The intestinal epithelium is a highly dynamic barrier that regulates digestion, absorption, immune responses, and communication between the gut microbiota and the nervous system. To maintain homeostasis, intestinal epithelial cells (IECs) must efficiently manage protein production and secretion, a process tightly controlled by the unfolded protein response (UPR).
New research published in eGastroenterology demonstrates that disruptions in the UPR contribute to inflammatory bowel diseases (IBD), colorectal cancer, and other gut-related disorders. This highlights potential therapeutic strategies to restore proteostasis.
The endoplasmic reticulum (ER) is the primary site of protein folding and processing. When IECs experience high secretory demand or environmental stress, the ER activates the UPR to ensure proper protein folding and degradation. This pathway is mediated by three key stress sensors: inositol-requiring enzyme 1 (IRE1), protein kinase RNA-like ER kinase (PERK), and activating transcription factor-6 (ATF6). These sensors work together to mitigate ER stress, restore cellular balance, and regulate immune responses.
However, chronic ER stress or genetic mutations affecting key UPR mediators can lead to severe intestinal dysfunction. The study highlights how sustained ER stress is a hallmark of IBD, with findings showing that IECs from patients with Crohn's disease and ulcerative colitis exhibit heightened ER stress markers. Dysfunction of Paneth and goblet cells, essential for antimicrobial defense and mucus secretion, is linked to defects in the UPR, contributing to dysbiosis and heightened inflammatory responses.
X-box binding protein 1 (XBP1), a transcription factor activated by the IRE1 pathway, is crucial in maintaining IEC function. The study's experimental models reveal that XBP1 deletion in the gut epithelium results in spontaneous inflammation increased susceptibility to bacterial infections, and defective antimicrobial peptide production. Furthermore, polymorphisms in the XBP1 gene have been associated with an increased risk of developing IBD, underscoring its significance in gut health.
Beyond IBD, the study explores the emerging role of the UPR in colorectal cancer. While ER stress can drive apoptosis, it can also support tumor progression by enabling cancer cells to survive in hypoxic and nutrient-deprived environments. Reduced XBP1 activity has been linked to poor survival outcomes in colorectal cancer patients, suggesting that UPR modulation may influence disease progression.
Given the leading role of ER stress in gut pathology, researchers are investigating pharmacological approaches to modulate the UPR. Chemical chaperones, such as 4-phenylbutyrate (4-PBA) and tauroursodeoxycholic acid (TUDCA), have been shown to alleviate ER stress and reduce inflammation in experimental colitis models. Additionally, recombinant BiP, an ER-resident chaperone, has demonstrated promise in enhancing gut barrier integrity and reducing immune cell infiltration in the intestine.
The study also discusses novel therapeutic avenues, including ER hormesis—a strategy that leverages mild stress to enhance cellular resilience. Experimental treatments such as CTB-KDEL, a modified cholera toxin B subunit that induces mild ER stress, have shown potential in promoting wound healing and strengthening intestinal barrier function.
In addition to pharmacological interventions, dietary components that influence ER proteostasis are gaining attention. Natural compounds like flavonoids and probiotics with proteostasis-enhancing properties could serve as complementary approaches to conventional treatments.
Furthermore, the study explores the intricate relationship between the UPR and the gut-brain axis. Emerging evidence suggests that neuronal UPR activation can influence intestinal proteostasis through systemic signaling, opening new avenues for understanding how brain function impacts gut health.
The findings of this study underscore the importance of the UPR in intestinal biology. Targeting ER proteostasis presents a promising strategy to improve gut health, offering potential breakthroughs in treating IBD, colorectal cancer, and age-related gut dysfunction. As research progresses, integrating UPR modulation into clinical practice could revolutionize therapeutic approaches for gastrointestinal disorders.
See the article:
Hetz C, Silva-Agüero JF, Ellerby LM. Essential roles of the unfolded protein response in intestinal physiology. eGastroenterology 2024;2:e100129. doi:10.1136/egastro-2024-100129
About eGastroenterology
eGastroenterology is a new, open-access, and open peer-reviewed BMJ Journal, which focuses on basic, clinical, translational, and evidence-based medicine research in all areas of gastroenterology (including hepatology, pancreatology, esophagology, and gastrointestinal surgery). eGastroenterology is now indexed by PMC, Scopus, DOAJ, Dimensions, OpenAlex, ROAD, and COPE, with more to come!
