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標題: | 兒童幽門桿菌相關鐵質缺乏機制: 宿主因素探討 The Mechanism of Helicobacter pylori-related Iron Deficiency in Children: Focus on Host Factors |
作者: | Szu-Ta Chen 陳思達 |
指導教授: | 劉興華(Shing-Hwa Liu) |
共同指導教授: | 倪衍玄(Yen-Hsuan Ni) |
關鍵字: | 幽門螺旋桿菌,鐵質缺乏,宿主基因多型性,細胞激素,鐵調素,代謝體, H. pylori,iron deficiency,susceptibility,cytokines,hepcidin,metabolomics, |
出版年 : | 2018 |
學位: | 博士 |
摘要: | 幽門螺旋桿菌感染主要發生於兒童時期且可能造成嚴重的鐵質缺乏或缺鐵性貧血,然而並非所有幽門桿菌感染的兒童全都會造成鐵質缺乏。為了解幽門桿菌感染兒童導致鐵質缺乏的相關宿主因素,我們進行一系列研究,納入幽門桿菌感染兒童及對照兒童,比較可能導致鐵質缺乏相關的宿主因素。第一部分,為探討宿主基因易感性,我們在雲林縣進行了幽門桿菌流行病學調查,從一般族群納入644位10至18歲兒童,依血清抗體結果分為2組,分別檢測5個宿主基因多型性,包含IL1B (rs1143627 and rs16944)、IL8 (rs4073)、IL10 (rs1800896)及ABO (rs505922),並比較血中鐵的程度。本研究中使用的鐵質缺乏定義為鐵飽和度小於15百分比。結果顯示在多變數分析下,抗體陽性兒童相較抗體陰性兒童,顯著帶有較高比率之rs505922基因型T allele (OR = 6.128; P < 0.001)及rs1143627基因型T allele (OR = 0.846; P = 0.014)。在59位抗體陽性兒童中,鐵質缺乏兒童相較無鐵質缺乏兒童,顯著帶有較高比率之rs1143627基因型T allele (OR = 3.156; P = 0.043)。本研究顯示ABO 基因多型性rs505922及 IL1B 基因多型性rs1143627可能影響幽門桿菌感染之易感性,且IL1B 基因多型性rs1143627也可能影響感染後鐵質缺乏之風險。第二部份,針對探討宿主血清鐵調素、血清細胞激素濃度及鐵質缺乏於幽門桿菌感染之關聯,我們納入86位兒童(43位幽門桿菌抗體陽性,43位抗體陰性),檢測血液內鐵質程度、血清細胞激素IL-1β、IL-6、IL-8濃度,及鐵調素濃度,其中幽門桿菌抗體陽性兒童分為低鐵調素組(共22人)與高鐵調素組(共21人)做比較。結果發現血清細胞激素IL-1β、IL-6濃度在抗體陽性與抗體陰性兒童間並無不同,血清鐵調素濃度亦然(濃度為6.5 ng/mL及8.6 ng/mL; P = 0.1318)。於抗體陽性兒童中,低鐵調素組相較高鐵調素組,其血中鐵質、鐵蛋白及總鐵結合能均顯著較低(P = 0.0123, P = 0.0001及P = 0.0004),且具有較高比率之鐵質缺乏 (33.3%比4.5%; P = 0.015)。同時,低鐵調素組其血清細胞激素IL-1β及IL-6濃度亦顯著較低(P = 0.0151及P = 0.0015),IL-8則無顯著差異。研究結果顯示發炎反應之細胞激素IL-1β及IL-6可能與幽門桿菌抗體陽性兒童之高鐵調素相關。血清鐵調素組下降可能是幽門桿菌感染相關鐵質缺乏之負回饋抑制的結果,而非導致鐵質缺乏的原因。第三部分,為探討幽門桿菌相關鐵質缺乏兒童血清代謝物的差異,我們納入35位幽門桿菌抗體陽性兒童,其中鐵質缺乏17位,無鐵質缺乏18位。運用液相層析質譜儀方法,分析比較血清代謝體差異。經由代謝路徑分析發現,鐵質缺乏兒童相較無鐵質缺乏兒童,最顯著改變的代謝路徑為離胺酸降解路徑、丙酸代謝路徑、纈胺酸/異白胺酸/白胺酸降解路徑、菸鹼酸/菸鹼胺降解路徑,及酪胺酸代謝路徑。綜合而言,本研究探討了許多可能影響兒童幽門桿菌相關鐵質缺乏之宿主因素。未來仍需更多研究驗證宿主因素在幽門桿菌感染的重要性。 Helicobacter pylori (H. pylori) infection occurs predominantly in childhood and could results in severe iron deficiency (ID) or iron deficiency anemia (IDA). However, not all H. pylori-infected patients exhibit iron deficiency. To understand the host factors related to the occurrence of ID among H. pylori-infected children, we conducted a pediatric study of H. pylori-infected children and controls and analyzed the differential factors regarding to the H. pylori-induced ID. First, to investigate the host susceptibility, we conducted a seroprevalence study of H. pylori infection in Yun-Lin County. Subjects (n = 644) from the general population aged 10 to 18 years were divided into two groups based on serology testing for anti-H. pylori IgG. Five single nucleotide polymorphisms (SNPs) in IL1B (rs1143627 and rs16944), IL8 (rs4073), IL10 (rs1800896), and ABO (rs505922), were genotyped and the iron status of the two groups was compared. ID is defined as iron saturation less than 15%. The results showed, in multivariate analysis, significantly higher frequency of the T allele of rs505922 (OR = 6.128; P < 