Sorbonne Université, INSERM, Nutriomics Team, Paris, France.
Assistance Publique-Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Department of Hepato-Biliary and Pancreatic Surgery, Paris, France.
J Pathol. 2018 Oct;246(2):217-230. doi: 10.1002/path.5134. Epub 2018 Aug 28.
Obesity and its metabolic complications are characterized by subclinical systemic and tissue inflammation. In rodent models of obesity, inflammation and metabolic impairments are linked with intestinal barrier damage. However, whether intestinal permeability is altered in human obesity remains to be investigated. In a cohort of 122 severely obese and non-obese patients, we analyzed intestinal barrier function combining in vivo and ex vivo investigations. We found tight junction impairments in the jejunal epithelium of obese patients, evidenced by a reduction of occludin and tricellulin. Serum levels of zonulin and LPS binding protein, two markers usually associated with intestinal barrier alterations, were also increased in obese patients. Intestinal permeability per se was assessed in vivo by quantification of urinary lactitol/mannitol (L/M) and measured directly ex vivo on jejunal samples in Ussing chambers. In the fasting condition, L/M ratio and jejunal permeability were not significantly different between obese and non-obese patients, but high jejunal permeability to small molecules (0.4 kDa) was associated with systemic inflammation within the obese cohort. Altogether, these results suggest that intestinal barrier function is subtly compromised in obese patients. We thus tested whether this barrier impairment could be exacerbated by dietary lipids. To this end, we challenged jejunal samples with lipid micelles and showed that a single exposure increased permeability to macromolecules (4 kDa). Jejunal permeability after the lipid load was two-fold higher in obese patients compared to non-obese controls and correlated with systemic and intestinal inflammation. Moreover, lipid-induced permeability was an explicative variable of type 2 diabetes. In conclusion, intestinal barrier defects are present in human severe obesity and exacerbated by a lipid challenge. This paves the way to the development of novel therapeutic approaches to modulate intestinal barrier function or personalize nutrition therapy to decrease lipid-induced jejunal leakage in metabolic diseases. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
肥胖及其代谢并发症的特征是亚临床全身和组织炎症。在肥胖的啮齿动物模型中，炎症和代谢损伤与肠道屏障损伤有关。然而，人类肥胖是否会改变肠道通透性仍有待研究。在一项由 122 名严重肥胖和非肥胖患者组成的队列中，我们结合体内和体外研究分析了肠道屏障功能。我们发现肥胖患者的空肠上皮紧密连接受损，表现为闭合蛋白和三细胞素减少。两种通常与肠道屏障改变相关的标志物——血清封闭蛋白和脂多糖结合蛋白的水平也在肥胖患者中升高。通过定量检测尿乳果糖/甘露醇 (L/M) 来评估肠道通透性的体内情况，并在 Ussing 室中直接测量 jejunal 样本的 ex vivo 结果。在禁食状态下，肥胖和非肥胖患者的 L/M 比值和 jejunal 通透性没有显著差异，但肥胖组中小分子 (0.4 kDa) 的高 jejunal 通透性与全身炎症有关。总之，这些结果表明，肥胖患者的肠道屏障功能受到轻微损害。因此，我们测试了这种屏障损伤是否会因膳食脂质而加剧。为此，我们用脂质微滴刺激 jejunal 样本，结果表明单次暴露会增加大分子 (4 kDa) 的通透性。与非肥胖对照组相比，肥胖患者在脂质负荷后的 jejunal 通透性增加了两倍，并且与全身和肠道炎症相关。此外，脂质诱导的通透性是 2 型糖尿病的一个解释变量。总之，在人类严重肥胖中存在肠道屏障缺陷，并且在脂质刺激下会加剧。这为开发新型治疗方法以调节肠道屏障功能或针对代谢疾病中脂质诱导的空肠渗漏进行营养治疗个体化奠定了基础。
