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Diyet yağ asitlerinin metabolik etkilerinin metabolomiks yöntemiyle çalışılması

Investigation of the metabolic effects of dietary fatty acids using a metabolomics approach

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  1. Tez No: 1010309
  2. Yazar: ECE KILIÇ
  3. Danışmanlar: PROF. DR. PERVİN BAŞARAN, PROF. DR. KIVANÇ BİRSOY
  4. Tez Türü: Doktora
  5. Konular: Biyokimya, Gıda Mühendisliği, Biochemistry, Food Engineering
  6. Anahtar Kelimeler: Belirtilmemiş.
  7. Yıl: 2026
  8. Dil: Türkçe
  9. Üniversite: İstanbul Teknik Üniversitesi
  10. Enstitü: Lisansüstü Eğitim Enstitüsü
  11. Ana Bilim Dalı: Gıda Mühendisliği Ana Bilim Dalı
  12. Bilim Dalı: Belirtilmemiş.
  13. Sayfa Sayısı: Belirtilmemiş.

Özet

Obezite, başta bağırsak olmak üzere çeşitli dokularda işlev bozukluklarına yol açarak metabolik bozukluklar, kanser ve bağışıklık sistemi hastalıkları riskini artıran küresel bir sağlık sorunudur. Yaşam tarzı faktörleri, özellikle yüksek yağlı beslenme alışkanlıkları, bu riski artırmada önemli rol oynamaktadır. Diyet değiştirilebilir bir risk faktörü olmasına karşın, obeziteye yol açan beslenme düzenlerinin bu hastalıkların gelişimine nasıl katkıda bulunduğu henüz tam olarak aydınlatılamamıştır. Literatürdeki bulgular, doymuş yağ oranı yüksek diyetlerin mikrobiyom üzerinden obezite, kalp-damar hastalıkları ve bağırsak kanseri gibi metabolik bozuklukların riskini artırdığını göstermektedir. Genel eğilim, doymuş yağ asitleri bakımından zengin diyetlerin obeziteyle karakterize edilen tipik yüksek yağlı diyet fenotipine yol açtığını; buna karşılık Akdeniz tipi beslenme gibi çoklu doymamış yağ asitleri açısından zengin diyetlerin ise koruyucu ve yararlı etkiler sağladığını ortaya koymaktadır. Bu etkileri daha ayrıntılı incelemek amacıyla, bu çalışma farklı yağ asidi bileşimlerine sahip yüksek yağlı diyetleri sistematik olarak karşılaştırmış ve spesifik yağ asitlerinin temel metabolik yolakları nasıl etkilediğini araştırmıştır. Çalışma, bu diyetlerin metabolik sonuçlarını karakterize etmenin yanı sıra, gözlenen değişikliklerin geri dönüşümlülüğünü de değerlendirerek, diyet müdahalelerinin metabolik homeostazı yeniden sağlama potansiyeline ilişkin önemli bir bakış açısı sunmuştur. Sonuçlar, hindistancevizi, balık veya süt yağı ile zenginleştirilmiş yüksek yağlı diyetin, kontrol diyetiyle karşılaştırıldığında, kardiyovasküler hastalık riskiyle güçlü bir şekilde ilişkilendirilen bağırsak mikrobiyotası kaynaklı bir metabolit olan trimetilamin N-oksit (TMAO) düzeylerinde belirgin bir azalmaya yol açtığını göstermiştir. Buna karşılık, domuz yağı, hurma yağı, zeytinyağı ve ketojenik diyet dahil olmak üzere diğer yüksek yağlı diyet gruplarında TMAO düzeylerinde anlamlı bir değişiklik gözlenmemiştir. Bu bulgular, diyet yağının türünün, bağırsak mikrobiyotası kaynaklı metabolitlerin düzenlenmesinde ve bunların kardiyovasküler sağlık üzerindeki potansiyel etkisinde kritik bir rol oynadığını vurgulamaktadır. TMAO öncülleri olan kolin ve L-karnitin seviyeleri incelendiğinde, diyetler arasında yalnızca balık yağı grubunda, kontrol grubuna kıyasla L-karnitin seviyelerinde azalma gözlenmiş; diğer gruplarda ise anlamlı bir değişiklik tespit edilmemiştir. Balık yağı grubunda gözlenen TMAO seviyesindeki azalmanın, öncülü L-karnitin ile ilişkili olabileceği düşünülebilir. Öte yandan, hindistancevizi ve süt yağı diyetleri sonrasında gözlenen TMAO düşüşü, TMAO üreten bağırsak mikroorganizmalarının sayısındaki azalma veya hepatik flavin monooksijenaz enzimlerinin baskılanması sonucunda ortaya çıkmış olabilir. Bu bulgular, farklı yağ türlerinin TMAO metabolizması üzerindeki etkilerinin mekanizmalarını anlamak açısından önemli ipuçları sunmaktadır. Süt yağı ve hindistancevizi yağı gruplarının yağ asidi kompozisyonundaki belirleyici özellik, diğer gruplara kıyasla sırasıyla kısa ve orta zincirli yağ asitleri açısından zengin olmalarıdır. Bu nedenle, TMAO seviyelerini düşürme potansiyellerinin, bu kısa ve orta zincirli yağ asitlerinin içerikleriyle ilişkili olabileceği öne sürülmektedir. Beslenmenin çeşitli metabolik bozuklukların patogenezindeki rolü göz önüne alındığında, diyet yağ asitlerinin optimize edilmesinin, kalp hastalıkları da dahil olmak üzere metabolik bozuklukların önlenmesinde değerli bir terapötik strateji olabileceği düşünülmektedir

