# Probiotic supplementation to mitigate berotralstat gastrointestinal side effects: a multicenter case series from the ITACA network.

- **DOI:** [10.3389/fimmu.2026.1790199](https://doi.org/10.3389/fimmu.2026.1790199)
- **Rating:** Sound (3.4 out of 5)
- **Verdict:** A clinically relevant pilot identifies a feasible tolerability strategy for berotralstat initiation, but the uncontrolled design prevents attribution of benefit to probiotics.
- **Framework version:** v5.9
- **Pipeline version:** v0.4
- **Evaluation date:** 2026-09-18
- **Evaluation page:** https://www.nabu.science/paper/10.3389%2Ffimmu.2026.1790199

## Key claims

1. Probiotic co-administration during early berotralstat therapy was accompanied by a low incidence of GI side effects, while clinical effectiveness was maintained.
   - Support: Tentative
   - Type: Primary finding
   - Basis: an uncontrolled cohort cannot determine whether probiotics explain the low reported incidence
   - Location: Abstract, Conclusion
2. Mean monthly attack rate decreased from 2.6 to 0.8 attacks per month, ~3.3-fold reduction from baseline.
   - Support: Supported
   - Type: Secondary
   - Basis: recorded rates support the descriptive change, although baseline observation and prior-treatment washout were not standardized
   - Location: Abstract, Results
3. 2/25 GI complaints occurred after probiotic discontinuation.
   - Support: Supported
   - Type: Secondary
   - Basis: routine records establish temporal order in two cases but cannot identify a protective probiotic effect
   - Location: Abstract; Results

## Strengths

- **Specific, clinically relevant research question** The study examines a concrete supportive strategy for early GI complaints that may affect persistence with oral HAE prophylaxis and identifies a prospective controlled evaluation as the next step.
  - Dimension: contribution
  - Location: Introduction, final two paragraphs; Abstract, Conclusion
- **Detailed event and exposure reporting** The Results report probiotic products, treatment durations, event severity, timing relative to discontinuation, and interruption outcomes, allowing the observed clinical course to be broadly reconstructed.
  - Dimension: methodological rigour
  - Location: Results, probiotic product mix and GI-event paragraphs; Tables 1–3
- **Limitations tied to interpretation** The Discussion explains how the missing control group, variable follow-up, residual prior-treatment effects, absent adherence measures, and lack of microbiome data restrict causal and mechanistic conclusions.
  - Dimension: positioning
  - Location: Discussion, limitations paragraph

## Limitations

- **No internal comparison group** All participants received probiotics, so the observed 12% on-treatment GI-event rate cannot establish improvement relative to berotralstat alone. Historical trial and surveillance rates are not exchangeable controls.
  - Dimension: methodological rigour
  - Location: Materials and Methods, opening paragraph; Discussion, paragraphs 1 and 4
- **Exposure and ascertainment were unstandardized** Probiotic product, duration, adherence, follow-up, and adverse-event collection varied across routine practice, limiting internal comparability and leaving alternative explanations unresolved.
  - Dimension: methodological rigour
  - Location: Materials and Methods, opening paragraph; Results, treatment-duration paragraph
- **Implementation language exceeds readiness** The concluding proposal for a standardized 8–12-week starter course is operationally concrete, but the current case series does not identify probiotic efficacy or an optimal product and duration.
  - Dimension: application pathway
  - Location: Discussion, concluding paragraph

## Reliability checks

Caveats (4 of 4 checks).

- **Internal coherence:** Noted. The principal counts and attack-rate figures are internally consistent. The Abstract reports mean age 45 years, whereas the Results reports median age 48 years; these statistics can coexist but the change of summary measure is not explained.
- **Research conduct:** Clean. Registry ethics approval and written informed consent are declared, and the article includes a data-availability statement. No supplied-text concern indicates misconduct or a material conduct failure.
- **Reference integrity:** Clean. 24 of 24 checkable references verified
  - 24 references in manuscript
  - References not verified automatically are resolved manually within 24 hours.

## Post-publication record

- **Status:** Clean
- **Summary:** No retraction or expression of concern found in Crossref (includes Retraction Watch).
- **Last checked:** 2026-10-17