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Molecular Diagnostics

Gut microbiota-associated predictors as biomarkers of neoadjuvant treatment response in rectal cancer-a systematic review

British Journal of Cancer (2026)Cite this article

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Abstract

Background

The gut microbiome is increasingly recognized as a modulator of cancer therapy outcomes and a potential predictive biomarker. This systematic review synthesizes current evidence on microbial biomarkers associated with neoadjuvant treatment (NT) response in rectal cancer (RC).

Methods

PubMed, Embase, and Ovid Medline databases were searched through March 2025. Eligible studies included RC patients treated with NT with baseline microbial analysis stratified by treatment response. Two reviewers independently performed screening, data extraction, and quality assessment (NIH and STORMS tools). Due to substantial heterogeneity, a structured qualitative synthesis without meta-analysis was conducted following SWiM guidelines, using a direction-of-effect vote-counting approach.

Results

Sixteen observational studies (842 patients) were included, covering chemoradiotherapy (nCRT), total neoadjuvant therapy, chemotherapy, and immunochemoradiotherapy. Microbiota composition was investigated by 16S rRNA sequencing, metagenomics, or metatranscriptomics on fecal or tissue samples. While microbial diversity showed inconsistent associations, specific taxa -notably Bacteroides, Fusobacterium and Akkermansia- emerged as recurrent biomarkers of poor response to nCRT. Twelve predictive models reported AUROC values from 0.73 to 0.97, with limited external validation.

Conclusions

Specific microbial taxa show a consistent association with nCRT resistance across independent cohorts. However, methodological heterogeneity and limited reproducibility warrant standardized prospective validation before clinical implementation. PROSPERO: CRD42023433704.

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Fig. 1: PRISMA diagram.
Fig. 2: Model discrimination.
Fig. 3: Microbial biomarkers associated with response to nCRT in rectal cancer.

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Data availability

The data used for this systematic review were extracted from articles that were all public and available from PubMed, Ovid MEDLINE and EMBASE.

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Funding

This work was supported by AIRC under Grant IG 2019 - ID. 23381 – P.I. Scarpa Marco.

Author information

Author notes

  1. These authors contributed equally: Marco Scarpa, Melania Scarpa.

Authors and Affiliations

  1. General Surgery Unit 3, Azienda Ospedale Università Padova, Padova, Italy

    Astghik Stepanyan, Marco Scarpa, Imerio Angriman, Quoc Riccardo Bao, Andrea Baldo, Romeo Bardini, Giulia Becherucci, Marco Brolese, Michela Campi, Valentina Chiminazzo, Luca Dal Santo, Antonella D’Angelo, Luca Facci, Francesco Marchegiani, Isacco Maretto, Silvia Negro, Giulia Pozza, Salvatore Pucciarelli, Giorgio Rivella, Cesare Ruffolo, Luca Saadeh, Federico Scognamiglio, Gaya Spolverato, Gaia Tussardi & Chiara Vignotto

  2. Immunology and Molecular Oncology Diagnostics, Veneto Institute of Oncology IOV - IRCCS, Padua, Italy

    Andromachi Kotsafti, Antonio Rosato & Melania Scarpa

  3. Department of Molecular Medicine, University of Padova, Padova, Italy

    Ignazio Castagliuolo

  4. University of Padova, Padova, Italy

    Marco Agostini, Gianluca Businello, Giulia Capelli, Carlotta Ceccon, Angelo Paolo Dei Tos, Barbara Di Camillo, Matteo Fassan, Dario Gregori, Vincenza Guzzardo, Andrea Porzionato & Roberta Salmaso

  5. Azienda ULSS 7 Pedemontana, Bassano, Italy

    Michele Antoniutti & Lavinia Ceccarini

  6. Azienda Provinciale per i Servizi Sanitari, Trento, Italy

    Mattia Barbareschi, Giovanni Bertalot, Alberto Brolese & Laura Marinelli

  7. Veneto Institute of Oncology IOV - IRCCS, Padova, Italy

    Francesca Bergamo, Ottavia De Simoni, Boris Franzato, Pierluigi Pilati, Antonio Scapinello & Vittorina Zagonel

  8. Azienda ULSS 3 Serenissima, Venezia, Italy

    Giovanni Bordignon, Corrado Da Lio, Mario Godina, Licia Laurino, Roberto Merenda, Isabella Mondi, Giovanni Pirozzolo, Alfonso Recordare & Daunia Verdi

  9. Azienda ULSS 2 Marca Trevigiana, Treviso, Italy

    Stefano Brignola, Ivana Cataldo, Marco Massani, Valerio Pellegrini, Anna Pozza & Tommaso Stecca

