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., 2005; Abete 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., 2016; Sawicki 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., 2019; Oyama and Node, 2019; Yang F. et al., 2020; Wu et al., 2021) and lipopolysaccharide (LPS) content (Lorenzoni and Wideman, 2008; Mell et al., 2015; Yan et al., 2017; Dubinski 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., 2017; Zhu et al., 2017). Imbalance of intestinal flora can lead to nervous diseases such as AD (Liu et al., 2019), ischemic stroke (Ling et al., 2020; Liu et al., 2020), and Parkinson’s disease (Sampson et al., 2016; Pietrucci 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.

Mild cognitive impairment in hypertension patients is at risk of deterioration to dementia. Sensitive diagnosis and thereby early intervention for cognitive impairment caused by hypertension can prevent the incidence of dementia. The present study found that dysbiosis of the intestinal flora is involved in the cognitive dysfunction of hypertension patients. Specifically, LPS-containing taxa (Proteobacteria, Gammaproteobacteria, Enterobacterales, Enterobacteriaceae, and Escherichia–Shigella) and SCFA-producing taxon (Prevotella) were closely correlated with cognitive function of hypertension patients (Figure 7). Moreover, we established multiple joint bacteria-based models for objective diagnosis of cognitive impairment in hypertension patients. The current research is a meaningful effort to characterize the intestinal microbiota of hypertension patients with cognitive impairment and shed new light on the objective diagnosis of cognitive decline in hypertension patients.

Substantial evidence obtained in animals and humans showed that hypertension could induce intestinal flora disorder (Mell et al., 2015; Yang et al., 2015; Marques et al., 2017; Yan et al., 2017). Previous studies indicated that dysbiosis of the intestinal flora is involved in cognitive dysfunction caused by diseases such as Parkinson’s disease and type 2 diabetes (Ren et al., 2020; Zhang et al., 2020). Hence, we hypothesized that the hypertensive-induced dysbiosis of the gut microbiota might play a role in hypertension’s cognitive function decline, which could deteriorate to AD. In the present study, 48.44% of hypertension patients were determined to have cognitive impairment (MoCA < 26). According to Chao1, ACE, observed_species, and PD_whole_tree indexes, we found that the microbial diversity and community abundance significantly rose in cognitive-impaired patients compared to patients with normal cognitive function. The unique OTUs were more frequent in cognitive impairment patients, reaching from 510 in the NMCI group to 668 in the MCI group. Specifically, our results showed that the relative abundance of LPS-containing taxa, Proteobacteria, Gammaproteobacteria, Enterobacterales, Enterobacteriaceae, and Escherichia–Shigella, was dramatically higher in hypertension patients with cognitive impairment. LPS, as a cell wall component of Gram-negative bacteria, has been previously reported to induce the production of pro-inflammatory cytokines (Oyama et al., 2004). Existing literature has shown that hypertension causes increased permeability of the blood–brain barrier (Faraco et al., 2016). Hence, the gut microbiota-derived products, such as LPS, could leak to the CNS and regulate neuroinflammation, which is a critical mechanism of cognitive impairment (Erny et al., 2015; Rothhammer et al., 2016). A recent clinical study (Liu et al., 2019) demonstrated that Gammaproteobacteria, Enterobacteriales, and Enterobacteriaceae showed a progressively enriched prevalence from health control to amnestic mild cognitive impairment and AD patients, which is similar to our results of high relative abundance of LPS-containing taxa in hypertension patients with cognitive impairment. Accumulating studies revealed that cardiovascular diseases such as hypertension and AD have overlapping neuropathological processes (Zlokovic, 2011; Rodrigue et al., 2013; Iadecola, 2016). Hence, we speculate that these specific LPS-containing taxa, including Gammaproteobacteria, Enterobacterales, and Enterobacteriaceae, which simultaneously exhibited relatively high abundance in hypertension patients with cognitive impairment and AD patients, may contribute to cognitive deterioration and play a significant role in the neuropathogenesis of hypertension’s cognitive function decline progressive to AD. Further study is required to elucidate the precise role and clarify the mechanism for this phenomenon.

Moreover, we found that the relative abundance of Prevotella, which was demonstrated as a SCFA-producing probiotic in the gut (Ren et al., 2021), was significantly decreased in the patients with cognitive impairment compared to the patients without cognitive impairment. Previous evidence demonstrated that downregulation of SCFAs is involved in cognitive impairment diseases including AD, Parkinson’s Disease, congestive heart failure, and sulfamonomethoxine exposure (Ho et al., 2018; Zhu et al., 2019; Sarah et al., 2020; He et al., 2021). SCFAs, such as propionic acid, butyric acid, isobutyric acid, and valeric acid, can inhibit inflammation by regulating histone deacetylase and binding G-protein-coupled receptors (Tan et al., 2014; Yang W. et al., 2020). Our results of Tax4Fun predication showed that the glycan biosynthesis and metabolism were significantly decreased in hypertension patients with cognitive impairment. The trend was supposed to cause carbohydrate metabolism disorder (Woting and Blaut, 2016), resulting in insufficient SCFAs by intestinal flora after digestion of carbohydrate, inducing inflammatory and subsequently affecting cognitive function (Koh et al., 2016; Sawicki et al., 2017). In the present study, we found that the enrichment of glycan biosynthesis and metabolism was significantly positively associated with the SCFA-producing probiotic Prevotella, while it was substantially negatively correlated with the relative abundance of LPS-containing taxa (Proteobacteria, Gammaproteobacteria, Enterobacterales, Escherichia–Shigella, and Enterobacteriaceae).

