From Mediterranean diets to probiotics, scientists reveal how reshaping the gut microbiome could help protect brain function, while highlighting why timing may be critical for slowing cognitive decline.
Study: The association between gut microbiota and cognitive decline: A systematic review of the literature. Image credit: Toa55/Shutterstock.com
The gut-brain axis is gaining importance as a modulator of brain functional health. A recent paper in Nutrition Research synthesized evidence from the literature to show that multiple approaches to manipulating the gut microbiome share common biological pathways to improve cognitive performance in adults aged 45 years or older with cognitive impairment or at risk of dementia.
Aging gut microbiota shifts linked to dementia risk
Multiple neurodegenerative disorders like Alzheimer’s disease (AD) are mediated in part by alterations in the gut-brain axis caused by aging-related shifts in the gut microbiota. Dementia is progressive and irreversible, causing neurological decline and a reduced life expectancy.
This is in contrast to the early stages of cognitive impairment, or mild cognitive impairment (MCI), when functional deficits can be detected but typically do not affect daily functioning.
Gut-brain mechanisms underlying cognitive decline
The gut-brain axis is a bidirectional communication system between the central nervous system and the gut. It involves signaling via nerves, hormones, and immunological mediators. Recent research has established its important role in regulating neurodevelopment, mood, and cognition.
However, age- and diet-related changes in the gut microbiota may induce dysbiosis, which is thought to contribute to the onset of neurodegeneration.
With gut dysbiosis, the gut epithelial barrier is compromised. This allows bacteria and microbial-associated molecular patterns to enter the bloodstream. The resulting systemic endotoxemia may trigger chronic low-grade inflammation. Gut dysbiosis also causes immune cell abnormalities, resulting in a systemic pro-inflammatory state.
Systemic inflammation may weaken the blood-brain barrier (BBB), exposing the brain to pro-inflammatory triggers and mediators. The resulting neuroinflammation is associated with the accumulation of abnormal proteins, such as amyloid-β and tau, the hallmark of AD. Neuronal synapses are damaged, and function is impaired. The eventual outcome is cognitive decline, whether as a part of aging or of AD.
The microbiome, immune system, and brain are engaged in a continuous dialogue, where perturbations in one component can reverberate throughout the system, creating a vicious cycle that promotes cognitive decline.
Microbiome research evolves from observation to intervention
The researchers outlined the progression of such studies. The earliest, purely descriptive, studies of gut microbial responses were followed by detailed microbiome characterizations driven by advances in DNA and RNA sequencing and metabolomics. This was followed by the current interventional studies with a stronger mechanistic focus.
Integrating evidence on dysbiosis and cognition
The authors aimed to pull together evidence from studies covering various microbiota-targeting interventions in isolation. They reviewed the literature on cognitive changes in adults aged 45 years or older with cognitive impairment or at risk of dementia who participated in experimental manipulations of the gut microbiota.
The interventions included probiotics, prebiotics, methyl donor nutrient supplementation, omega-3 fatty acid intake, synbiotics, fecal microbiota transplants (FMT), and diets like the Mediterranean or keto diets. The patients were evaluated for inflammatory and metabolic changes, as well as alterations in fecal microbiota.
Microbiota changes linked to cognitive improvement
The review included 15 studies covering a range of demographic characteristics. The study sample ranged from 5 to over 1,200 participants. Overall, there were 4,275 participants.
Only two studies, both RCTs, were scored at 100 % based on the quality scoring criteria, with one additional quasi-experimental study also achieving a 100 % score. Dietary interventions are almost impossible to administer in a blinded manner, but this introduces bias. Even so, most studies maintained quality scores of 76.9 % or higher.
The findings show improved memory, executive function, and global cognitive function associated with multiple dietary approaches to modulating the gut microbiota. The improvement was most marked in individuals with MCI.
The effects of gut microbiota modulation were limited in individuals with advanced Alzheimer’s disease.
Dietary interventions and the gut microbiota
The benefits of these approaches for cognition were correlated with increased gut microbial diversity, leading to increased short-chain fatty acid (SCFA) production. Higher SCFA levels are associated with lower levels of neuroinflammatory markers.
Dietary interventions such as the Mediterranean and keto diets increase the abundance of SCFA-producing bacteria in the gut. SCFAs are thought to be associated with reduced oxidative stress and improved mitochondrial function. This may promote the clearance or reduced accumulation of AD-associated abnormal proteins, contributing to improved cognitive outcomes.
Bile acids from the liver are modified by beneficial gut bacteria. Along with SCFAs, they help regulate lipid metabolism in the brain and throughout the body. This is essential for neuronal health and function.
The keto diet reportedly improved cognitive outcomes, associated with an increased relative abundance of species such as Akkermansia muciniphila, which strengthen the gut barrier and promote anti-inflammatory effects. The Mediterranean diet also promotes anti-inflammatory and antioxidant activity through monounsaturated fatty acids.
Probiotics directly introduce bacterial strains that can produce inhibitory neurotransmitters, such as GABA. This may help prevent or mitigate damage from excessive excitatory neurotransmitters, which are linked to MCI and AD. Probiotics may also enhance colonization by microbes that produce neuroprotective nutrients, facilitate nutrient transfer between the host and the microbiota, and reduce inflammation.
Fecal microbiota transplantation (FMT) produced rapid and stable shifts in the gut microbiota and, in a small preliminary study, was associated with improvements in cognitive scores, alongside greater bacterial diversity and altered expression of genes involved in lipid metabolism. However, these findings are based on a very small, uncontrolled study, and standardized trial protocols and long-term data are still needed to confirm reproducibility and clinical relevance.
The APOE ε4 allele is associated with a higher risk of AD. Here, the authors suggest, based on recent evidence, that this is partly mediated by gut dysbiosis resulting from APOE4-linked disruption of lipid metabolism in the central nervous system. This promotes neuroinflammation and BBB permeability.
At the gut level, these changes in lipid pathways and bile acid modification are reflected in gut dysbiosis, which is perpetuated by associated systemic inflammation and weakened mucosal immunity. Dietary approaches to microbiome modulation could thus reduce the risk in specific ways, depending on the genetic constitution. However, this remains a hypothesis and requires further validation in large, well-designed clinical studies.
Study limitations
The authors point out several limitations of this review. Meta-analysis was not possible due to substantial heterogeneity; therefore, a narrative review was conducted. Only publications in English were included in the search, introducing language bias, and variations in study characteristics hampered direct comparison of the results.
The results should be cautiously interpreted for these reasons. Future studies should be larger and use robust methods to allow definitive analysis of the impact of nutritional interventions on cognitive function via the gut microbiome.
Larger trials are needed to validate microbiome interventions
This study integrates multiple approaches to gut microbiota modulation to assess the results and links them to underlying pathways connecting systemic and neuronal metabolism, immunoregulation, and inflammation. It also highlights the importance of early intervention, with limited success in attending such approaches in advanced AD compared to MCI or early AD. Finally, it suggests mechanistic pathways associated with specific aspects of cognition.
These findings suggest that these distinct diet-based approaches hold promise as non-pharmacological tools to enhance cognitive health, in conjunction with medication and lifestyle interventions. Despite their biological plausibility, further large-scale RCTs with longitudinal follow-up are necessary to validate them as therapeutic targets for dementia prevention.
Download your PDF copy by clicking here.
Vaginal microbiome may play key role in pregnancy health and preterm birth risk, researchers say