Abstract
Cardiometabolic diseases (CMD) are the most common cause of morbidity and mortality worldwide, representing a major public health challenge. Besides well-established genetic and environmental risk factors, circulating metabolites, especially gut bacteria-derived metabolites, play a crucial role in the development and progression of CMD. Among these metabolic products, short-chain fatty acids (SCFA), including acetate, propionate and butyrate, have gained attention for their potential role in regulating glucose and lipid metabolism, gut barrier integrity, blood pressure, and immune responses.Two main hypotheses were proposed for this work: (i) specific metabolites contribute to the individual cardiometabolic risk and are useful biomarkers of prevalent and incident disease and (ii) gut microbial metabolites in serum and in stool, such as SCFAs, are important determinants of CMD and represent specific pathways to be targeted by gut microbiome interventions. These hypotheses were explored by employing different statistical and computational approaches in data from multiple population-based cohorts. These include TwinsUK, ZOE Personalised Responses to Dietary Composition Trial (PREDICT)-1, the Cooperative Health Research in the Region of Augsburg (KORA) and an acute trauma case-control study, and cohorts from the Consortium of METabolomics Studies (COMETS) with myocardial infarction (MI) information. The overarching aims of this thesis were to (i) identify circulating and faecal biomarkers of prevalent and incident CMD, and (ii) investigate the role of SCFAs in the interplay between the gut microbiota and CMD.
To achieve the first aim, in Chapter 4, I searched for circulating biomarkers of atherosclerotic cardiovascular disease risk (ASCVD). I identified a panel of 21 circulating metabolites cross-sectionally associated with ASCVD and longitudinally predictiveAbstract 3 of CVD mortality and morbidity independently of environmental and traditional risk factors. Then, in Chapter 5, I searched for circulating biomarkers of incident MI in the largest metabolome study of MI to date consisting of 6 intercontinental COMETS cohorts with diverse race backgrounds. I identified 56 biomarkers (of which 10 were novel) of incident MI. Finally, in Chapter 6, I explored the role of faecal metabolites and gut microbiota in prediabetes. I created a faecal metabolite signature that was cross-sectionally associated with impaired fasting glucose in two independent cohorts and was also predictive of incident type-2 diabetes. Although the signature consisted of xenobiotics and host-produced metabolites, it was strongly associated with the gut microbiota composition. For the second aim, in Chapter 7, I comprehensively assessed the host genetics and gut microbiota contribution to a panel of eight serum and stool SCFAs, examined their postprandial changes, and explored their links with chronic and acute inflammatory responses in three independent cohorts. I showed that SCFA levels present a heritable genetic component, and that the gut microbiome is strongly correlated with their faecal levels. Moreover, I reported significant changes in SCFA postprandial circulating levels. Furthermore, I found different correlation patterns with inflammatory markers depending on the type of inflammatory response. Lastly, in Chapter 8, I further analysed acetate, one of the major SCFAs, and explored the associations between its circulating levels, gut microbiota and visceral fat. I found specific gut bacterial genera associated with its levels, including Coprococcus and Lachnoclostridium, and identified the mediatory role of acetate in the association between gut microbiota and visceral fat.
In conclusion, these findings illustrate the breadth of the physiological relevance of metabolites, particularly SCFAs, on CMD, and highlight the importance of the gut microbiota in the pathogenesis of CMD not only by producing metabolic products but also by affecting intestinal absorption/excretion of host-produced metabolites. Future studies should determine causality and explore translational strategies that could modulate the identified metabolites by targeting the gut microbiota.
| Date of Award | 1 May 2024 |
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| Original language | English |
| Awarding Institution |
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| Supervisor | Cristina Menni (Supervisor) & Ana Valdes (Supervisor) |