Additionally, we found that the total score of MoCA was strongly associated with the taxa (e.g., Proteobacteria, Coriobacteriales, and Enterobacteriaceae), which were significantly altered in the hypertension patients with cognitive impairment. In particular, visuospatial and executive function domain, attention domain, orientation domain, delayed recall domain, and language domain of the MoCA dramatically correlated with selected taxa, respectively. Notably, attention domain, orientation domain, and delayed recall domain were simultaneously correlated with Escherichia–Shigella, while attention domain, orientation domain, and visuospatial and executive function domain were consistently associated with Coriobacteriia and Coriobacteriales. Cattaneo et al. (2017) reported that cognitively impaired patients with brain amyloidosis showed a higher abundance of inflammatory bacteria taxon Escherichia–Shigella compared with both healthy controls and patients with no brain amyloidosis. The enrichment of Escherichia–Shigella is also found to be implicated in post-operative cognitive dysfunction (Lian et al., 2021). Studies investigating the effects of specific bacteria on a distinct domain of cognitive function were still limited. It was revealed by a prospective, longitudinal study that children with a history of bacterial meningitis were at greater risk of impairment in executive ability (Anderson et al., 2004). A study that employed a total 140 participants who were selected using purposive sampling from the patients within the age group of 18–60 years old at Tehran in 2016 found that Helicobacter pylori infection increases the prevalence of memory and executive dysfunction (Rezvani et al., 2017). To the best of our knowledge, our study is the first to demonstrate the corresponding associations of selected taxa with specific domains of cognitive functioning among hypertension patients. Although a possible causal relationship between these selected taxa and different aspects of cognitive functioning deserves further investigation, our results promote the possibility that the precision intervention may be achieved by targeting specific bacteria associated with distinct cognitive dysfunction of hypertension patients.

To date, the current diagnosis of neurocognitive disorders mainly relies on neuropsychological scales and expensive neuroimaging. Exploration of potential objective and cost-effective indicators of neurocognitive decline is still limited. In the current study, we aimed to establish an objective and no-invasion prediction model based on selected gut bacteria to predict mild cognitive impairment of hypertension patients. To choose the optimal model for diagnosis of cognitive impairment of hypertension patients, the area under the ROC was analyzed. Our results showed that the bacteria-based multi-index prediction model (9×) performed best on mild cognitive impairment in hypertension patients (AUC = 0.944). Additionally, the single index prediction model based on Escherichia–Shigella has also promised efficiency prediction (AUC = 0.783), despite the accuracy being less than that of the multi-index prediction model. However, because a single intestinal flora is more efficient, this single index prediction model might also be valuable in applications.

Nevertheless, our studies have some limitations. Firstly, we only recruited a limited number of participants, making it possible to ignore the slight alteration of the intestinal microbiota. Secondly, it is needed to recruit a new cohort to verify the accuracy of our prediction models. In future experiments, we will expand the sample size and conduct a longer duration of follow-up visits for further verification of the results. Thirdly, 16S amplicon sequencing is not enough for functional analysis, and microbiome metagenomics should be carried out to improve the resolution of the taxonomic functional composition of the microbiome.

Evidence demonstrated that hypertension-associated cognitive impairment and AD have overlapped pathophysiology. Effective diagnosis and early intervention for this neurocognitive decline could prevent the incidence of AD. The present study provides evidence for the involvement of intestinal microbiota dysbiosis in the cognitive impairment of hypertension patients. Moreover, we established efficiency prediction models based on selected taxa that strongly correlated with cognitive function performance. This work exposed a sensitive and objective index for the mild cognitive impairment of hypertension patients, and elucidate targets for preventing or reversing intestinal microbiota dysbiosis for future no-pharmacology therapeutics.

The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found below: https://www.ncbi.nlm.nih.gov/, SAMN21436827-21436923.

The studies involving human participants were reviewed and approved by Institution Review Board of Binzhou Medical University (No. 2018-085). The patients/participants provided their written informed consent to participate in this study.

YW and MC conceived and supervised the project. YW, MC, LQ, and YL designed and performed the main experiments. ZD, SM, LQ, and YL participated in 16S rRNA amplicon sequencing analysis. YL, LQ, WZ, ZW, CW, RM, XJ, and TZ recruited the subjects and collected samples. YL, ZD, and LQ drafted the manuscript. MC and ZD revised the manuscript. All authors have approved the final version of the manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.