Department of Biomedical Sciences, Graduate School, Kyung Hee University, Seoul, 02447, Republic of Korea.
Division of Biosystems and Biomedical Sciences, College of Health Sciences, Korea University, Seoul, 02841, Republic of Korea.
Sci Rep. 2024 Mar 15;14(1):6263. doi: 10.1038/s41598-024-56936-z.
Psychological stress and intestinal leakage are key factors in atopic dermatitis (AD) recurrence and exacerbation. Here, we demonstrate the mechanism underlying bacterial translocation across intestinal epithelial barrier damaged due to stress and further aggravation of trimellitic anhydride (TMA)-induced itch, which remain unclear, in AD mice. Immobilization (IMO) stress exacerbated scratching bouts and colon histological damage, and increased serum corticosterone and lipopolysaccharide (LPS). Orally administered fluorescein isothiocyanate (FITC)-dextran and surgically injected (into the colon) Cy5.5-conjugated LPS were detected in the serum and skin after IMO stress, respectively. The relative abundance of aerobic or facultative anaerobic bacteria was increased in the colon mucus layer, and Lactobacillus murinus, E. coli, Staphylococcus nepalensis, and several strains of Bacillus sp. were isolated from the spleens and mesenteric lymph nodes. Oral antibiotics or intestinal permeability blockers, such as lubiprostone (Lu), 2,4,6-triaminopyrimidine (TAP) and ML-7, inhibited IMO stress-associated itch; however, it was reinduced through intradermal or i.p. injection of LPS without IMO stress. I.p. injection of TAK-242 (resatorvid), a TLR4 inhibitor, abrogated IMO stress-associated itch, which was also confirmed in TLR4-KO mice. IMO stress alone did not cause itch in naïve mice. IMO stress-induced itch aggravation in TMA-treated AD mice might be attributed to the translocation of gut-derived bacterial cells and LPS, which activates peripheral TLR4 signaling.
心理压力和肠漏是特应性皮炎(AD)复发和恶化的关键因素。在这里,我们证明了应激导致肠道上皮屏障损伤后细菌易位的机制,以及三(2-羟乙基)异氰尿酸酯(TMA)诱导的瘙痒进一步恶化的机制,这在 AD 小鼠中仍然不清楚。固定(IMO)应激加剧了搔抓发作和结肠组织损伤,并增加了血清皮质酮和脂多糖(LPS)。IMO 应激后,分别在血清和皮肤中检测到口服荧光素异硫氰酸酯(FITC)-葡聚糖和手术注射(进入结肠)的 Cy5.5 缀合 LPS。结肠粘液层中需氧或兼性厌氧菌的相对丰度增加,从脾脏和肠系膜淋巴结中分离出鼠乳杆菌、大肠杆菌、尼泊尔葡萄球菌和几株芽孢杆菌。口服抗生素或肠道通透性阻滞剂,如鲁比前列酮(Lu)、2,4,6-三氨基嘧啶(TAP)和 ML-7,可抑制 IMO 应激相关瘙痒;然而,通过皮内或腹腔注射 LPS 而不进行 IMO 应激,则会重新引起 IMO 应激相关瘙痒。TLR4 抑制剂 TAK-242(resatorvid)腹腔注射可消除 IMO 应激相关瘙痒,在 TLR4-KO 小鼠中也得到了证实。单独 IMO 应激不会引起未致敏小鼠瘙痒。IMO 应激引起 TMA 处理的 AD 小鼠瘙痒加重可能归因于肠道来源的细菌细胞和 LPS 的易位,这激活了外周 TLR4 信号。