Gut Microbiome Signatures Are Predictive of Cognitive Impairment in Hypertension Patients—A Cohort Study

Lei Qu1†Zhouyan Dong1†Songcui Ma2Yaping Liu3†Wei Zhou3Zitong Wang3Chen Wu4Rui Ma3Xinze Jiang3Tingting Zu5Mei Cheng3*† and Yulong Wu1*†
  • 1Department of Pathogenic Biology, Binzhou Medical University, Yantai, China
  • 2Yantai Yuhuangding Hospital, Yantai, China
  • 3Institute of Health and Disease Management, Binzhou Medical University, Yantai, China
  • 4 School of Nursing and Rehabilitation, Shandong University, Jinan, China
  • 5Clinical Medicine School, Binzhou Medical University, Yantai, China

Growing evidence has demonstrated that hypertension was associated with dysbiosis of intestinal flora. Since intestinal microbes could critically regulate neurofunction via the intestinal–brain axis, the study aimed to reveal the role and prediction value of intestinal flora alteration in hypertension-associated cognitive impairment. A cohort of 97 participants included 63 hypertension patients and 34 healthy controls. The structure of intestinal flora was analyzed by V3–V4 16S rRNA amplicon sequencing. The cognitive function was assessed using the Montreal Cognitive Assessment (MoCA) scale, and 31 patients were considered to have cognitive impairment (MoCA < 26). Patients with cognitive impairment had considerable alterations in intestinal flora structure, composition, and function compared with normal-cognitive patients. In particular, the abundance of LPS-containing taxa (Proteobacteria, Gammaproteobacteria, Enterobacterales, Enterobacteriaceae, and Escherichia–Shigella) and SCFA-producing taxon (Prevotella) significantly changed in cognition-impaired patients. Tax4Fun predication results showed downregulation of glycan biosynthesis and metabolism in hypertension patients with cognitive impairment. Additionally, the pathway was demonstrated to be significantly correlated with LPS-containing taxa (Proteobacteria, Gammaproteobacteria, Enterobacterales, Enterobacteriaceae, and Escherichia–Shigella) and SCFA-producing taxon Prevotella. Furthermore, the taxa-based multiple joint prediction model (9×) was demonstrated to have excellent diagnostic potential for cognitive impairment of hypertension patients (AUC = 0.944). The current study revealed the involvement of intestinal microbiota dysbiosis in cognition-impaired hypertension patients and provided an objective predictive index for this cognition disorder.


Hypertension is a worldwide public health issue. A recent study reported that the number of adults aged 30–79 with hypertension has increased from 650 million to 1.28 billion in the past 30 years (NCD Risk Factor Collaboration, 2021). It is well known that hypertension could lead to multi-system complications, including heart failure, chronic kidney disease, and mild cognitive impairment. Noteworthy, epidemiological studies found that hypertension is an important risk factor of cognitive function impairment, which significantly increased the incidence of Alzheimer’s disease (AD) and vascular dementia (Qiu et al., 2005Abete et al., 2014). Previous studies revealed that the neuropathological features of AD, such as the number of amyloid plaques and nerve fiber tangles, were significantly increased in the cerebral cortex and hippocampus of patients with chronic hypertension (Petrovitch et al., 2000). To date, effective or disease-modifying drugs against AD are not available since the pathological factors of AD are still unclear. The lack of efficient therapy for AD has put forward the emphasis of treatments on people at risk of dementia, such as mild cognitive impairment condition (Akbari et al., 2016). Hence, it is necessary to investigate the pathogenesis of mild cognitive impairment induced by hypertension, thereby promoting strategies for this cognitive decline.

Recently, ample research has solidly proved the association of intestinal flora dysbiosis with hypertension. Yang et al. (2015) reported that the abundance and diversity of intestinal flora in hypertension patients were significantly decreased, and the structure of intestinal flora was significantly different from those of healthy people. Besides, specific metabolic pathways were considered to be relevant to hypertension (Koh et al., 2016Sawicki et al., 2017). It is worth noting that specific functions of intestinal flora, such as those involved in short-chain fatty acid (SCFA) metabolism (Huart et al., 2019Oyama and Node, 2019Yang F. et al., 2020Wu et al., 2021) and lipopolysaccharide (LPS) content (Lorenzoni and Wideman, 2008Mell et al., 2015Yan et al., 2017Dubinski et al., 2021), were found to be associated with both hypertension and certain cognitive impairment diseases. Cumulative evidence indicated the pivotal role of intestinal flora in regulating brain function through the microbe–gut–brain axis (Westfall et al., 2017Zhu et al., 2017). Imbalance of intestinal flora can lead to nervous diseases such as AD (Liu et al., 2019), ischemic stroke (Ling et al., 2020Liu et al., 2020), and Parkinson’s disease (Sampson et al., 2016Pietrucci et al., 2019). Hence, we hypothesized that dysbiosis of the gut microbiota might be involved in the process of hypertension-associated cognitive impairment.

The present study investigated the alteration of the intestinal microbiota and cognition by 16S rRNA amplicon sequencing and Montreal Cognitive Assessment, respectively. Moreover, we analyzed the correlation of the significantly changed specific intestinal taxa with the score of cognitive function scale among hypertension patients. Furthermore, we established a bacteria-based biological predictive model for hypertension-associated cognitive impairment, which enables sensitive diagnosis of cognitive impairment of hypertension patients, and therefore facilitates the potential novel therapy targeting at regaining gut microbiota homeostasis.