Background and Aims Intestinal fibrotic stenosis is a major reason for surgery in Crohn's disease [CD], but the mechanism is unknown. Thus, we asked whether intestinal adipocytes contribute to intestinal fibrosis. Adipocytes were found to transdifferentiate into myofibroblasts and confirmed to be involved in mesenteric fibrosis in our recent study. Here, we investigated the role and possible mechanisms of intestinal adipocytes in intestinal fibrosis in CD. Methods The intestinal tissue of patients with CD with or without fibrotic stenosis [CDS or CDN] and normal intestinal tissue from individuals without CD were obtained to assess alterations in submucosal adipocytes in CDS and whether these cells transdifferentiated into myofibroblasts and participated in the fibrotic process. Human primary adipocytes and adipose organoids were used to evaluate whether adipocytes could be induced to transdifferentiate into myofibroblasts and to investigate the fibrotic behaviour of adipocytes. LPS/TLR4/TGF-β signalling was also studied to explore the underlying mechanism. Results Submucosal adipocytes were reduced in number or even absent in CDS tissue, and the extent of the reduction correlated negatively with the degree of submucosal fibrosis. Interestingly, submucosal adipocytes in CDS tissue transdifferentiated into myofibroblast-like cells and expressed collagenous components, possibly due to stimulation by submucosally translocated bacteria. LPS-stimulated human primary adipocytes and adipose organoids also exhibited transdifferentiation and profibrotic behaviour. Mechanistically, TLR4-mediated TGF-β signalling was associated with the transdifferentiation and profibrotic behaviour of intestinal adipocytes in CDS tissue. Conclusions Intestinal adipocytes transdifferentiate into myofibroblasts and participate in the intestinal fibrosis process in CD, possibly through LPS/TLR4/TGF-β signalling.

中文翻译：

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肠道脂肪细胞转分化为肌成纤维细胞样细胞并导致克罗恩病纤维化

背景和目的肠纤维化狭窄是克罗恩病[CD]手术的主要原因，但其机制尚不清楚。因此，我们想知道肠道脂肪细胞是否会导致肠道纤维化。我们最近的研究发现脂肪细胞可转分化为肌成纤维细胞，并证实其参与肠系膜纤维化。在这里，我们研究了肠道脂肪细胞在 CD 肠纤维化中的作用和可能机制。方法 获取伴或不伴纤维化狭窄[CDS或CDN]的CD患者的肠道组织和无CD个体的正常肠道组织，以评估CDS中粘膜下脂肪细胞的变化以及这些细胞是否转分化为肌成纤维细胞并参与纤维化过程。使用人原代脂肪细胞和脂肪类器官来评估脂肪细胞是否可以被诱导转分化为肌成纤维细胞并研究脂肪细胞的纤维化行为。还研究了 LPS/TLR4/TGF-β 信号传导以探索其潜在机制。结果CDS组织中粘膜下脂肪细胞数量减少甚至缺失，减少程度与粘膜下纤维化程度呈负相关。有趣的是，CDS组织中的粘膜下脂肪细胞转分化为肌成纤维细胞样细胞并表达胶原成分，这可能是由于粘膜下易位细菌的刺激所致。LPS 刺激的人类原代脂肪细胞和脂肪类器官也表现出转分化和促纤维化行为。从机制上讲，TLR4 介导的 TGF-β 信号传导与 CDS 组织中肠脂肪细胞的转分化和促纤维化行为相关。结论 CD肠道脂肪细胞转分化为肌成纤维细胞，可能通过LPS/TLR4/TGF-β信号通路参与CD肠道纤维化过程。