Introduction

Chronic stress has been well-documented to exacerbate the progression of colorectal cancer (CRC), yet the role of the gut microbiota in this process remains elusive.

Aims & Methods

Subcutaneous MC38 tumor models and AOM/DSS-induced murine CRC models were utilized to evaluate the tumor-promoting effects of chronic restraint stress. Antibiotic cocktail (ABXs) administration and Fecal microbiota transplantation (FMT) were employed to determine whether the gut microbiota shaped by chronic stress could potentiate CRC progression.16S rRNA gene sequencing was conducted to analyze microbiota alterations induced by chronic stress.

Results

Chronic stress significantly accelerated CRC progression in both subcutaneous and AOM/DSS-induced models (all P < 0.05), while ABX administration in AOM/DSS-induced models attenuated this effect (P = 0.9897). Notably, Mice receiving FMT from the chronic stress group exhibited a higher tumor burden compared to FMT from controls (P < 0.01), indicating that the gut microbiota may be involved in the progression of CRC induced by chronic stress. Further analysis of the disturbed gut microbiota revealed a significant depletion of Lactobacillus in CRC models with chronic stress. Specifically, Lactobacillus johnsonii, Lactobacillus gasseri and Lactobacillus plantarum were reduced and inversely correlated with tumor numbers in AOM/DSS induced mouse models, respectively (all P value <0.05). Interestingly, chronically stressed mice harbored fewer CD8⁺ T cells and IFN-γ⁺ CD8⁺ T cells within colon tumors compared to controls, however, this disparity was abrogated upon ABX administration. Furthermore, mice receiving FMT from the chronic stress group exhibited a paucity of CD8⁺ T cells and IFN-γ⁺ CD8⁺ T cells in tumors relative to FMT from control group, suggesting that the chronic stress-shaped gut microbiota may dampen the anti-tumor effects of CD8⁺ T cells. Additionally, we found that CD8⁺ T cells in tumor were positively associated with relative abundance of Lactobacillus johnsonii, Lactobacillus gasseri and Lactobacillus plantarum, respectively (all P < 0.05). Collectively, these results suggest that the reduction of Lactobacillus species under chronic stress conditions may dampen CD8⁺ T cell anti-tumor immunity, thereby promoting CRC progression.

Conclusion

Our study indicates that chronic stress may promote the progression of CRC by reducing intestinal Lactobacillus bacteria, and the possible mechanism is to weaken Lactobacillus-mediated CD8⁺ T cell anti-tumor immunity. Future investigations should focus on elucidating the mechanisms by which specific Lactobacillus species modulate CD8⁺ T cell function and tumor immunity, as well as exploring the therapeutic potential of Lactobacillus-based interventions in managing stress-related CRC exacerbation.

Introduction

Pancreatic ductal adenocarcinoma (PDAC) surveillance programs are recommended for individuals with a PDAC lifetime-risk ≥5% to improve outcomes.¹ While familial adenomatous polyposis (FAP) is linked to increased PDAC risk, robust data to guide surveillance recommendations is lacking.^2,3 This study evaluates PDAC risk in a large FAP-cohort and cost-effectiveness of PDAC-surveillance in this group.

Aims & Methods

Data were collected from FAP cohorts in the United States (US) and the Netherlands (NL), including individuals (≥18 years) with a confirmed (likely) pathogenic APC variant. To minimize ascertainment bias, individuals whose initial visit or registration was prompted by a PDAC diagnosis were excluded from the analysis. Cumulative PDAC incidence, adjusted for death as competing risk, was calculated for the FAP cohorts and compared with control data from the Netherlands Cancer Registry and Statistics Netherlands. The cost-effectiveness of surveillance was evaluated using our previously developed Markov model.⁴ In comparison to the previous study, the model was modified by setting the inflation rate at 3%, discontinuing surveillance at age 75 and incorporating the relative risk derived from our FAP cohort.

Results

The US-cohort (n=357) and the NL-cohort (n=1000) had a median age at the end of follow-up of 46 years (IQR, 32.0-60.0) and 60 years (IQR, 47.5-72.5), respectively. Female participants comprised 52.9% of the US-cohort and 47.2% of the NL-cohort. Within the US-cohort, three PDAC cases were identified, however, two individuals had been referred to the Mayo Clinic at the time of PDAC diagnosis and were subsequently excluded from the analysis to reduce the risk of ascertainment bias. When combining both FAP-cohorts, the cumulative risk of PDAC by age 70 was 0.7% (95% CI, 0.3-1.8). Detailed cumulative risk estimates, stratified by cohort and age, are presented in Table 1. For comparison, the cumulative incidence of PDAC in the general population at age 70 was 0.32% (95% CI, 0.31-0.33), corresponding to a relative risk of 2.2 (95% CI, 0.9-5.7) for individuals with FAP. The cost-effectiveness analysis estimated that annual magnetic resonance imaging-based PDAC surveillance, starting at age 40, would be considered cost-effective if the relative risk reached at least 4.0, based on a willingness-to-pay threshold of $100 000.

Table 1. Adjusted cumulative incidence of pancreatic ductal adenocarcinoma in individuals with familial adenomatous polyposis

Conclusion

This is the largest cohort study to date to assess PDAC risk in individuals with FAP. Our findings indicate that PDAC risk in FAP patients is not significantly higher than in the general population. Moreover, their surveillance is shown not to be cost-effective.

References

1. Goggins M, Overbeek KA, Brand R, Syngal S, Del Chiaro M, Bartsch DK, et al. Management of patients with increased risk for familial pancreatic cancer: updated recommendations from the International Cancer of the Pancreas Screening (CAPS) Consortium. Gut. 2020;69(1):7-17.
2. Giardiello FM, Offerhaus GJ, Lee DH, Krush AJ, Tersmette AC, Booker SV, et al. Increased risk of thyroid and pancreatic carcinoma in familial adenomatous polyposis. Gut. 1993;34(10):1394-6.
3. Karstensen JG, Bülow S, Højen H, Jelsig AM, Jespersen N, Andersen KK, et al. Cancer in Patients With Familial Adenomatous Polyposis: A Nationwide Danish Cohort Study With Matched Controls. Gastroenterology. 2023;165(3):573-81.e3.
4. Corral JE, Das A, Bruno MJ, Wallace MB. Cost-effectiveness of Pancreatic Cancer Surveillance in High-Risk Individuals: An Economic Analysis. Pancreas. 2019;48(4):526-36.

Disclosure

None