Department of Medicine and Surgery, Gastroenterology, Hepatology & Digestive Endoscopy Section University of Perugia Medical School, Piazza Lucio Severi, Perugia 06132, Italy, and Santa Maria della Misericordia Hospital, Gastroenterology & Hepatology Unit Perugia 06156, Italy.
School of Biosciences and Veterinary Medicine, University of Camerino, Matelica 62024, Italy.
World J Gastroenterol. 2023 Jan 28;29(4):582-596. doi: 10.3748/wjg.v29.i4.582.
() is progressively colonizing humans and animals living with humans. During this process, hypervirulent strains and mutated toxin A and B of (TcdA and TcdB) are originating and developing. While in healthy subjects colonization by becomes a risk after the use of antibiotics that alter the microbiome, other categories of people are more susceptible to infection and at risk of relapse, such as those with inflammatory bowel disease (IBD). Recent studies suggest that this increased susceptibility could be due to the strong cytotoxic synergism between TcdB and proinflammatory cytokines the tumor necrosis factor-alpha and interferon-gamma (CKs). Therefore, in subjects with IBD the presence of an inflammatory state in the colon could be the driver that increases the susceptibility to infection and its progression and relapses. TcdB is internalized in the cell three receptors: chondroitin sulphate proteoglycan 4; poliovirus receptor-like 3; and Wnt receptor frizzled family. Chondroitin sulphate proteoglycan 4 and Wnt receptor frizzled family are involved in cell death by apoptosis or necrosis depending on the concentration of TcdB and cell types, while poliovirus receptor-like 3 induces only necrosis. It is possible that cytokines could also induce a greater expression of receptors for TcdB that are more involved in necrosis than in apoptosis. Therefore, in subjects with IBD there are the conditions: (1) For greater susceptibility to infection, such as the inflammatory state, and abnormalities of the microbiome and of the immune system; (2) for the enhancement of the cytotoxic activity of TcdB +Cks; and (3) for a greater expression of TcdB receptors stimulated by cytokines that induce cell death by necrosis rather than apoptosis. The only therapeutic approach currently possible in IBD patients is monitoring of colonization for interventions aimed at reducing tumor necrosis factor-alpha and interferon-gamma levels when the infection begins. The future perspective is to generate bacteriophages against for targeted therapy.
艰难梭菌逐渐定植于人和与人共生的动物。在此过程中，产毒株和突变型毒素 A、B（TcdA 和 TcdB）正在出现和发展。在健康个体中，使用改变微生物组的抗生素后，艰难梭菌定植会带来风险，而其他类别的人群更易感染且存在复发风险，例如炎症性肠病（IBD）患者。最近的艰难梭菌研究表明，这种易感性增加可能是由于 TcdB 与肿瘤坏死因子-α和干扰素-γ（CKs）等促炎细胞因子之间的强烈细胞毒性协同作用所致。因此，在 IBD 患者中，结肠中炎症状态可能是增加艰难梭菌感染及其进展和复发易感性的驱动因素。TcdB 通过三种受体进入细胞：硫酸软骨素蛋白聚糖 4；脊髓灰质炎病毒受体样蛋白 3；Wnt 受体卷曲家族。硫酸软骨素蛋白聚糖 4 和 Wnt 受体卷曲家族根据 TcdB 的浓度和细胞类型参与细胞凋亡或坏死导致的细胞死亡，而脊髓灰质炎病毒受体样蛋白 3 仅诱导坏死。细胞因子也可能诱导更多参与坏死而不是凋亡的 TcdB 受体表达增加。因此，在 IBD 患者中存在以下条件：（1）更大的艰难梭菌感染易感性，如炎症状态，以及微生物组和免疫系统的异常；（2）增强 TcdB+CKs 的细胞毒性活性；（3）细胞因子刺激下 TcdB 受体表达增加，导致细胞通过坏死而不是凋亡死亡。目前在 IBD 患者中唯一可行的治疗方法是监测艰难梭菌定植，以便在感染开始时干预以降低肿瘤坏死因子-α和干扰素-γ水平。未来的展望是针对艰难梭菌产生噬菌体，进行靶向治疗。
