Rebuilding the gut: Decoding enteric pathogenesis using next-generation human in vitro models
- 1Department of Pediatrics, BC Children’s Hospital, University of British Columbia, Vancouver, British Columbia, Canada
Abstract
Traditional in vitro and in vivo models often fail to replicate the complex physiology of the human gastrointestinal (GI) tract, and consequently, do not fully capture how this environment influences the infective strategies employed by enteric pathogens. Here, we evaluate air-liquid interface (ALI) cultures and gut-on-a-chip (GoC) microfluidic systems as next-generation in vitro models (NGIMs) that recreate critical features of the human GI mucosal surface, including the mucus layer, crypt-villus architecture, and biomechanical forces that modulate enteric pathogenesis. We review their application towards bacterial, fungal, viral, and parasitic infections, highlighting novel mechanisms that were previously undetected using traditional models. Comparing the two approaches, we outline how ALI excels for studies involving mucus and for cost-effective implementation, whereas GoC systems uniquely capture peristalsis and luminal flow, revealing dynamic pathogen-host interactions. Notably, both platforms enable complex co-culturing, allowing pathogen-host-commensal dynamics to be studied in a reductionist manner. Lastly, we discuss how future efforts aimed at better mimicking the human GI tract could incorporate stromal, immune, and enteric nervous system components, while also improving accessibility and standardization. Taken together, both ALI and GoC systems offer significant opportunities to provide new insights into infection biology, while also serving as effective preclinical platforms for precision medicine and the evaluation of next-generation antimicrobial therapies.
Related
- Omics-based Decoding of Metabolic Dysfunction-associated Fatty Liver Disease: From Pathogenesis to Clinical Translation
- LRRK2 expression in normal and pathologic human gut and in rodent enteric neural cell lines
- Notch signalling governs human enteric nervous system progenitor dynamics
- From Molecular Pathogenesis to Therapeutic Innovations in Human Cytomegalovirus Research
- Beyond polio: advanced human in vitro models for studying non-polio enterovirus pathogenesis
BibTeX
@article{schweizer2026rebuilding,
title = {{Rebuilding the gut: Decoding enteric pathogenesis using next-generation human in vitro models}},
author = {Linus H. Schweizer and Ashley Gilliland and Yan Chen and Artemis Melville-Bowser and Bruce A. Vallance},
journal = {PLOS Pathogens},
year = {2026},
month = oct,
doi = {10.1371/journal.ppat.1014718},
url = {https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014718},
note = {CC BY},
}
RIS
TY - JOUR
TI - Rebuilding the gut: Decoding enteric pathogenesis using next-generation human in vitro models
AU - Linus H. Schweizer
AU - Ashley Gilliland
AU - Yan Chen
AU - Artemis Melville-Bowser
AU - Bruce A. Vallance
PY - 2026
DA - 2026/10/01
JO - PLOS Pathogens
DO - 10.1371/journal.ppat.1014718
UR - https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014718
AB - Traditional in vitro and in vivo models often fail to replicate the complex physiology of the human gastrointestinal (GI) tract, and consequently, do not fully capture how this environment influences the infective strategies employed by enteric pathogens. Here, we evaluate air-liquid interface (ALI) cultures and gut-on-a-chip (GoC) microfluidic systems as next-generation in vitro models (NGIMs) that recreate critical features of the human GI mucosal surface, including the mucus layer, crypt-villus architecture, and biomechanical forces that modulate enteric pathogenesis. We review their application towards bacterial, fungal, viral, and parasitic infections, highlighting novel mechanisms that were previously undetected using traditional models. Comparing the two approaches, we outline how ALI excels for studies involving mucus and for cost-effective implementation, whereas GoC systems uniquely capture peristalsis and luminal flow, revealing dynamic pathogen-host interactions. Notably, both platforms enable complex co-culturing, allowing pathogen-host-commensal dynamics to be studied in a reductionist manner. Lastly, we discuss how future efforts aimed at better mimicking the human GI tract could incorporate stromal, immune, and enteric nervous system components, while also improving accessibility and standardization. Taken together, both ALI and GoC systems offer significant opportunities to provide new insights into infection biology, while also serving as effective preclinical platforms for precision medicine and the evaluation of next-generation antimicrobial therapies.
SN - 1553-7374
SN - 1553-7366
ER -