Özet (Çeviri)

Obesity is a worldwide epidemic that leads to functional impairments in various tissues, including the gut, and increases the risk of conditions such as metabolic disorders, cancer, and immune-related diseases. Lifestyle factors, particularly high-fat diets, play a significant role in increasing this risk. Although diet is recognized as a modifiable risk factor, the mechanisms through which obesity-inducing diets contribute to these diseases remain poorly understood. Previous data show that diets high in saturated fat increases the risk of metabolic disorders, including obesity and heart disease, as well as colorectal cancer through the microbiome. The general trend in the literature suggests that diets rich in saturated fatty acids lead to the typical high-fat diet (HFD) phenotype characterized by obesity, whereas diets rich in polyunsaturated fatty acids exert beneficial effects. HFDs elevate cardiovascular disease risk in part through gut microbial generation of trimethylamine (TMA), the precursor to trimethylamine-N-oxide (TMAO). This gut microbiota-derived metabolite is associated with increased cardiovascular disease risk and may serve as a biomarker for heart failure. TMAO formation represents a host-microbiome interaction wherein intestinal bacteria transform dietary substrates into TMA, which subsequently undergoes hepatic oxidation to TMAO through flavin monooxygenase (FMO) enzyme activity. Choline and carnitine constitute the primary dietary substrates for microbiota-mediated TMAO production. These TMA-generating bacteria possess genes that encode key enzymes required for TMA biosynthesis, such as choline-TMA lyase (CutC), carnitine monooxygenase (CntAB), glycine betaine reductase (GrdH), and TMAO reductases (collectively designated as TorA). Although genes for choline breakdown are common across intestinal bacteria, facultative anaerobes preferentially expand in hosts consuming HFDs. Comparative dietary studies revealed that when mice received HFDs supplemented with choline, Escherichia coli gained a CutC-mediated competitive advantage, an effect not observed under low-fat feeding conditions. This indicates that E. coli strains possessing the cut operon utilize choline specifically under intestinal conditions created by HFD consumption. In contrast to Western high-fat diets, the Mediterranean diet offers protective mechanisms against TMAO-driven atherosclerosis and intestinal barrier dysfunction. This dietary pattern is characterized by two components that collectively promote cardiovascular health. One key element is the intake of omega-3 fatty acids, which are derived from regular fish consumption. The other essential component is the abundant dietary fiber provided by diverse plant-based foods such as vegetables, fruits, legumes, whole grains, and nuts. These dietary fibers increase fecal short-chain fatty acid levels through bacterial fermentation of carbohydrates that humans cannot digest. The produced short-chain fatty acids play a crucial role in maintaining gut health by strengthening the intestinal barrier and reducing systemic inflammatory responses. To examine these effects in greater detail, this study systematically compared HFDs with different fatty acid compositions, investigating how specific fatty acids influence key metabolic pathways. In addition to characterizing the metabolic consequences of these diets, the study also evaluated the reversibility of the observed changes, providing insight into the potential for dietary interventions to restore metabolic homeostasis. The results demonstrated that a HFD enriched with coconut, fish, or milk fat led to a significant reduction in TMAO levels, a gut microbiota–derived metabolite strongly associated with cardiovascular disease risk, compared to the control diet. In contrast, the other high-fat diet groups including lard, palm oil, olive oil, and a ketogenic diet showed no significant changes in TMAO levels, highlighting that the type of dietary fat plays a critical role in modulating gut microbiota–derived metabolites and their potential impact on cardiovascular health. When examining the levels of choline and L-carnitine precursors, a decrease in L-carnitine was observed only in the fish oil group, while no significant changes were detected in the other groups. The observed decrease in TMAO levels following fish oil supplementation is most likely attributable to reduced dietary precursor availability. In contrast, the reductions observed with coconut oil and milk fat diets may result from either decreased abundance of TMAO-producing microorganisms or inhibition of hepatic flavin monooxygenases responsible for converting TMA to TMAO. A distinguishing characteristic of the milk fat and coconut oil groups is their substantially higher content of short- and medium-chain fatty acids compared to other dietary groups. This enrichment likely underlies their TMAO-lowering effects, as these fatty acid classes differentially influence gut microbial ecology. Although most fatty acids are absorbed in the upper digestive tract, excessive intake allows residual amounts to reach the colon, where they can alter intestinal microbiota composition. Unlike long-chain fatty acids (LCFAs), short- and medium-chain fatty acids (SCFAs and MCFAs) are mostly absorbed by intestinal epithelial cells through passive diffusion due to their shorter chain length and greater water solubility. This efficient proximal absorption minimizes their colonic accumulation and subsequent microbial disruption. Conversely, HFDs rich in LCFAs induce gut dysbiosis primarily by altering colonic oxygen tension and microbial energy substrate availability. The colon's characteristically