Yudong Jiang

Background: Our previous study revealed that Piezo1 in colonic goblet cells senses mechanical stimuli to regulate the production and secretion of MUC2, but the underlying mechanism remains unclear. Altered endoplasmic reticulum function and the unfolded protein response (UPR), which are critical for MUC2 protein folding and secretion, were observed in goblet cell‐specific Piezo1 knockout mice. This study aimed to investigate whether and how Piezo1 in goblet cells modulates mucus barrier function by regulating the UPR. Methods: In vitro, LS174T cells were subjected to orbital shaking to simulate fluid shear stress (FSS) stimulation. The expression of UPR‐related molecules and MUC2 was detected using real‐time PCR, Western blotting, and immunofluorescence staining in the presence or absence of Piezo1 and UPR inhibition. In vivo, goblet cell‐specific Piezo1 knockout (cKO) mice were treated with dextran sulphate sodium (DSS) and water avoidance stress (WAS). We analysed changes in goblet cell morphology, mucus layer thickness, UPR‐related protein expression and ER structure. In addition, DSS‐induced colitis mice were intraperitoneally injected with Yoda1 to activate Piezo1, and alterations in pathological structures and mucus layer thickness were subsequently evaluated. Results: Compared with PERK or ATF6, FSS activated PIEZO1 and promoted calcium influx, thereby maintaining ER calcium homeostasis and selectively activating the IRE1α–XBP1 signalling pathway. This cascade facilitated MUC2 production, whereas pharmacological inhibition of PIEZO1 or IRE1α expression significantly abolished these effects. Compared with WT mice, cKO mice exhibited aggravated mucus barrier impairment, downregulated IRE1α‐XBP1 and aggravated ER swelling under DSS and WAS. In contrast, pharmacological activation of Piezo1 via Yoda1 treatment restored intestinal mucus layer thickness and ameliorated colitis in DSS mice. Conclusions: Piezo1 senses mechanical stimulation to maintain ER calcium homeostasis and modulates the UPR via the IRE1α–XBP1 pathway, thereby facilitating MUC2 production in goblet cells and maintaining intestinal mucosal barrier homeostasis. Key points: Piezo1 in colonic goblet cells senses intestinal mechanical stimulation and modulates endoplasmic reticulum calcium homeostasis via Ca ²⁺ influx. The Piezo1‐Ca ²⁺ ‐IRE1α‐XBP1 signaling axis controls Mucin2 synthesis and production to maintain intestinal mucus barrier integrity. Pharmacological activation of Piezo1 by Yoda1 rescues mucus barrier defects, providing a potential therapeutic strategy for gastrointestinal mucosal injury.

Mucus secreted by goblet cells (GCs) may play an important role in intestinal transit function. Our previous study found that Piezo1 protein is essential for GC function; however, the effect of GC Piezo1 on intestinal transit function is unclear. Our study aimed to investigate the effect of Piezo1 in GCs on intestinal transit and the potential mechanism. We compared intestinal mucus, fecal form, intestinal transit time, intestinal epithelial cell composition, and stem cell function in WT and GC-specific Piezo1-deficient (Piezo1^ΔGC) mice. Our results revealed a correlation between mucus and intestinal transit: the less mucus there was, the slower the intestinal transit. Piezo1 deficiency in GCs led to decreased mucus synthesis and also disrupted the ecological niche of colon stem cells (CSCs). Through organoid culture, we found that the capacity of proliferation and differentiation in Piezo1^ΔGC mouse CSCs was significantly decreased, which also led to a reduced source of GCs. Further studies found that the reduced Wnt and Notch signals in colon crypts might be the potential mechanism. These results indicated the importance of GC Piezo1 in intestinal transit function, which acts by maintaining the homeostasis of intestinal epithelial cells and mucus.

FUT2, a protein that uses l ‐fucose to mediate fucosylation of intestinal epithelial cells, is one of the detected gene variants in IBD patients. We aimed to investigate whether exogenous l ‐fucose could be an enteral nutritional supplement to protect intestinal barrier function. The effect of l ‐fucose on the restoration of epithelial barrier function in both the DSS‐induced colitis mouse model and LPS‐stimulated Caco‐2 cells was investigated, and the impact on fucosylation of epithelial cells was examined. The severity of DSS‐induced colitis was significantly reduced by l ‐fucose. Restoration of epithelial barrier function by l ‐fucose was detected. Direct l ‐fucose‐mediated protection of tight junctions was observed in Caco‐2 cells. Moreover, exogenous l ‐fucose promoted the exogenous metabolic pathway of l ‐fucose, and fucosylation of epithelial cells both in vivo and in vitro. Moreover, knockout of the FUT2 gene restrained fucosylation and the protective effect of l ‐fucose on barrier function. The severity of colitis was not improved by l ‐fucose in Fut2 knockout mice. Therefore we conclude that exogenous l ‐fucose protects intestinal barrier function and relieves intestinal inflammation via upregulation of FUT2‐mediated fucosylation of intestinal epithelial cells.

The incidence of digestive symptoms may vary depending on doctors’ professional backgrounds when they inquired suspected COVID-19 patients in a fever clinic. We sought to understand the characteristics of inquiries about digestive symptoms by doctors in different specialties; therefore, inquiry records of 2 gastroenterologists and 6 nongastroenterologists were reviewed. We compared the difference in inquiry of digestive symptoms (diarrhea, vomit, distension, anorexia, and abdominal pain) between these two groups among identified COVID-19 patients. And we further compared the difference of digestive symptoms between confirmed patients and suspected cases who excluded from COVID-19. Among 495 confirmed COVID-19 cases (254 cases by gastroenterologists and 241 cases by nongastroenterologists), 22.83% patients experienced various digestive symptoms in the gastroenterologists’ group, while only 4.47% reported digestive symptoms by nongastroenterologists ( ). Additionally, among initially suspected 611 patients who presented with similar respiratory symptoms inquired by gastroenterologists, confirmed cases presented far more frequency of digestive symptoms than excluded cases (22.8% vs. 3.64%, ). Furthermore, confirmed patients reported more percentage of watery diarrhea (56% vs. 36%, ) and higher frequent vomit ( vs. per day, ) than excluded cases. We concluded that gastroenterologists could detect a greater proportion of gastrointestinal symptoms in COVID-19 patients during fever clinic inquiries. Moreover, confirmed COVID-19 patients are more likely to have higher severity in digestive symptoms than excluded cases. Therefore, physicians in fever clinic should pay more attention to the triage of gastrointestinal symptoms.