Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center and Department of Pediatrics, University of Cincinnati College of Medicine, Ohio, Cincinnati, USA.
Division of Immunobiology and Center for Inflammation and Tolerance, Cincinnati Children's Hospital Medical Center and Department of Pediatrics, University of Cincinnati College of Medicine, Ohio, Cincinnati, USA.
Neurogastroenterol Motil. 2023 Dec;35(12):e14681. doi: 10.1111/nmo.14681. Epub 2023 Sep 22.
BACKGROUND & AIMS: Disorders of gut-brain interaction (DGBI) are complex conditions that result in decreased quality of life and a significant cost burden. Linaclotide, a guanylin cyclase C (GCC) receptor agonist, is approved as a DGBI treatment. However, its efficacy has been limited and variable across DGBI patients. Microbiota and metabolomic alterations are noted in DGBI patients, provoking the hypothesis that the microbiota may impact the GCC response to current therapeutics.
Human-derived intestinal organoids were grown from pediatric DGBI, non-IBD colon biopsies (colonoids). Colonoids were treated with 250 nM linaclotide and assayed for cGMP to develop a model of GCC activity. Butyrate was administered to human colonoids overnight at a concentration of 1 mM. Colonoid lysates were analyzed for cGMP levels by ELISA. For the swelling assay, colonoids were photographed pre- and post-treatment and volume was measured using ImageJ. Principal coordinate analyses (PCoA) were performed on the Bray-Curtis dissimilarity and Jaccard distance to assess differences in the community composition of short-chain fatty acid (SCFA) producing microbial species in the intestinal microbiota from pediatric patients with IBS and healthy control samples.
Linaclotide treatment induced a significant increase in [cGMP] and swelling of patient-derived colonoids, demonstrating a human in vitro model of linaclotide-induced GCC activation. Shotgun sequencing analysis of pediatric IBS patients and healthy controls showed differences in the composition of commensal SCFA-producing bacteria. Butyrate exposure significantly dampened linaclotide-induced cGMP levels and swelling in patient-derived colonoids.
CONCLUSIONS & INFERENCES: Patient-derived colonoids demonstrate that microbiota-derived butyrate can dampen human colonic responses to linaclotide. This study supports incorporation of microbiota and metabolomic assessment to improve precision medicine for DGBI patients.
肠-脑相互作用障碍（DGBI）是一种复杂的疾病，会降低生活质量，并造成巨大的经济负担。利那洛肽是一种鸟苷酸环化酶 C（GCC）受体激动剂，已被批准用于治疗 DGBI。然而，其疗效在不同的 DGBI 患者中存在差异。DGBI 患者存在微生物群和代谢组学改变，这促使人们提出假设，即微生物群可能会影响当前治疗药物对 GCC 的反应。
从儿科 DGBI 和非 IBD 结肠活检（类器官）中培养出人类来源的肠类器官。用 250 nM 利那洛肽处理类器官，并检测 cGMP 以建立 GCC 活性模型。将 1 mM 丁酸 overnight 作用于人类类器官。通过 ELISA 分析类器官裂解物中的 cGMP 水平。对于肿胀实验，在治疗前和治疗后拍摄类器官的照片，并使用 ImageJ 测量体积。对 Bray-Curtis 不相似性和 Jaccard 距离进行主坐标分析（PCoA），以评估 IBS 儿科患者和健康对照样本的肠道微生物群落中产生短链脂肪酸（SCFA）的微生物物种的群落组成差异。
利那洛肽治疗显著增加了患者来源的类器官的[cGMP]和肿胀，证明了利那洛肽诱导 GCC 激活的人类体外模型。对 IBS 儿科患者和健康对照的 shotgun 测序分析显示，共生 SCFA 产生菌的组成存在差异。丁酸暴露显著抑制了患者来源的类器官中利那洛肽诱导的 cGMP 水平和肿胀。
患者来源的类器官表明，微生物群衍生的丁酸可以抑制人类结肠对利那洛肽的反应。这项研究支持将微生物群和代谢组学评估纳入 DGBI 患者的精准医学。