  10. Azienda Unità Socio-Sanitaria Locale 5 Polesana, Rovigo, Italy

    Gianluca Buzzi, Dario Parini, Daniela Prando & Beatrice Salmaso

  11. Azienda Unità Socio-Sanitaria Locale 1 Dolomiti, Belluno, Italy

    Salvatore Candioli, Laura Gavagna & Fabio Ricagna

  12. Independent Statistician, Solagna, Italy

    Francesco Cavallin

  13. Azienda Unità Socio-Sanitaria Locale 6 Euganea, Padova, Italy

    Chiara Cipollari, Roberto Cola, Giulia Noaro, Giuseppe Portale, Ylenia Camilla Spolverato & Matteo Zuin

  14. Ospedale GB Grassi ASL ROMA 3, Ostia, Italy

    Loretta Di Cristofaro

  15. Azienda Ospedaliero Universitaria delle Marche, Ancona, Italy

    Mario Guerrieri & Monica Ortenzi

  16. Area Vasta 4 di Fermo, Ospedale Murri, Fermo, Italy

    Silvio Guerriero, Alessandra Piccioli & Chiara Romiti

  17. Casa di Cura di Abano, Abano, Italy

    Giovanni Tagliente, Monica Tomassi & Umberto Tedeschi

  18. Azienda Unità Sanitaria Locale - IRCCS di Reggio Emilia, Reggio Emilia, Italy

    Maurizio Zizzo

Authors
  1. Astghik Stepanyan
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  2. Andromachi Kotsafti
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  3. Antonio Rosato
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  4. Ignazio Castagliuolo
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  5. Marco Scarpa
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  6. Melania Scarpa
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Consortia

on behalf of the IMMUNOREACT Study Group

  • Marco Agostini
  • , Imerio Angriman
  • , Michele Antoniutti
  • , Quoc Riccardo Bao
  • , Andrea Baldo
  • , Mattia Barbareschi
  • , Romeo Bardini
  • , Giulia Becherucci
  • , Francesca Bergamo
  • , Giovanni Bertalot
  • , Giovanni Bordignon
  • , Stefano Brignola
  • , Alberto Brolese
  • , Marco Brolese
  • , Gianluca Businello
  • , Gianluca Buzzi
  • , Michela Campi
  • , Salvatore Candioli
  • , Giulia Capelli
  • , Ivana Cataldo
  • , Francesco Cavallin
  • , Lavinia Ceccarini
  • , Carlotta Ceccon
  • , Chiara Cipollari
  • , Valentina Chiminazzo
  • , Roberto Cola
  • , Corrado Da Lio
  • , Luca Dal Santo
  • , Antonella D’Angelo
  • , Ottavia De Simoni
  • , Angelo Paolo Dei Tos
  • , Barbara Di Camillo
  • , Loretta Di Cristofaro
  • , Luca Facci
  • , Matteo Fassan
  • , Boris Franzato
  • , Laura Gavagna
  • , Mario Godina
  • , Dario Gregori
  • , Mario Guerrieri
  • , Silvio Guerriero
  • , Vincenza Guzzardo
  • , Licia Laurino
  • , Francesco Marchegiani
  • , Isacco Maretto
  • , Laura Marinelli
  • , Marco Massani
  • , Roberto Merenda
  • , Isabella Mondi
  • , Silvia Negro
  • , Giulia Noaro
  • , Monica Ortenzi
  • , Dario Parini
  • , Valerio Pellegrini
  • , Alessandra Piccioli
  • , Pierluigi Pilati
  • , Giovanni Pirozzolo
  • , Andrea Porzionato
  • , Giuseppe Portale
  • , Anna Pozza
  • , Giulia Pozza
  • , Daniela Prando
  • , Salvatore Pucciarelli
  • , Alfonso Recordare
  • , Fabio Ricagna
  • , Giorgio Rivella
  • , Chiara Romiti
  • , Cesare Ruffolo
  • , Luca Saadeh
  • , Beatrice Salmaso
  • , Roberta Salmaso
  • , Antonio Scapinello
  • , Federico Scognamiglio
  • , Gaya Spolverato
  • , Ylenia Camilla Spolverato
  • , Tommaso Stecca
  • , Giovanni Tagliente
  • , Monica Tomassi
  • , Umberto Tedeschi
  • , Gaia Tussardi
  • , Chiara Vignotto
  • , Daunia Verdi
  • , Vittorina Zagonel
  • , Maurizio Zizzo
  •  & Matteo Zuin

Contributions

AS: data curation, investigation, visualization, writing-review and editing; AK, AR, IC: writing-review and editing; MS: funding acquisition, supervision, writing-review and editing; MeS: conceptualization, investigation, methodology, writing-original draft, writing-review and editing.

Corresponding authors

Correspondence to Marco Scarpa or Melania Scarpa.

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The authors declare no competing interests.

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Stepanyan, A., Kotsafti, A., Rosato, A. et al. Gut microbiota-associated predictors as biomarkers of neoadjuvant treatment response in rectal cancer-a systematic review. Br J Cancer (2026). https://doi.org/10.1038/s41416-026-03443-9

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