standard postoperative pathways[1].