Hematopoietic Cell Transplantation Rescues Inflammatory Bowel Disease and Dysbiosis of Gut Microbiota in XIAP Deficiency

Ono, Shintaro; Takeshita, Kozue; Kiridoshi, Yuko; Kato, Motohiro; Kamiya, Takahiro; Hoshino, Akihiro; Yanagimachi, Masakatsu; Arai, Katsuhiro; Takeuchi, Ichiro; Toita, Nariaki; Imamura, Toshihiko; Sasahara, Yoji; Sato, Junichi; Hamamoto, Kazuko; Takeuchi, Masanobu; Saito, Shoji; Onuma, Masahiro; Yasui, Masayoshi; Taga, Takashi; Arakawa, Yuki; Mitani, Yuichi; Yamamoto, Nobuyuki; Imai, Kohsuke; Suda, Wataru; Hattori, Masahira; Ohara, Osamu; Morio, Tomohiro; Honda, Kenya; Kanegane, Hirokazu

doi:10.1016/j.jaip.2021.05.045

Cited by 17 publications

(18 citation statements)

References 59 publications

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“…XIAP deficiency is a rare IEI, and it is characterized by recurrent hemophagocytic lymphohistiocytosis and refractory inflammatory bowel disease (IBD) similar to Crohn's disease. Furthermore, patients with XIAP deficiency showed intestinal dysbiosis and IBD, which are rescued by allogeneic hematopoietic cell transplantation (Ono et al, 2021). These data further establish the hypothesis that monogenic disease is the cause of gut dysbiosis.…”

Section: Discussionsupporting

confidence: 59%

“…Haploinsufficiency of A20 (HA20) causes autoinflammatory and autoimmune disorders (Kadowaki et al, 2018). Dysbiosis of the intestinal microbiome has been observed in some inborn errors of immunities (IEIs)/primary immunodeficiency disease, such as chronic granulomatous disease (CGD) (Sokol et al, 2016), X-linked inhibitor of apoptosis (XIAP) deficiency (Sokol et al, 2016;Ono et al, 2021), tetratricopeptide repeat domain 7A (TTC7A) deficiency (Sokol et al, 2016), common variable immunodeficiency (CVID) (Jørgensen et al, 2016;Varricchi et al, 2021), and Wiskott-Aldrich syndrome (Zhang et al, 2020). Despite IEIs having a monogenetic nature, they vary in severity relating to the microbiome .…”

Section: Introductionmentioning

confidence: 99%

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Dysregulation of the Intestinal Microbiome in Patients With Haploinsufficiency of A20

Toyofuku

Takeshita

Ohnishi

et al. 2022

Front. Cell. Infect. Microbiol.

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IntroductionHaploinsufficiency of A20 (HA20) is a form of inborn errors of immunity (IEI). IEIs are genetically occurring diseases, some of which cause intestinal dysbiosis. Due to the dysregulation of regulatory T cells (Tregs) observed in patients with HA20, gut dysbiosis was associated with Tregs in intestinal lamina propria.MethodsStool samples were obtained from 16 patients with HA20 and 15 of their family members. Infant samples and/or samples with recent antibiotics use were excluded; hence, 26 samples from 13 patients and 13 family members were analyzed. The 16S sequencing process was conducted to assess the microbial composition of samples. Combined with clinical information, the relationship between the microbiome and the disease activity was statistically analyzed.ResultsThe composition of gut microbiota in patients with HA20 was disturbed compared with that in healthy family members. Age, disease severity, and use of immunosuppressants corresponded to dysbiosis. However, other explanatory factors, such as abdominal symptoms and probiotic treatment, were not associated. The overall composition at the phylum level was stable, but some genera were significantly increased or decreased. Furthermore, among the seven operational taxonomic units (OTUs) that increased, two OTUs, Streptococcus mutans and Lactobacillus salivarius, considerably increased in patients with autoantibodies than those without autoantibodies.DiscussionDetailed interaction on intestinal epithelium remains unknown; the relationship between the disease and stool composition change helps us understand the mechanism of an immunological reaction to microorganisms.

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Section: Discussionsupporting

confidence: 59%

Section: Introductionmentioning

confidence: 99%

Dysregulation of the Intestinal Microbiome in Patients With Haploinsufficiency of A20

Toyofuku

Takeshita

Ohnishi

et al. 2022

Front. Cell. Infect. Microbiol.

