Recurring Gastrointestinal Infections Increase the Risk of Dementia

INTRODUCTION

The microbiome of the human gastrointestinal tract has attracted great attention because recent discoveries have shown that it affects human development and health in multiple and previously unimaginable ways, playing a role, for instance, in obesity, cancer, autoimmune diseases, and autism spectrum disorders [1–4]. The influence of the gut microbiome on the development, aging, and degeneration of the central nervous system (CNS), the microbiota-gut-brain axis, is still only poorly understood and remains to be fully explored [1, 5]. Recently, we showed that dysbiosis of the gastrointestinal tract in form of gastrointestinal infections (GIIs) increases the subsequent risk of Parkinson’s disease (PD), the second most common neurodegenerative disorder after Alzheimer’s disease (AD) [6]. Dementia patients with AD have an altered gut microbiome with a decreased microbial diversity, which is replicated in animal models of AD [7–10]. Moreover, antibiotic treatment-induced changes in microbiota composition as well as microbial deficiency in germ-free mice have been associated with reduced neuropathology in AD [9, 11–13]. The major pathogens causing GIIs are viruses, bacteria, and protozoa, which often remain unidentified. GIIs can cause gastroenteritis and colitis, also known as infectious diarrhea, which is an acute inflammatory condition of the GI tract with symptoms of diarrhea, vomiting, and abdominal pain [14]. Symptoms typically last less than two weeks and most cases resolve within 24–48 h after contracting the infectious agent. GIIs cause significant health problems and are one of the leading causes for death worldwide, especially among children of the developing world [15]. Many acute and chronic consequences have been ascribed to GIIs, including those affecting the immune, musculoskeletal, and the nervous system [16, 17]. Intrigued by our earlier findings, we wondered if GIIs could also have an effect on more prevalent neurodegenerative conditions such as dementia. With an extensive impact on individuals, families, and the healthcare system, the etiology of dementia is of increasing concern. According to a recent estimate from the World Alzheimer Report 2019 the global number of people with dementia is over 50 million and is estimated to increase to 152 million by 2050 [18]. Dementia is defined as deterioration in memory, thinking, and behavior affecting a patient’s daily functioning and independent living. The most common types of dementia are neurodegenerative and include AD, vascular dementia, frontotemporal dementia, Lewy body dementia, and PD with dementia, which are all collectively irreversible and usually progressive. Among the dementias, AD is the most common and contributes to 60–80%of all cases [19]. Vascular dementia, the second most common type of dementia causing up to 15%of all cases, is caused by vascular injury or disease within the brain and may predispose some individuals to acquire AD, or may exacerbate the clinical course of AD, and thus frequently coexists with AD [20, 21]. Clinical, epidemiological, genetic, and neuropathological studies show that the causes for dementia are complex. The strongest risk factor for developing dementia is advancing age [22]. For AD, the major genetic risk factor is presence of the ɛ4 allele of apolipoprotein E (APOE) [23]. Other risk factors contributing to cognitive decline and dementia are family history, depression, physical frailty, low educational attainment, poor social relationships, smoking, cardiovascular disease, hypercholesterolemia, diabetes mellitus, hypertension, cerebrovascular disease, and intracranial injury [20]. To our best knowledge there is no population study which has investigated the impact of GIIs, including gastroenteritis and colitis, on dementia. In the present nested case-control study using population-based data, we investigated the risk of dementia in patients who previously suffered from GIIs compared to unexposed counterparts.

METHODS

Selection of cases and controls

We used data of 202,806 individuals aged 50 and older who had no diagnosis of dementia, no diagnosis of PD (ICD-10: G20), and no diagnosis of stroke or complications of stroke (ICD-10: I63-I64, I69.3, I69.4) in their medical history during the years 2004 and 2005. We excluded persons with previous diagnoses of PD or stroke because they are more likely to develop a subsequent dementia due to those pre-existing illnesses, which could bias our analysis. From among the 202,806 individuals in our analysis sample 23,354 were diagnosed with dementia between the beginning of 2006 and the end of 2014 (Fig. 1).

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Fig. 1

Inclusion of patients and controls in the analyses.

We defined dementia as having at least one of the following ICD-10 codes: dementia in AD (F00); vascular dementia (F01); dementia in other diseases classified elsewhere (F02); unspecified dementia (F03); delirium superimposed on dementia (F05.1); AD (G30); and circumscribed brain atrophy (G31.0). We applied an established two-stage validation strategy to overcome the problem of false-positive diagnoses [24, 25]. In the first stage, “verified” outpatient diagnoses as well as inpatient discharge or secondary diagnoses were identified. In the second stage, the diagnoses were confirmed by a simultaneous in- and outpatient diagnosis, by two diagnoses from two different types of physicians within the same quarter, or by co-occurrence over the study period plus the year 2015, which was only used for validation. A diagnosis was also considered valid if an individual died within the same quarter during which dementia was diagnosed for the first time. All persons were censored at the time of death, attrition, or at the end of 2014. The date of the first diagnosis is subsequently referred to as the diagnosis date. Each dementia case was matched to one control by age (in ten-year age groups), gender, and time since observation using incidence density sampling (Stata command sttocc). For the controls, the index date was set to the date of dementia diagnosis of the matched cases.

RESULTS

DISCUSSION

Our findings reveal increased ORs for dementia among individuals with GIIs. The risk of dementia was still significantly increased when adjusted for antibiotics, comorbidities, and institutionalization status. The results of a sensitivity analysis suggest that the risk of dementia after the last documented GII diagnosis remains increased up to two quarters prior to the diagnosis/index date. Our data argue that GIIs increase the subsequent risk of dementia and suggest that gut microbiota can have a strong influence on higher cognitive functions.

