Circulating metabolomics profiling reveals novel pathways associated with cognitive decline in patients with hypertension

Abstract

Background: Hypertension is a significant risk factor for cardiovascular disease, and it is associated with dementia, including Alzheimer’s disease (AD). Although it may be correlated with AD in terms of symptoms, the link between hypertension and AD pathological biomarkers, and the potential underlying mechanism of hypertension with cognitive decline, are still not well understood. Methods: The Mini-Mental State Examination (MMSE) scores were used to evaluate cognitive function. Enzyme-linked immunosorbent assays were used to examine plasma amyloid-beta (Aβ)40, Aβ42, and tau concentration in hypertensive patients. Metabolomics and metagenomics were performed to identify the significantly changed circulating metabolites and microbiota between healthy individuals and hypertensive patients. Pearson’s correlation was used to examine the association between cognitive indicators and differential metabolites. Results: We found significantly decreased MMSE scores, elevated plasma Aβ40, and decreased Aβ42/Aβ40 ratio in hypertensive patients, which are critically associated with AD pathology. Based on metabolomics, we found that significantly altered metabolites in the plasma of hypertensive patients were enriched in the benzoate degradation and phenylpropanoid biosynthesis pathways, and they were also correlated with changes in MMSE scores and Aβ42/Aβ40 ratio. In addition, metabolomics signaling pathway analysis suggested that microbial metabolism was altered in hypertensive patients. We also identified altered blood microbiota in hypertensive patients compared with the controls. Conclusions: Our study provides a novel metabolic and microbial mechanism, which may underlie the cognitive impairment in hypertensive patients.

Human Blood Bacteriome: Eubiotic and Dysbiotic States in Health and Diseases

“…Lee et al (2020) and Chang et al (2021) reported that Firmicutes were the most abundant phylum in the circulating bacterial EVs [44,45]. On the contrary, other studies found that the majority of the EVs comprised Proteobacteria instead of Firmicutes [42,43,46]. The total numbers of healthy subjects in the latter studies were far fewer than those in those two former studies.…”

“…HIV infection was shown to develop blood dysbiosis as indicated by an increase in Proteobacteria and a decrease in Actinobacteria and Firmicutes [40]. Gut bacterial translocation as a result of gut epithelial disruption from mucosal immune defects might be responsible for blood dysbiosis [43]. Although HIV patients treated well with combined antiviral therapy (cART) could show improved immune status and diminished viral load, a non-nucleotide-reverse-transcriptaseinhibitor-based regimen, as well as a protease-inhibitor-based regimen, might not ameliorate the disruption of the gut epithelial barriers [38].…”

Research progress on the correlation between sacubitril-valsartan and cognitive function in hypertensive patients

“…Activation of the RAAS system in hypertensive patients induces oxidative stress on the one hand, and reduces the production of neuroprotective factors on the other. Angiotensin II (Ang II) can activate angiotensin receptor 1 (AT1R) on the surface of perivascular macrophages to induce oxidative stress [11], resulting in damages of blood-brain barrier disruption [12], thereby affecting the clearance of Aβ process [13] and cause neuroinflammation and myelin damage [14]. The cleavage of endogenous amyloid precursor protein (APP) by α-secretase can generate the neuroprotective factor APPα [15], while Ang II can activate AT2R and reduce the activity of α-secretase in human brain microvascular endothelial cells, resulting in decreased Appα production [16].…”

Metabolic Profiling and Metabolites Fingerprints in Human Hypertension: Discovery and Potential

“…Metabolomics and metabolite profiling/fingerprinting offer a comprehensive measurement of metabolic changes resulting from responses to intrinsic or extrinsic agents, including diet, drugs, gut microbial, lifestyle, and other factors [ 4 , 21 ]. They are extensively used to assess metabolic changes in human health and disease and for biomarker discovery, especially in CVD, including hypertension [ 20 , 22 , 23 ]. Metabolomics has made possible the unbiased detection, identification, and quantification of several low molecular weight metabolites that are present within different matrices (cells, tissues, and body fluids) [ 23 , 24 ].…”

“…A similar difference was reported between men and women when the metabolomics profiles of 28 individuals with arterial hypertension were compared with their healthy control counterparts [ 35 ]. More interest is gradually building on applying metabolomics in clinical hypertension, with equally interesting outcomes [ 6 , 22 , 33 , 36 ]. The metabolic pathways associated with hypertension are discussed in the following section and illustrated in Figure 2 .…”