Alzheimer’s disease (AD) is a devastating neurodegenerative disease causing neuropathological changes and a severe decline in cognitive function.
The most common cause of dementia, AD has no known cure. Although some medications may delay the loss of cognition and memory, definitive interventions are elusive. Recent research has focused on the role of the human microbiome in regulating multiple neurochemical pathways through the gut-brain axis and on looking for new therapeutic approaches for microbiota modulation.
Alzheimer’s disease, in brief
It is estimated that more than 50 million people worldwide live with AD. Those numbers are expected to grow dramatically —152 million by 2050—as the elderly population soars globally. The most important risk factor is age, with the vast majority of people with Alzheimer’s dementia being 65 or older.
AD is a slowly progressive brain disease that begins many years before symptoms emerge. Difficulty remembering recent conversations, names, or events is often an early symptom. Impaired communication, disorientation, confusion, poor judgment, behavioral changes, and, ultimately, difficulty speaking, swallowing, and walking follows.
The hallmark pathologies of AD are the accumulation of the protein beta-amyloid (plaques) outside neurons and twisted strands of the protein tau (tangles) inside neurons in the brain. These changes are accompanied by the death of neurons and damage to brain tissue.
Alzheimer’s disease and the microbiome
The gut microbiota has a pivotal role in regulating multiple neuro-chemical pathways via the gut-brain axis. Gut-brain communication is based on signals generated in the gut microbiota that send and receive information from distant organs. This axis of information includes neural pathways through the autonomic nervous system, endocrine transmission through hormones, and immunological propagation through chemokines and cytokines.
Modulation of this bidirectional communication has been reported to affect the pathogenesis of neurodegenerative diseases, such as AD.
Recent research shows that aging, unhealthy lifestyle behaviors, medications, birth delivery method, and genetics can negatively alter gut microbiota composition and diversity, contributing to a dysbiosis linked to the onset and progression of neurodegenerative disorders, including AD.
Aging itself —the biggest risk factor in AD— alters the gut microbiota. Changes may favor increased intestinal permeability, impaired blood-brain barrier function, and the development of a neuroinflammatory cascade. Researchers found that older adults showed an increased abundance of the pro-inflammatory bacteria Escherichia/Shigella, whereas individuals with evidence of amyloid deposition on PET imaging exhibited decreased abundance of the anti-inflammatory bacteria Eubacterium rectale.
Studies show alteration in gut microbiota in AD. When compared to healthy controls, research on rodent AD models and AD patients has shown that the gut microbiota of AD patients differs from controls. For example, an analysis of the microbiome between healthy subjects and AD patients among 108 nursing home elders showed a lower prevalence of bacteria synthesizing the anti-inflammatory and neuroprotective SCFA butyrate and higher levels of pro-inflammatory taxa. And in another study, subjects with normal vs. impaired cognition show no notable difference in microbiome diversity but several unique microbial signatures were detected in subjects with mild cognitive impairment.
Mechanisms underlying neurodegeneration
More specifically, dysbiosis may trigger multiple mechanisms involved in the neurodegeneration of AD through:
- Changes to synthesis and/or function of neurotransmitters including acetylcholine, gamma-aminobutyric acid, serotonin, brain-derived neurotrophic factor, and glutamate are possible. For example, bacteria-produced SCFAs can stimulate endocrine cells of the gastrointestinal tract to synthesize neuroactive compounds.
- Neuroinflammation is caused by a compromised blood-brain barrier (BBB) that is permeable to neurotoxins. Under healthy conditions, microbiota and metabolites such as short-chain fatty acids bolster BBB integrity but in dysbiosis with a weakened intestinal barrier, the gut can leak inflammatory factors such as lipopolysaccharide and amyloids. These may accumulate in the brain and contribute to AD neuroinflammation and subsequent apoptosis and accumulation of β-amyloid protein.
- Oxidative stress leads to increased inflammation through mitochondrial destruction and activation of astrocytes (cells in the brain and spinal cord) by reactive oxygen species. In this way, oxidative stress contributes not only to the onset of AD but also to the progression and severity of the disease.
- Hyperactivation of the hypothalamic-pituitary-adrenal axis (HPA) is caused by stress. The interaction of the intestinal microbiota is an important factor in the stress response of the HPA axis.
- Changes in gut peptide hormones such as ghrelin and leptin have a role in AD as they regulate energy homeostasis and food intake and modulate nervous functions like learning and memory.
Modulation of gut microbiota in Alzheimer’s disease
Preclinical and human studies on microbiota modulation showed anti-inflammatory and antioxidant effects, upregulation of plasma concentration of neuroprotective hormones, restoration of impaired proteolytic pathways, amelioration of energy homeostasis with consequent decrease of AD molecular hallmarks, and improvement of behavioral and cognitive performances. A list of studies is available here.
Regarding probiotics, formulations are usually made of Lactobacillus and Bifidobacterium species, since members of both groups have been used extensively in promoting human health.
In addition, fecal microbiota transplantation (FMT) which involves the transfer of stool from a healthy donor into the gastrointestinal tract of a patient is a valid treatment for recurrent Clostridioides difficile) infections and other intestinal conditions and may be promising in AD.
Several studies reported cognitive improvements with probiotic administration in patients.
- In one study, chronic supplementation with a strain of Bifidobacterium breve improved cognitive functions in elderly people with impaired memory.
- In another study, chronic supplementation with milk enriched with L. acidophilus, L. casei, B. bifidum, and L. fermentum improved learning and memory in AD patients.
- Another study reported that AD patients supplemented with a multispecies probiotic formulation (various Lactobacillus and Bifidobacterium strains) showed changed gut bacteria composition notably by increased concentrations of anti-inflammatory Faecalibacterium prausnitzii.
No data on FMT in human AD patients are available but results from ongoing clinical trials are expected in the near future. However, in a case report, a 90-year-old AD patient who received FMT for severe C. difficile showed cognitive function improvement afterward.
The possibility to modulate the composition of gut microbiota using probiotics represents a promising and sustainable approach in AD.
However, further research on the appropriate strains of probiotics relative to disease stage as well as guidelines is necessary to enhance the effectiveness of gut microbiota modulation.
*Image by Gerd Altmann from Pixabay
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