Department of Digestive Surgery and Transplantation, Lille University Hospital, Lille 59037, France.
U1286 - INFINITE - Institute for Translational Research in Inflammation, Univ. Lille, Inserm, CHU Lille, Lille 59000, France.
World J Gastroenterol. 2023 Feb 7;29(5):851-866. doi: 10.3748/wjg.v29.i5.851.
Postoperative recurrence (POR) after ileocecal resection (ICR) affects most Crohn's disease patients within 3-5 years after surgery. Adherent-invasive (AIEC) typified by the LF82 strain are pathobionts that are frequently detected in POR of Crohn's disease and have a potential role in the early stages of the disease pathogenesis. CNCM I-3856 is a probiotic yeast reported to inhibit AIEC adhesion to intestinal epithelial cells and to favor their elimination from the gut.
To evaluate the efficacy of CNCM I-3856 in preventing POR induced by LF82 in an HLA-B27 transgenic (TgB27) rat model.
Sixty-four rats [strain F344, 38 TgB27, 26 control non-Tg (nTg)] underwent an ICR at the 12 wk (W12) of life and were sacrificed at the 18 wk (W18) of life. TgB27 rats were challenged daily with oral administration of LF82 (10 colony forming units (CFUs)/day (d), = 8), PBS ( = 5), CNCM I-3856 (10 CFUs/d, = 7) or a combination of LF82 and CNCM I-3856 ( = 18). nTg rats receiving LF82 ( = 5), PBS ( = 5), CNCM I-3856 ( = 7) or CNCM I-3856 and LF82 ( = 9) under the same conditions were used as controls. POR was analyzed using macroscopic (from 0 to 4) and histologic (from 0 to 6) scores. Luminal LF82 quantifications were performed weekly for each animal. Adherent LF82 and inflammatory/regulatory cytokines were quantified in biopsies at W12 and W18. Data are expressed as the median with the interquartile range.
nTg animals did not develop POR. A total of 7/8 (87%) of the TgB27 rats receiving LF82 alone had POR (macroscopic score ≥ 2), which was significantly prevented by CNCM I-3856 administration [6/18 (33%) TgB27 rats, = 0.01]. Macroscopic lesions were located 2 cm above the anastomosis in the TgB27 rats receiving LF82 alone and consisted of ulcerations with a score of 3.5 (2 - 4). Seven out of 18 TgB27 rats (39%) receiving CNCM I-3856 and LF82 had no macroscopic lesions. Compared to untreated TgB27 animals receiving LF82 alone, coadministration of CNCM I-3856 and LF82 significantly reduced the macroscopic [3.5 (2 - 4) 1 (0 - 3), = 0.002] and histological lesions by more than 50% [4.5 (3.3 - 5.8) 2 (1.3 - 3), = 0.003]. The levels of adherent LF82 were correlated with anastomotic macroscopic scores in TgB27 rats ( = 0.49, = 0.006), with a higher risk of POR in animals having high levels of luminal LF82 (71.4% 25%, = 0.02). Administration of CNCM I-3856 significantly reduced the levels of luminal and adherent LF82, increased the production of interleukin (IL)-10 and decreased the production of IL-23 and IL-17 in TgB27 rats.
In a reliable model of POR induced by LF82 in TgB27 rats, CNCM I-3856 prevents macroscopic POR by decreasing LF82 infection and gut inflammation.
回肠结肠切除术后的术后复发（POR）影响大多数克罗恩病患者在手术后 3-5 年内。以 LF82 株为代表的黏附侵袭性（AIEC）是共生病原体，在克罗恩病的 POR 中经常被检测到，并在疾病发病机制的早期阶段具有潜在作用。CNCM I-3856 是一种益生菌酵母，据报道可抑制 AIEC 与肠道上皮细胞的黏附，并有利于其从肠道中消除。
评估 CNCM I-3856 在预防 HLA-B27 转基因（TgB27）大鼠模型中 LF82 诱导的 POR 中的疗效。
64 只大鼠[品系 F344，38 只 TgB27，26 只对照非 Tg（nTg）]在 12 周龄（W12）时进行回肠结肠切除术，并在 18 周龄（W18）时进行安乐死。TgB27 大鼠每天接受口服 LF82（10 个菌落形成单位（CFU）/天，n=8）、PBS（n=5）、CNCM I-3856（10 CFU/d，n=7）或 LF82 和 CNCM I-3856 的组合（n=18）。nTg 大鼠在相同条件下接受 LF82（n=5）、PBS（n=5）、CNCM I-3856（n=7）或 CNCM I-3856 和 LF82（n=9）作为对照。POR 通过宏观（0 至 4 分）和组织学（0 至 6 分）评分进行分析。每周对每个动物进行腔内容物 LF82 定量。在 W12 和 W18 时，对黏附 LF82 和炎症/调节细胞因子进行定量分析。数据以中位数和四分位距表示。
nTg 动物未发生 POR。单独接受 LF82 的 8/8（87%）只 TgB27 大鼠发生 POR（宏观评分≥2），CNCM I-3856 给药显著预防了这种情况[18 只 TgB27 大鼠中的 6/18（33%），n=0.01]。单独接受 LF82 的 TgB27 大鼠的宏观病变位于吻合口上方 2 厘米处，病变为溃疡，评分 3.5（2-4）。18 只接受 LF82 和 CNCM I-3856 的 TgB27 大鼠中，有 7 只（39%）没有宏观病变。与单独接受 LF82 的未治疗 TgB27 动物相比，CNCM I-3856 和 LF82 的联合给药使宏观[3.5（2-4）至 1（0-3），n=0.002]和组织学病变减少了 50%以上[4.5（3.3-5.8）至 2（1.3-3），n=0.003]。腔内容物 LF82 的水平与 TgB27 大鼠吻合口的宏观评分相关（n=0.49，n=0.006），在具有高腔内容物 LF82 水平的动物中，POR 的风险更高（71.4%[25%]，n=0.02）。CNCM I-3856 的给药显著降低了腔内容物和黏附 LF82 的水平，增加了白细胞介素（IL）-10 的产生，降低了 IL-23 和 IL-17 的产生。
在 TgB27 大鼠中，LF82 诱导的 POR 的可靠模型中，CNCM I-3856 通过降低 LF82 感染和肠道炎症来预防宏观 POR。
