The oral microbiome and inflammation in mild cognitive impairment
Introduction
Alzheimer's disease is the most frequent cause of dementia in Western societies with recent United States (U.S.) estimates of 5.5 million people affected (Mayeux and Stern, 2012). As the population ages, a rapid rise in the prevalence of Alzheimer's disease is expected with a possible 16 million people affected by 2050 (Lim et al., 2015). Persons with this disease have a life expectancy of 5–9 years after diagnosis (Lim et al., 2015), and the progressive cognitive decline experienced during that time makes it among one of the most disabling diseases incurred by aging populations (Ferri et al., 2006). Annual costs for dementia care are assessed to be between $41,000 to $56,000 per person, with a total cost of up to $215 billion in the U.S. in 2010 (Hurd et al., 2013). To date, there is no effective, mechanism-based treatment strategy for the condition (Lim et al., 2015).
Inflammation and immune mechanisms are believed to play important roles in Alzheimer's disease pathogenesis (Krstic and Knuesel, 2013). Systemic inflammation may dysregulate the normal mechanism for clearing out misfolded or damaged neuronal proteins in aging brains. This would result in a neurotoxic inflammatory environment marked by the build-up of amyloid beta plaques and neurofibrillary tangles leading to neurodegeneration and the cognitive decline that marks Alzheimer's Disease (Krstic and Knuesel, 2013; Lim et al., 2015). What then could trigger this systemic inflammation and possible subsequent chain of events? Given that persistent low level bacterial infection may play a role in inducing chronic inflammation among the elderly (Licastro et al., 2014), a possible source for this inflammation is oral cavity infection.
As an individual ages, immunosenescence increases susceptibility to chronic and common infections (Targonski et al., 2007) like oral infection. Risk for oral infection is related to declining general health, medication use, and impaired access to oral healthcare (Singhrao et al., 2014). Periodontal disease and dental caries represent the two most common infections of the oral cavity (Löe, 2000). Periodontal disease affects 64% of adults in the U.S. aged 65 years and older (Eke et al., 2012) and includes two conditions: gingivitis and periodontitis. Gingivitis represents an inflammatory response to the microorganisms that inhabit the biofilm at the interface of the tooth and the gingiva (Kinane, 2001). For some, progressive gingivitis leads to periodontitis, defined as a polymicrobial inflammatory disease involving the irreversible destruction of supportive soft tissue and bone, ultimately leading to tooth loss (Darby et al., 2000). Dental caries occur on the exposed surfaces of the teeth, developing through a complex interaction over time between acid-producing bacteria and fermentable carbohydrates (Selwitz et al., 2007).
Several studies supporting the link between oral health and Alzheimer's disease have reported that poor oral health, chronic periodontal disease, and tooth loss are associated with worsening cognitive impairment (Gatz et al., 2006; Noble et al., 2009; Stein et al., 2007; Stewart et al., 2008). A recent literature review cites epidemiologic links between poor oral health and dementia including post-mortem evidence of higher quantities of oral organisms in the brains of people with Alzheimer's disease compared to controls and higher levels of systemic inflammatory markers in Alzheimer's disease patients compared to controls (Shoemark and Allen, 2015). These culture based and immunologic investigations have identified a few oral bacterial suspects, including Porphyromonas gingivalis (Poole et al., 2013), Fusobacterium nucleatum, and Prevotella intermedia (Stein et al., 2012). It is becoming increasingly clear, however, that oral infectious etiology is based on a complex set of bacterial species (Holt and Ebersole, 2005) and that human disease and inflammation related disorders are linked to bacterial community imbalance or dysbiosis of the oral cavity (Schippa and Conte, 2014).
Despite the suggested link between compromised oral health and Alzheimer's disease and the complexity and diversity of the oral microbiome (Wade, 2013), few studies have profiled the oral microbiome of individuals with Alzheimer's disease, and no previous study has considered the relationship between the oral microbiome and inflammation as a contributor to early cognitive decline related to Alzheimer's Disease. This pilot study focuses on a precursor to Alzheimer's disease, mild cognitive impairment (MCI). MCI refers to a transitional period between normal aging and Alzheimer's disease in which individuals demonstrate subtle signs of cognitive decline, not yet meeting the criteria for Alzheimer's dementia, but still greater in extent than what would be expected for their age (Petersen et al., 2001). Individuals with MCI progress to clinically probable Alzheimer's disease at an accelerated rate compared with healthy age-matched individuals (Petersen et al., 2001), and those with MCI that is linked to underlying Alzheimer's pathology have a near 100% likelihood of progressing to mild dementia within five years (Hansson et al., 2006). Currently there is no cure for MCI, however, given the potential for progression, the condition is a suitable target for prevention and/or mitigation of Alzheimer's disease.
Using 16S rRNA sequencing, this pilot study characterized, for the first time, the oral microbiome of individuals with MCI providing fundamental knowledge for future explorations of the role of the oral microbiome in the inflammatory mechanisms underlying early stages of Alzheimer's disease. The hypothesis of the project was that the oral microbiome would be associated with Alzheimer's disease and inflammation, with our aims being to characterize and compare the composition and diversity of the oral microbiome among individuals with MCI and their aged-matched controls, and to explore associations between the composition of the oral microbiome, central nervous system (CNS), systemic inflammation, and presence of MCI.
Section snippets
Design
Institutional review board approval was obtained. A total of 92 older adults were enrolled for this pilot study, however to control for significant differences in race between our case and control groups as well as DNA library size (see 2.3.7), data from 68 participants were included for analysis.
Setting and sample
Participants were recruited from a large, ongoing longitudinal observational study of 500 participants in the Emory Goizueta Alzheimer's Disease Research Center (ADRC) Clinical Core and ADRC-associated
Results
The mean age of all the participants was 72.0 ± 5.8 years. Other sociodemographic, oral health behavioral, and oral symptom characteristics can be found in Table 1. Of the 68 participants included, 34 met the criteria for MCI due to biomarker-proven Alzheimer's disease. All had either single- or multi-domain amnestic MCI. There were no significant differences between groups on age, sex, or other demographic, oral hygiene behavioral, or symptomatic characteristics listed in Table 1.
Discussion
Using 16S rRNA sequencing, this pilot study characterized the oral microbiome of individuals with normal cognition and MCI and hypothesized that the oral microbiome would be associated with Alzheimer's disease and markers of systemic and neuroinflammation.
The top five phyla represented in the oral microbiome of both groups were Firmicutes, Proteobacteria, Bacteroidetes, Fusobacteria, and Actinobacteria. This is consistent with previous studies that used 16S rRNA sequencing which reported that
CRediT authorship contribution statement
Irene Yang: Conceptualization; methodology; data curation; formal analysis; writing – original draft; visualization; supervision; funding acquisition.
Robert Adam Arthur: Formal analysis; data curation; writing – original draft; visualization.
Liping Zhao: Formal analysis; writing – original draft.
Jasmine Clark: Writing – original draft; writing – review and editing.
Yijuan Hu: Formal analysis; writing – review and editing.
Elizabeth Corwin: Conceptualization; writing – review and editing; funding
Funding sources
NIH – NIA, Emory Alzheimer's Disease Research Center, P50 AG025688, Robert W. Woodruff Health Science Center Fund Synergy Award (2016).
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