Cold Exposure Induces Intestinal Barrier Damage and Endoplasmic Reticulum Stress in the Colon via the SIRT1/Nrf2 Signaling Pathway

Abstract

Ambient air temperature is a key factor affecting human health. Long-term exposure to a cold environment can cause various diseases, while the impact on the intestine, the organ which has the largest contact area with the external environment, cannot be ignored. In this study, we investigated the effect of chronic cold exposure on the colon and its preliminary mechanism of action. Mice were exposed to 4°C for 3 hours a day for 10 days. We found that cold exposure damaged the morphology and structure of the colon, destroyed the tight junctions of the colonic epithelial tissue, and promoted inflammation of the colon. At the same time, cold exposure also activated the unfolded protein response (UPR) in the colon and promoted apoptosis in intestinal epithelial cells. Chronic cold exposure induced oxidative stress in vivo, but also significantly enhanced the response of the Nrf2 pathway that promotes an anti-oxidant effect. Furthermore, we demonstrated that chronic cold exposure promoted p65 acetylation to aggravate the inflammatory response by inhibiting SIRT1. Similar results were observed following SIRT1 knock-down by shRNA in Caco-2 cells treated with Thapsigargin (Tg). Knock-down of SIRT1 promoted nuclear localization of Nrf2, and increased the level of Nrf2 acetylation. Taken together, our study indicates that cold exposure may aggravate endoplasmic reticulum stress and damage epithelial tight junctions in the colon by inhibiting SIRT1, which promotes nuclear localization of Nrf2 and induces an anti-oxidant response to maintain intestinal homeostasis. These findings suggest that SIRT1 is a potential target for regulating intestinal health under cold exposure conditions.

Effect of chronic cold stress on gut microbial diversity, intestinal inflammation and pyroptosis in mice

“…Numerous studies have demonstrated that cold stress can harm a number of mammalian tissues, including the lungs, colon, liver, and hippocampus [7,15,28,33]. In this study, chronic cold stress led to structural damage and in ammatory cell in ltration in the ileum, jejunum and colon of mice.…”

Temperature‐Dependent Relationship of Autophagy and Apoptotic Signaling During Cold‐Water Immersion in Young and Older Males

“…[11] Despite an increase in TNF-𝛼 during the high cold stress condition suggesting an increase in intracellular inflammation, no changes were observed in IL-6 in young males (Table 1). This may be attributed to the level of cold stress in the present study representing cold stress-inducing reductions in core temperature that are physiologically relevant to humans, as others have observed elevations in both TNF-𝛼 and IL-6 in the colon of C57BL/6 mice exposed to extreme temperatures of 4 °C for 3 h. [20] Interestingly in the present study, we observed activation of the HSR during moderate cold stress, as represented by elevations in both HSP70 and HSP90 immediately following cold exposure, that were sustained throughout the 3 h recovery (Table 1). Although stressors that upregulate HSPs initially increase autophagy during or immediately following a stress insult (as also shown in the present investigation), HSPs typically upregulate following the cessation of the stressor.…”

“…[ 11 ] Despite an increase in TNF‐α during the high cold stress condition suggesting an increase in intracellular inflammation, no changes were observed in IL‐6 in young males (Table 1). This may be attributed to the level of cold stress in the present study representing cold stress‐inducing reductions in core temperature that are physiologically relevant to humans, as others have observed elevations in both TNF‐α and IL‐6 in the colon of C57BL/6 mice exposed to extreme temperatures of 4 °C for 3 h. [ 20 ]…”

Dietary full-fat rice bran prevents the risk of heart ferroptosis and imbalance of energy metabolism induced by prolonged cold stimulation

“…Food & Function substances such as Cyt C. 42 It has been shown that prolonged cold stimulation increases the protein levels of Cyt C in the colon and induces apoptosis. 43 Of particular interest, our results showed that PGC1-α was upregulated during prolonged cold stimulation. This implied that the mitochondrial protective mechanisms in the heart of pigs are triggered during prolonged cold stimulation, thereby facilitating the clearance of ROS.…”