low-oxygen environment typically supports beneficial anaerobic bacteria while restricting facultative anaerobes like Enterobacteriaceae. HFDs compromise enterocyte mitochondrial activity and oxygen utilization, resulting in elevated luminal oxygen and nitrate concentrations. This environmental change promotes facultative anaerobes such as E. coli while suppressing strict anaerobes, thereby increasing the Gram-negative to Gram-positive bacterial ratio. Lipopolysaccharide (LPS) release from Gram-negative bacteria triggers inflammatory responses that further propagate proinflammatory microbial communities. This dysbiotic pattern is characterized by reduced obligate anaerobic Firmicutes and expanded facultative anaerobic Enterobacteriaceae populations. Certain commensal species, including E. coli, thrive under inflammatory conditions by utilizing nitric oxides for energy, conferring a survival advantage. Saturated fat-rich HFDs may additionally facilitate TMAO generation by providing organic sulfur to sulfate-reducing bacteria such as Desulfovibrionaceae, including Desulfovibrio species. Dietary fat consumption stimulates hepatic bile acid synthesis, producing taurine- or glycine-conjugated bile acids that enter the duodenum to aid small intestinal lipid absorption. During intestinal passage, most bile acids are deconjugated, liberating taurine and thus increasing sulfur availability for sulfate-reducing microorganisms. Additionally, hydrophobic bile acids disrupt intestinal barrier function, potentially enabling microbial metabolites like TMA to enter systemic circulation. FAs may also modulate gut microbiota through their antimicrobial characteristics, with effectiveness determined by chain length, saturation degree, and double bond positioning. Saturated FAs demonstrate maximal antimicrobial activity at shorter chain lengths, whereas monounsaturated (MUFAs) and polyunsaturated FAs (PUFAs) show enhanced activity at longer chain lengths. SCFAs exhibit pH-dependent antimicrobial effects, primarily disrupting energy metabolism in Gram-negative bacteria. Elevated SCFA concentrations lower pH, promoting Bifidobacteriaceae and Lactobacillaceae while inhibiting Enterobacteriaceae. SCFAs inhibit pathogenic bacteria, thereby preventing dysbiosis and inflammation, while simultaneously reducing nitric oxide production that stimulates TMA lyase activity. The literature demonstrates that saturated long-chain fatty acids promote the production of trimethylamine (TMA), a precursor of TMAO, through multiple mechanisms. These include elevated colonic oxygen levels and increased taurine-conjugated bile acids, which favor the proliferation of TMA-producing bacteria. Conversely, short-chain fatty acids (SCFAs) and omega-3 polyunsaturated fatty acids exert beneficial effects by modulating intestinal pH and supporting SCFA-producing bacteria, thereby suppressing TMA-producing bacterial populations. Our findings partially align with these established mechanisms. Diets containing short-chain and omega-3 fatty acids resulted in reduced TMAO levels, consistent with literature predictions. Unexpectedly, however, long-chain fatty acid-containing diets did not elicit the anticipated increase in TMAO levels. This difference likely reflects the complex composition of whole food oil sources, which contain various bioactive compounds beyond their fatty acid profiles. For instance, olive oil naturally contains 3,3-dimethyl-1-butanol, a choline analog that suppresses TMA production by inhibiting microbial TMA lyase activity. Similarly, various oils are rich in polyphenolic compounds that modulate intestinal microbial communities independent of their fatty acid composition. These observations highlight a critical limitation in attributing metabolic effects solely to fatty acid content when whole food sources are used. A notable strength of our study is its examination of MCFAs and their effects on TMAO levels, an area that remains significantly underexplored despite the growing popularity of ketogenic diets and medium-chain triglyceride (MCT) supplementation. However, our findings also underscore the need for more refined experimental approaches to fully elucidate fatty acid-specific mechanisms. Advancing our mechanistic understanding of how dietary fatty acids shape gut microbiota and TMAO metabolism requires future investigations that address several critical methodological gaps. First, controlled experimental designs are essential, wherein all dietary variables remain constant except for the specific fatty acid under investigation. This can be achieved by supplementing diets with purified fatty acids rather than whole oils or fat sources containing diverse bioactive constituents. Such a reductionist approach would eliminate confounding variables from the food matrix, enabling precise determination of how individual fatty acids influence gut microbial TMAO production and establishing definitive cause-and-effect relationships necessary for targeted dietary recommendations. Second, establishing dose–response relationships through well-designed human clinical trials is imperative to characterize the concentration-dependent effects of distinct fatty acids on TMAO generation and to delineate thresholds distinguishing beneficial from detrimental outcomes. Addressing these research gaps is fundamental to formulating evidence-based dietary guidelines and therapeutic interventions. Given the established role of nutrition in the pathogenesis of various metabolic disorders, optimizing dietary fatty acid composition represents a promising therapeutic strategy for preventing metabolic diseases, including cardiovascular disorders.

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