How exactly dysbiosis of the gut microbiome re-sults in dementia remains to be clarified. Acute as well chronic GIIs can alter the composition of gut microbiota either directly or through the use of medications such as antibiotics [26]. Sequence analyses comparing the gut microbiome of cognitively impaired elderly and controls have identified significant differences between the two groups that associate brain amyloidosis causing dementia with proinflammatory gut bacterial taxa and peripheral inflammation markers [8, 27]. Remarkably, gut microbiota directly control the maturation and inflammatory capabilities of microglia in the CNS through the production of small chain fatty acids in the gastrointestinal tract, and the lack of a complex gut microbiota can affect microglia innate immune function [28]. Bacterial and viral neuroinvasion of the CNS could be initiated and further exacerbated by inflammation of the gastrointestinal tract during GIIs, which is known to increase the leakiness of the gastrointestinal tract for gut microbiota, microbial components and products, allowing them to be transported to the brain via blood where they can contribute to the impairment of the blood-brain barrier and neuroinflammation [29, 30]. Moreover, microbial products that have escaped the gastrointestinal tract can bind to and activate peripheral immune cells, inducing the release of proinflammatory cytokines as observed, for example, for lipopolysaccharides of Gram-negative bacteria after binding to Toll-like receptor 4 on macrophages and B cells [31]. This affects not only systemic but also CNS inflammation and injury, foremost through the activation of microglia and by increasing the permeability of the blood-brain barrier, which allows the entry of immune cells and inflammatory molecules into the brain [32].

Due to the structure of our data, we could not assess the role of recurring GIIs on the risk of dementia dependent on patients’ APOE genotypes, which influences susceptibility to AD [23]. APOE4 is not only the greatest genetic risk factor for AD but also leads to blood-brain barrier dysfunction predicting cognitive decline, which would allow peripheral penetration of the brain by microbial components and pathogens, and proinflammatory cytokines [33]. Moreover, several studies suggest that APOE4 is tied to an increased susceptibility to several pathogens, including herpes simplex virus 1 (HSV-1), human immunodeficiency virus (HIV), or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [34–37]. Lastly, the APOE genotype influences the gut microbiome structure and function, by which it could also affect the risk of AD [38, 39].

Interestingly, our data show that increasing numbers of preceding quarters with a GII diagnosis cumulatively augment the risk for dementia, supporting the association in a dose-response manner, even when adjusted for one or more prescriptions of antibiotics (Table 2, model 3). However, when adjusted for various comorbidities, especially urinary tract infections and pneumonia, increasing numbers of preceding quarters with a GII diagnosis still cumulatively augmented the risk for dementia among patients without a prescription for antibiotics but were harmless for those receiving antibiotics (Table 2, model 4), which warrants further studies.

Despite a careful study plan, this study has limitations. Because our data only contain individuals aged 50 years and older, we do not have information on the exposure to GIIs or antibiotics prior to the age of 50 and prior to 2004. Also, the data are based on health records, meaning they include only the medical histories of those individuals who sought medical attention. Especially, in the case of very short-term and acute infections of the gastrointestinal tract, people often abstain from seeking medical help which results in an underestimation of very mild cases. Furthermore, due to the data structure we cannot assess a potential interaction effect for the severity of GIIs. On that basis, severe GIIs may be more likely to predict dementia than mild GIIs. Detailed clinical data, such as results of stool or blood samples, biomarkers, or results of neuropsychological tests, are missing so that the validity of diagnoses could not be verified by clinical data. Moreover, there were factors known to be associated with dementia that are not available in health claims data, such as family history, educational attainment, the quantity and quality of social relationships, physical activity, and tobacco or alcohol consumption. Further, the AOK’s proportions of people with lower income and low education is higher than in private or other public health insurers in Germany, which may lead to higher morbidity rates. We tried to capture this bias by including several comorbidities and nursing home status, which are in turn associated with a person’s socio-economic status. Another limitation is that the actual onset of dementia is unknown. However, we take this issue into account by excluding individuals with dementia and possible prodromes of dementia, such as PD, stroke, and complications of stroke during the years 2004 and 2005, and we find that GIIs remain significantly associated with an elevated risk of dementia. We cannot completely exclude the possibility that our findings are coincidental and that both GIIs and dementia are correlated with a third, unquantified factor. Also, prodromal dementia patients may have a higher risk of developing GIIs. However, the correlation between GIIs and dementia risk disappears in patients with a prescription for AB, suggesting a causal relationship.

Our analyses rely on a large sample size with 23,354 dementia cases and 23,354 matched controls. Health claims data are only marginally biased due to attrition for reasons other than death as the data are complete over time and the rate of change between public health insurance funds is low, especially at the oldest ages. The medical diagnoses were not prone to recall bias. Selection bias by health care providers or self-selection into the study can be ruled out. Moreover, all insured individuals, regardless of their functional and cognitive status, were included in the study.

In conclusion, this is the first population-based nested case-control study that is given on a national basis showing an increased risk of dementia after GIIs. The risk of dementia was increased with at least a single preceding GII diagnosis and further increased with the cumulative number of preceding quarters with a GII diagnosis among individuals without a prescription for antibiotics. The higher risk indicates a plausible biological association between GIIs and dementia. Our study has exploratory validity and is aimed to guide future research towards the investigation of underlying gastrointestinal pathogens and mechanisms by which GIIs could cause or contribute to dementia. Lastly, our findings should be considered by patients, clinicians, and health policy makers when assessing the relative risks and benefits of delivering clinical follow-up and monitoring patients with frequent gastrointestinal infections.