KITY Study Protocol: A Randomised Controlled Trial for Eczema Prevention by Ingestion of Kestose in High‐Risk Neonates

Atopic eczema represents one of the prevalent dermatological conditions encountered in routine clinical settings, with cohort investigations revealing that approximately 30% of infants exhibit symptoms of eczema during the early stages of life. This condition serves as a critical precursor to a series of allergic manifestations termed the ‘atopic march’, thereby underscoring the significance of implementing preventive measures at an early stage [1]. Eczema is characterised as a multifactorial disorder, indicating that an integrative approach addressing various interconnected elements is imperative. Investigations centered around the ‘skin-gut axis’ have been progressing, revealing that the microbiome is instrumental in the pathophysiology of dermal conditions. The microbiome operates as a critical regulator of the immune system, facilitating bidirectional communication with diverse tissues and organs to sustain homeostasis. Dysbiosis, defined as an imbalance within the microbiome, in both the skin and gastrointestinal tract, is significantly correlated with aberrant immune responses and is recognised as a contributing factor to the onset of eczema. In recent years, it has been posited that enteral strategies aimed at modulating microbiomes could serve as a promising avenue for the management and prophylaxis of allergic diseases. Our cohort studies (T-CHILD and JECS) has indicated a relationship between antibiotic exposure as disrupting gut microbiome and the incidence of allergic conditions, including eczema [2] and FPIES [3] in general populations, suggesting that enhancing gut microbiota equilibrium such as prebiotics may play a role in prevention. However, the specific preventive strategies advocated by existing guidelines currently lack robust empirical support. Notwithstanding, from a scientific viewpoint, the promotion of a balanced gut microbiota is highly plausible to exert preventive effects against the development of eczema. Prebiotics are defined as compounds that remain unaltered and unabsorbed within the proximal gastrointestinal tract, functioning as substrates for intestinal microbiota and contributing to the preservation of gastrointestinal health. Grüber et al. [4] demonstrated that a formulation incorporating oligosaccharides from the time of birth could significantly mitigate the incidence of eczema. Nonetheless, in 2017, Cuello-Garcia et al. [5] published a comprehensive systematic review assessing the prophylactic impact of prebiotics on eczema, which revealed no statistically significant variations. This review showed that the overall effect of prebiotics was a reduction in the risk of eczema when compared to the control group, although the confidence interval did not exclude a null effect (RR, 0.68; 95% CI, 0.40–1.15; 2030 participants; six trials). Among the diverse array of prebiotics, our investigation concentrated specifically on kestose. Kestose is classified as one of the trisaccharides, comprising a combination of sucrose and fructose interconnected via a β-1,1-glycosidic linkage. Kestose is resistant to digestion. when ingested orally, kestose is transported to the lower gastrointestinal tract without being digested [6]. It is selectively utilised by gut microbiota. Kestose has been shown to enhance the proliferation of butyrate-producing bacterial strains (Faecalibacterium prausnitzii) within the gut [7], thereby elevating butyrate concentrations. Butyrate is anticipated to facilitate the differentiation of regulatory T cells (Tregs) and mitigate allergic manifestations. Shibata et al. [8] reported findings regarding the therapeutic efficacy of kestose in the context of eczema. In an investigation involving 30 children below the age of three diagnosed with eczema, intervention group ingested kestose daily over a 12-week period, whereas the control group consumed maltose. Post-intervention, the SCORAD score registered at 19.5 for the kestose group compared to 37.5 for the maltose group, signifying a statistically significant amelioration of eczema symptoms in the kestose cohort (p < 0.001). As for milk allergy children, kestose enhanced the relative abundance of Faecalibacterium species and modestly increased the dose of cow's milk tolerated [9]. However, there exists a dearth of prior studies examining the preventative efficacy of kestose against eczema. We are undertaking a double-blind, randomised, two-group parallel comparison study aimed at assessing the preventative effect of kestose, a prebiotic, on eczema in high-risk infants by contrasting a kestose intake intervention with a maltose intake intervention (Kestose Intake for prevention of atopic dermatitis in Tokyo; KITY Study) with the registration of the Japan Registry of Clinical Trials (jRCT): ID: jRCTs031220020 (https://jrct.niph.go.jp/en-latest-detail/jRCTs031220020). The study does not administer kestose to pregnant women (Figure 1). The study protocol is in this article's Online Repository at 10.5281/zenodo.13905238. K.Y.-H., M.S.-A., Y.I. and Y.O. conceived the idea of the study. All authors contributed to fix the study protocol. K.P. contributes to study statistics. T.K. advised the study procedure. M.S.-A. drafted the original manuscript. M.S.-A., K.T., H.O. and D.H. recruited and followed the participants. Y.H., H.M. and K.M. handled blood samples. T.F., Y.O. and K.Y.-H. supervised the conduct of this study. M.S.-A., H.O. and K.Y.-H. reviewed the manuscript draft and revised it critically on intellectual content. All authors approved the publication of the final version of the manuscript. Ms. Miwako Seike and Ms. Mariko Noda developed a data management plan for this study. Dr. Mayumi Sako, Ms. Nozomi Fukui and Ms. Tomoko Matsushita developed a data monitoring plan for this study. Ms. Kozue Miyake, Ms. Yuki Saito, Ms. Junko Ikeda, Ms. Saki Ueno, Ms. Saya Kitami, Ms. Yukie Miyata, Mr. Sora Nazuka, Ms. Sayuri Tateai, Ms. Kazuko Hayase, Ms. Takako Kimura, Ms. Junko Nishimura, Ms. Kumiko Watabe and Ms. Emiko Matsuzaka supported this study. This research was based on the Japanese Clinical Trials Act (Act No. 16 of 14 April 2017) described on the website (https://www.mhlw.go.jp/file/06-Seisakujouhou-10800000-Iseikyoku/0000213334.pdf). The Certified Review Board of National Center for Child Health and Development reviewed and approved the study protocol on February 24, 2022 (Reference number: CRB3200005). This trial was registered with the Japan Registry of Clinical Trials (jRCT): ID: jRCTs031220020 (https://jrct.niph.go.jp/en-latest-detail/jRCTs031220020) on April 13, 2022. All parents provided their written consent for trial participation before we enrolled their children in the trial. This study is conducted as a collaborative research project funded by Natural Science Co. Ltd. Natural Science Co. Ltd. is involved in certain aspects of the study (such as the provision and delivery of the test sugar, control sugar and cosmetics to participants) and in preparing presentation materials (such as assisting with manuscript writing and conference presentations). However, they are not involved in the analysis of the research results. There is no conflict of interest between the collaborative research and the planning, implementation, interpretation or results of this study that would affect the rights or interests of the study participants. The principal investigator manages the conflict of interest with Natural Science Co. Ltd. following the Conflict of Interest Management Guidance under the Clinical Trials Act and has submitted a conflict of interest management standard and plan to the Certified Clinical Research Review Board for approval. Each researcher appropriately manages any conflicts of interest related to this study based on the conflict of interest management standards and plans and discloses them as required by academic conferences or medical journals in which the study results are presented. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.