A recent preclinical study reported that Wumei Pills (WMP) and Lactobacillus reuteri (L. reuteri) mitigate 5-fluorouracil-induced intestinal mucositis by promoting intestinal stem cell (ISC)-mediated repair via Wnt/β-catenin signaling. The mechanistic interpretation rests largely on systemic inflammation readouts, correlative microbiota changes, and immunohistochemistry of pathway markers.

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From a clinical standpoint, chemotherapy-induced mucositis remains a common and burdensome toxicity that leads to dose reductions, treatment delays, and infection risk; current care is largely supportive and does not directly restore ISC-mediated repair.

This unmet need motivates rigorous appraisal of the proposed “WMP → L. reuteri → ISC/Wnt” axis. To highlight key methodological considerations that may affect causal inference and analytical rigor in the proposed “WMP → L. reuteri → ISC/Wnt” pathway, a new letter critically appraises the study’s design, endpoints, and analyses against current best practices in mucositis biology, microbiome causality testing, Wnt/β-catenin pathway validation, and preclinical statistics, and synthesizes concrete, literature-grounded remedies.

Six issues

The authors identified six issues with potential impact on interpretation:

(1) Reliance on serum cytokines/lipopolysaccharide to infer local mucosal inflammation, with limited tissue-level indices (e.g., myeloperoxidase, interleukin-1β, immune-cell infiltration);

(2) Absence of necessity/sufficiency tests to verify microbiota mediation (e.g., L. reuteri depletion, WMP-donor fecal microbiota transplantation, probiotic add-back);

(3) Pathway evidence tiering - Wnt/β-catenin activation not confirmed by β-catenin nuclear translocation or downstream targets (Axin2, c-Myc, cyclin D1), and Lgr5 quantification/specificity insufficient;

(4) Statistical design under-specified (power justification, blinded assessment, control of multiple comparisons) and potential cage effects unmodeled;

(5) Limited dose-response and safety profiling for WMP/L. reuteri; and

(6) Constrained generalizability (single sex/strain/age, lack of ABX-only controls, single time-point).

The authors said the reported benefits of WMP and L. reuteri in chemotherapy-induced mucositis are promising, but stronger causal and analytical foundations are needed.

Incorporating tissue-level inflammation readouts, microbiota loss-/gain-of-function designs, definitive Wnt/β-catenin activation assays, rigorous statistical practices (including mixed-effects models for cage clustering and multiplicity control), dose-response/safety evaluation, and broader experimental scope (sex/age/strain, ABX-only controls, time-course) will yield more robust and translationally relevant conclusions.

The letter is published in World Journal of Stem Cells.

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