The intestinal epithelial barrier is the primary and most significant defense barrier against ingested toxins and pathogenic bacteria. When the intestinal epithelium barrier is breached, inflammatory response is triggered. GWAS data showed that endoplasmic reticulum (ER) stress markers are elevated in Inflammatory Bowel Disease (IBD) patients, which suggests ER stress regulation might alleviate IBD symptoms. Ferulic acid (FA) is a polyphenol that is abundant in plants and has antioxidant and anti-inflammatory properties, although it is unclear whether FA has these effects on the intestine. Therefore, we investigated the effect of FA in vitro and in vivo. It was found that FA suppressed ER stress, nitric oxide (NO) generation, and inflammation in polarized Caco-2 and T84 cells, indicating that the ER stress pathway was implicated in its anti-inflammatory activities. The permeability of polarized Caco-2 cells in the presence and absence of proinflammatory cytokines were decreased by FA, and MUC2 mRNA was overexpressed in the intestines of mice fed a high-fat diet (HFD) supplemented with FA. These results suggest that FA has a protective effect on intestinal tight junctions. In addition, mouse intestine organoids proliferated significantly more in the presence of FA. Our findings shed light on the molecular mechanism responsible for the antioxidant effects of FA and its protective benefits on the health of the digestive system.

Regular exercise as part of one’s lifestyle is well-recognized for its beneficial effect on several diseases such as cardiovascular disease and obesity; however, many questions remain unanswered regarding the effects of exercise on the gut environment. This study aimed to investigate the impact of long-term endurance exercise on modulating inflammation and endoplasmic reticulum (ER) stress. Fifteen-week-old male Sprague-Dawley (SD) rats were subjected to six months of endurance treadmill training, while age-matched controls remained sedentary. Results showed that IL-6 mRNA levels in colon tissues were significantly higher in the exercise group compared to the sedentary group. Exercise activated a significant ER stress-induced survival pathway by increasing BiP and phosphorylation of eIF2α (p-eIF2α) expressions in the liver and colon, while decreasing CHOP in the liver. Gene expressions of MUC2, Occludin, and Claudin-2 were increased in the colon of the exercise group, indicating enhanced intestinal integrity. Furthermore, the data showed a positive correlation between microbiota α-diversity and BiP (r = 0.464~0.677, p < 0.05). Populations of Desulfovibrio C21 c20 were significantly greater in the exercise group than the sedentary group. Additionally, predicted functions of the gut microbial community in terms of enzymes and pathways supported the enhancement of fatty-acid-related processes by exercise. These findings suggest that prolonged endurance exercise can affect the colon environment, which is likely related to changes in inflammation, ER stress, mucin layers and tight junctions, associated with modifications in the gut microbiome.

The role of diet is gaining attention among the modifiable factors associated with depression; thus, this case–control study examined the association between nutrition and depression in young Korean adults. Dietary surveys in individuals with depression (n = 39) and age- and gender-matched controls (n = 76) were conducted using food records and food frequency questionnaires. Men with depression consumed less mushrooms and meat, while women consumed significantly less grains (p < 0.05). Overall, the depression group consumed less energy and nutrients, and the difference was more pronounced in men. The male depression group had lower nutrient adequacy ratio (NAR) for energy, protein, vitamin A, thiamine, niacin, folate, and phosphorus, whereas the female depression group had lower NARs for energy, protein, niacin, and vitamin B₁₂. The depression group had a significantly lower mean adequacy ratio in both genders. Furthermore, the proportion of inappropriate nutrient intake was higher in both genders of the depression group, exhibiting significant differences in energy, protein, niacin, folate, and zinc in men and energy, riboflavin, folate, and vitamin C in women. Hence, both men and women in the depression group had poor nutrient intake and high rates of nutrient inadequacy and improper consumption. This suggests that the quantity and quality of meals should be improved for individuals with depressive symptoms.

Background: Sex differences are evident in anxiety and depression, and women more frequently present with comorbid anxiety and depression alongside gastrointestinal disturbances. This pattern suggests contributions from sex-specific biological mechanisms and gut–brain communication. Negr1 , a molecule regulating neuronal growth and connectivity, has been linked to depression-relevant behaviors in animal models. However, its mechanisms and potential sex-specific effects remain unclear. Methods: Behavioral tests were used to assess phenotypes related to depression, anxiety, and learning in male and female wild-type (WT) and Negr1 ^–/– mice, and molecular assays were performed to evaluate endoplasmic reticulum (ER) stress and apoptosis in the brain, liver, and colon. Behavioral test data were analyzed using a three-way mixed repeated-measures analysis of variance (RM-ANOVA), and molecular data were analyzed using two-way or three-way ANOVA. Result: Negr1 ^–/– mice exhibited sex-dependent phenotypes in both central and peripheral systems. Baseline analyses revealed increased intestinal permeability in Negr1 ^–/– mice and sex-specific patterns of brain-derived neurotrophic factor ( Bdnf ) mRNA expression across multiple time points. Behaviorally, Negr1 ^–/– mice showed increased anxiety-like behavior, decreased social interaction, and impaired spatial learning in the Morris water maze, regardless of sex. Female Negr1 ^–/– mice displayed impaired fear learning and increased depression-like behavior, while male Negr1 ^–/– mice exhibited heightened anxiety-like responses. At the molecular level, ER stress marker spliced X-box binding protein 1 ( Xbp1s) mRNA was upregulated in peripheral tissues of males but downregulated in females. Apoptosis analysis revealed enhanced caspase-3 activation in peripheral tissues of female Negr1 ^–/– mice, while males showed no significant changes. Brain tissue showed no significant apoptotic alterations in either sex. Conclusions: This study demonstrates that, in Negr1 ^–/– mice, both sexes show general behavioral alterations. However, female Negr1 ^–/– mice exhibit greater vulnerability to fear learning impairments and depression-like behavior, whereas males Negr1 ^–/– mice show heightened anxiety responses. These behavioral differences were associated with opposing ER stress responses and differential apoptotic signaling between the sexes in peripheral tissues. Our findings highlight the importance of considering sex as a biological variable in depression research and suggest that Negr1 plays a crucial role in the sex-specific pathophysiology of psychiatric disorders through complex mechanisms spanning central and peripheral systems.

Yoon SI, et al. Korean J Community Nutr. 2021 Apr;26(2):103-110. https://doi.org/10.5720/kjcn.2021.26.2.103

Ardina U, et al. J Nutr Health. 2024 Apr;57(2):228-243. https://doi.org/10.4163/jnh.2024.57.2.228