Exploring the Animal Models of Gastrointestinal and Emotional Comorbidity

With the comorbid anxiety/depression in gastrointestinal diseases occur at a high rate worldwide, it is particularly important to discover and optimize the protocols of comorbidity models, thus further to reveal the mechanism and develop the treatment strategies of comorbidity.

Using "functional dyspepsia (FD), animal model, anxiety, depression" as search terms, this search is conducted in PubMed, Web of Science, and SpringerLink databases, with the search period from 2020 to 2025.

We find that both iodoacetamide (IA) gavage and tail clamping (TC) are classical methods for establishing FD model; physical stress such as "ice water gavage" or "irregular feeding (IF)" also used. We propose that IA + TC + IF or TC + IF + ice water gavage can be used to prepare comorbidity models in future. Maternal separation (MS) may also potentially become one of the effective models for studying comorbidities. In anxiety/depression model, we show that both chronic restraint stress (CRS) and chronic unpredictable mild stress (CUMS) are classical models for emotional disorders. We suggest CRS/CUMS combines with IA/IF/TC can better to establish gastrointestinal-emotional comorbidity model which through brain-gut cross talk. Then the review also develops a comprehensive and standardized evaluation system for comorbidity models, with recording behavioral indicators related to gastrointestinal/emotional disorders, while including multidimensional parameters such as the microbiota, neuroinflammation, metabolomics, brain-gut peptide, and neurotransmitters.

This study is the first comprehensive comparison of FD and anxiety-depression modeling protocols to propose effective protocols of comorbidity models and develop a comprehensive and standardized evaluation system for comorbidity models.