0.001) and lower frequency of the T allele of rs1143627 (OR = 0.846; P = 0.014) in seropositive versus seronegative subjects. Among 59 seropositive subjects, the T allele frequency of rs1143627 was significantly higher in those with iron deficiency (OR = 3.156; P = 0.043), compared to those without iron deficiency. ABO (rs505922) and IL1B (rs1143627) may affect H. pylori infection susceptibility, and IL1B (rs1143627) may also influence iron deficiency risk in infected children. Secondly, to clarify relationship between serum hepcidin, cytokine levels and ID in H. pylori infected children, we enrolled 86 participants (43 seropositive and 43 seronegative) based on the anti-H. pylori IgG status. Serum hepcidin levels, iron profiles, and serum cytokines (IL-1β, IL-6, and IL-8) levels were measured. Seropositive children were divided into low hepcidin (n = 22) and high hepcidin (n = 21) groups. The results showed that serum IL-1β and IL-6 levels were comparable between H. pylori seropositive and seronegative children, as were the median serum hepcidin levels (6.5 ng/mL versus 8.6 ng/mL; P = 0.1318). Median levels of serum iron, ferritin, and iron saturation were significantly lower in seropositive children with low hepcidin than in those with high hepcidin (P = 0.0123, P = 0.0001, and P = 0.0004, respectively), as well as in those with a significantly higher prevalence of ID (33.3% versus 4.5%; P = 0.015). Compared to the high hepcidin seropositive group, the low hepcidin group had significantly lower median serum levels of cytokines IL-1β and IL-6, but not IL-8 (P = 0.0151 and P = 0.0015, respectively). Inflammatory cytokines IL-1β and IL-6, but not IL-8, might be associated with increased hepcidin levels among H. pylori seropositive children. Low serum hepcidin might be the result of feedback inhibition rather than the cause of ID in children with H. pylori–induced ID. Last, to analyze the differences of serum metabolites related to H. pylori–induced ID, we enrolled 35 H. pylori seropositive children with (n = 17) and without ID (n = 18). Using liquid chromatography mass spectrometry (LC-MS), the serum metabolites were analyzed and compared between children with and without ID. After metabolomic pathway analysis, the main altered pathways among H. pylori seropositive children with ID versus without ID were the lysine degradation, propanoate metabolism pathway, valine, leucine, and isoleucine degradation pathway, nicotinate and nicotinamide degradation pathway, and tyrosine metabolism pathway. Taken together, our studies demonstrated various host factors related to H. pylori–induced ID in children. More studies are warranted to clarify the significance of host factors H. pylori in infection. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/69926 |
DOI: | 10.6342/NTU201800555 |
全文授權: | 有償授權 |
顯示於系所單位: | 毒理學研究所 |
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