GDF-15 and Malnutrition in the Heart-Gut-Axis of Heart Failure

Malnutrition is common in heart failure (HF) and increased risk of re-hospitalisation and mortality but received poor recognition and underestimated. Cardio-intestinal syndrome is common in HF, such as anorexia, early satiety, abdominal discomfort, malabsorption, and diarrhoea, contributing to wasting and malnutrition in HF. Gut microbiota is of particular and crucial importance, as it's at the boundary between diet, metabolism and the innate immune response. The splanchnic haemodynamic changes in HF lead to gut hypoperfusion and oedema and impaired gut barrier function, which may enable bacteria and endotoxin translocation into the systemic circulation and alter gut microbiota composition, in consequence, stimuli pro-inflammatory pathway and ineffective anti-inflammatory response. Previous studies have indicated that gut microbiota dysbiosis may contribute to a pro-inflammatory state and metabolic derangement in HF. However, investigation about the role of gut microbiota in malnutrition and heart failure is scarce. Growth differentiation factor-15 (GDF-15) is a distant member of the transforming growth factor-β superfamily. GDF-15 is a stress-induced cytokine, have important effects on appetite and body weight and also inflammatory response. Preclinical studies have indicated that GDF-15 regulates immune response and metabolism homeostasis during starvation, infection and cardiac injury. However, the interrelationship between GDF-15, malnutrition and gut microbiota in HF is unknown. This thesis explicates the novel concept, the heart-gut axis in HF via the systematic metabolic and gut microbial features of older adults with HF and links their interplay with circulating GDF-15.Major findings of the research described in this thesis are:1. A matched case-control analysis in 103 older adults with HF compared to 103 older adults without a history of HF reveals that:1) One log(GDF-15) higher level is associated with a 3.5-fold increased risk of malnutrition identified by the GNRI.2) Metabolomic profiling reveals that abnormal lipoprotein subclasses and amino acids levels were distinct metabolic features in older adults with HF compared to age and sex-matched individuals without HF.3) GDF-15-metabolomic association pattern shifts in older adults with HF2. Survival analysis on 151 patients with HF reveals that:1) GDF-15 has superior capability in predicting GLIM-defined malnutrition in patients with HF compared to NT-proBNP.2) Patients with GLIM-defined malnutrition have a significantly increased risk of having heart failure hospitalisation (HFH) within one year.3) Malnutrition-related metabolites levels of HF patients are significantly associated with the risk of HFH within one year.3. Gut microbial features analysis of 37 patients with HF compared to 82 individuals without HF reveals that:1) 與 NT-proBNP 相比，GDF-15 在預測 HF 患者 GLIM 定義的營養不良方面具有更好的能力。2) GLIM 定義的營養不良患者在一年內發生心臟衰竭住院 (HFH) 的風險顯著增加。3）HF患者營養不良相關代謝物水平與一年內HFH風險顯著相關。3. 82 名非 HF 個體與37 名 HF 患者的腸道微生物特徵對比分析表明：1) Beta 多樣性分析表明，HF 患者的腸道微生物群組成與非 HF 對照組有顯著差異。2) 營養不良的 HF 患者的 alpha 多樣性顯著低於營養狀況良好的 HF 患者。 Alpha 多樣性與 HF 患者的營養風險指數呈正相關。3) 與非 HF 對照相比，HF 患者的 11 個屬細菌的相對豐度顯著改變。 HF 相關屬、擬桿菌屬和鏈球菌屬的豐度與 GDF-15 或 GNRI 呈顯著負相關。4) 與非 HF 對照組相比，HF 患者的代謝組學-微生物組相關模式發生了變化。支鏈氨基酸僅在非 HF 對照中與鏈球菌的豐度呈負相關。本論文中描述的研究描繪了 GDF-15、營養不良和腸道微生物群在 HF 代謝障礙中的相互關係。這項研究的結果將增加關於心-腸軸在 HF 病理生理學背景下的知識。改變飲食和腸道微生物群是 HF 管理潛在的創新干預。營養不良常見於在心臟衰竭 (HF)並增加再住院和死亡的風險，但心臟衰竭病人的營養狀況的認識並不多。心腸綜合徵在 HF 中很常見，例如厭食、早飽、腹部不適、吸收不良和腹瀉，導致消瘦和營養不良。其中腸道微生物群具有特別重要的意義，因為它處於飲食、新陳代謝和先天免疫反應之間的邊界。 HF 的內臟血流動力學變化導致腸道灌注不足和水腫以及腸道屏障功能受損，這可能使細菌和內毒素易位進入體循環並改變腸道微生物群組成，從而刺激促炎途徑和無效的抗炎反應。先前的研究表明，腸道微生物群失調可能導致 HF 的促炎狀態和代謝紊亂。然而，關於腸道微生物群在營養不良和HF中的作用的研究很少。生長分化因子-15 (GDF-15) 是轉化生長因子-β 超家族的遠親成員。 GDF-15 是一種應激誘導的細胞因子，對食慾和體重以及炎症反應有重要影響。臨床前研究表明，GDF-15 在飢餓、感染和心臟損傷期間調節免疫反應和代謝穩態。然而，GDF-15、營養不良和 HF 腸道微生物群之間的相互關係尚不清楚。本論文通過分析患有 HF 的老年人的血清代謝組學和腸道微生組學特徵來解釋一個新概念，即 HF 的心腸軸，並將發現它們與血清 GDF-15 的潛在的相互作用。本論文中的主要發現有：1. 對 103 名患有 HF 的老年人與 103 名沒有 HF 病史的老年人進行的匹配病例對照分析表明：1) 每 log(GDF-15) 單位升高可增加3.5倍GNRI 確定的營養不良風險。2) 代謝組學分析顯示，與年齡和性別匹配的無 HF 個體不同，患有 HF 的老年人的代謝特徵為異常血清脂蛋白亞類和氨基酸濃度。3) GDF-15-代謝組學關聯模式在患有 HF 的老年人中發生變化。2. 對 151 名 HF 患者的生存分析表明：1) Beta-diversity analysis reveals that the gut microbiota composition in patients with HF is significantly varied from non-HF controls.2) Malnourished HF patients have significantly lower alpha diversity than well-nourished HF patients. Alpha diversity is positively associated with nutritional risk index in patients with HF.3) The relative abundance of 11 genera is significantly altered in HF patients compared to non-HF controls. The abundance of HF-associated genera, Bacteroides and Streptococcus, have significant negative correlations with GDF-15 or GNRI.4) The metabolomics-microbiome correlation pattern shifts in patients with HF compared to non-HF controls. Branched-chain amino acids are negatively correlated with the abundance of Streptococcus only in non-HF controls.In conclusion, the research described in this thesis portrays the interrelationship of GDF-15, malnutrition and gut microbiota in the dysmetabolism of HF. The findings of this study will add knowledge to the novel concept of a heart-gut axis in the context of HF pathophysiology. Modification of diet and gut microbiota may be an innovative target for HF management.XIE, Suyi.Ph.D. Chinese University of Hong Kong 2021.Includes bibliographical references (leaves )Abstracts in English and Chinese.Title from PDF title page (viewed on ...