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“…Nine of the 10 patients were alive and well at a median of 21.2 months after HSCT ( 33 ). They recently reported that IBD associated with XIAP deficiency is caused by dysbiosis of the gut microbiota, and allogeneic HSCT ameliorated gut inflammation and dysbiosis in patients with XIAP deficiency ( 34 ). Amelioration of IBD symptoms is expected to improve the quality of life of patients treated with HSCT.…”

Section: Treatmentsmentioning

confidence: 99%

Primary Immunodeficiencies Associated With Early-Onset Inflammatory Bowel Disease in Southeast and East Asia

et al. 2022

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BackgroundCauses of early-onset inflammatory bowel disease (IBD) vary, and primary immunodeficiency diseases (PIDs) are associated with early-onset IBD as monogenic disorders.AimThis review investigates the prevalence, clinical manifestation, genetic profile, and treatment of patients with early-onset IBD in Southeast and East Asia.MethodsA systemic review of articles reporting PID patients associated with early-onset IBD in Southeast and East Asia was conducted.ResultsThe prevalence of PID associated with IBD was higher than that reported in western nations, and the frequency of patients with bloody stools as an early symptom was relatively higher in monogenic diseases. A total 13 (12.0%) of 108 patients with early-onset IBD were diagnosed as PID by exome sequencing and targeted gene panel analysis in Japan, including four patients with XIAP, three with IL10RA, and two or one patient with other gene mutations. In addition, ten patients were reported as having IL-10 receptor alpha (IL-10RA) deficiency in China and Hong Kong. Allogeneic hematopoietic stem cell transplantation was performed in patients with X-linked inhibitor of apoptosis deficiency, IL-10RA deficiency, or other PID as a curative treatment, and the preferable outcome of reduced-intensity conditioning and complete resolution of IBD symptoms and dysbiosis were achieved.ConclusionComprehensive molecular diagnosis has been widely applied to screen for patients with PID-associated IBD in Southeast and East Asia. These results contributed to the awareness of monogenic PID in early-onset IBD patients and their differences in clinical manifestations and genetic profiles compared to the patients in western counties.

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“…Most IEI are due to defects in genes that are essential for hematopoietic cells to function normally, and supportive therapies, such as immunoglobulin G (IgG) infusions and antibiotics, are occasionally unsatisfactory for long-term outcomes. The only curative approach is the replacement of impaired cells by healthy donor hematopoietic stem cells and allogeneic HCT (allo HCT) (108)(109)(110). One of the clinical implications of HCT is the long-term complications that cause chronic and irreversible damage to various organs (111), including the endocrine glands.…”

Section: Endocrine and Metabolic Disorders Caused By Hct For Iei Impaired Reproductive Function Caused By Hctmentioning

confidence: 99%

Endocrinopathies in Inborn Errors of Immunity

et al. 2021

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Inborn errors of immunity (IEI), caused by hereditary or genetic defects, are a group of more than 400 disorders, in which the immune system, including lymphocytes, neutrophils, macrophages, and complements, does not function properly. The endocrine system is frequently affected by IEI as an associated clinical feature and a complex network of glands which regulate many important body functions, including growth, reproduction, homeostasis, and energy regulation. Most endocrine disorders associated with IEI are hypofunction which would be treated with supplementation therapy, and early diagnosis and appropriate management are essential for favorable long-term outcomes in patients with IEI. In this review, we aimed to comprehensively summarize and discuss the current understanding on the clinical features and the pathophysiology of endocrine disorders in IEI. This review is composed with three parts. First, we discuss the two major pathophysiology of endocrinopathy in IEI, autoimmune response and direct effects of the responsible genes. Next, the details of each endocrinopathy, such as growth failure, hypothyroidism, hypoparathyroidism, adrenal insufficiency, diabetes mellitus (DM) are specified. We also illustrated potential endocrinopathy due to hematopoietic stem cell transplantation, including hypogonadism and adrenal insufficiency due to glucocorticoid therapy.

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Hematopoietic Cell Transplantation Rescues Inflammatory Bowel Disease and Dysbiosis of Gut Microbiota in XIAP Deficiency

Cited by 17 publications

References 59 publications

Dysregulation of the Intestinal Microbiome in Patients With Haploinsufficiency of A20

Dysregulation of the Intestinal Microbiome in Patients With Haploinsufficiency of A20

Primary Immunodeficiencies Associated With Early-Onset Inflammatory Bowel Disease in Southeast and East Asia

Endocrinopathies in Inborn Errors of Immunity

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