Microbiota and cognitive impairment: Current challenges and future perspectives

The microbiota-gut-brain-axis is a hot topic in central nervous system disorders and age-related cognitive impairment. ¹ As such, the article by Wang et al. ² that examines the complex relationship between gut microbiota and cognition is both timely and relevant. In this study, 205 community-dwelling older Chinese adults were included, 74 and 131 participants with or without cognitive impairment (CI), respectively. Wang and al. report a significantly reduced abundance of certain beneficial gut microbiota, and a lower α-diversity in the CI group, compared to controls. These interesting results raise questions that need to be addressed to better understand how gut microbiota may alter the gut-brain axis and cause cognitive disorders in older patients.

First, in the article by Wang and al., the definition of cognitive impairment was based only on Mini-Mental State Examination (MMSE) score results. ² Grouping the population on the basis of MMSE score was likely used because MMSE test is consensual, easy to administer, highly acceptable to health professionals, and also because a comprehensive clinical examination is sometimes difficult to organize. Moreover, previous studies have chosen this methodology, as discussed by the authors. However, this choice is questionable. Indeed, MMSE test is a screening tool of cognitive functioning and not a test for determining the presence of cognitive impairment. Moreover, there is little evidence that MMSE, as a stand-alone administration test, can identify patients with dementia or with mild cognitive impairment who could develop dementia. ³ Indeed, clinically, a neurocognitive disorder is defined by a decline from baseline and a perturbation of daily life activities independently.^4,5 Thus, even if it is comprehensible from a pragmatic point of view, furthers studies should be conducted, with a better characterization of the etiology of the cognitive disorders within the CI group.

One conclusion of this article could be that alterations in gut microbiota could be considered as a possible biomarker of cognitive vulnerability, although it is not clear what could cause the suspected alterations. However, neurodegenerative diseases are characterized, in vivo, by the appearance of disease-specific neuropathology over many years, in asymptomatic patients. These pathophysiologic mechanisms are associated with the detection of several biomarkers associated with alterations in the processing and clearance of protein fragments, such as tau, amyloid-β (Aβ) and alpha-synuclein proteins. ⁶ At this point, it is necessary to keep in mind that there is a difference between a syndrome (clinically identified impairment), biology (etiology), and biomarkers. ⁵ Indeed, some patients can even share a common phenotype but caused by different neuropathology, or by co-pathologies. ⁷ Thus, defining diseases biologically, rather than by syndromic presentation, is becoming a unifying concept to all neurodegenerative diseases. ⁵ Although there is evidence that gut microbiota could play an indirect role in neurocognitive diseases, its direct impact on neuropathology is not clear in humans. Particularly, the role of microbiota at different stages of disease evolution is not well defined, nor is its association with inflammatory/immune processes, vascular brain pathophysiology and tau/α-synuclein/Aβ pathology.^8–10 To note, a recent study conducted by Verhaar et al. which included 170 patients from the Amsterdam Dementia Cohort (33 with Alzheimer's disease, 21 patient with mild impairment, and 116 with subjective cognitive impairment), highlighted that gut microbiota composition was associated with neurodegenerative disease-associated entities including Aβ and phospho-tau status. ¹⁰ While improving early preventive trials to diagnose presymptomatic neurocognitive disease is crucial, only biomarkers that have been proven to be accurate and that reflect neuropathological abnormalities should be used. ⁵ Further studies are required to confirm if the microbiota could be considered as a relevant biomarker for neurocognitive disease.

By combining different modes of analysis Wang al. have showed that significant lifestyle factors (consumption of grains, beans, fruits, eggs, exercise, and sleep duration) were associated with the relative abundance of microbiota biomarkers. ² Although the cross-sectional design involves potential confounding factors, this result is not surprising and still interesting. Indeed, the causality between lifestyle factors, microbiota, and their beneficial impact on cognitive function is known, with some studies suggesting that the presence of some clusters of bacteria are associated with healthy ageing or presence of disease, including cognitive disorders. ¹¹ Among them, particular attention has been given to bacteria producing short-chain fatty acid (SCFA), and particularly butyrate, derived from carbohydrate fermentation, which has been demonstrated to have a systemic and neural anti-inflammatory activity, and promote the synthesis of several neurotransmitters and hormones. ¹¹ Moreover, it has been shown that alpha synuclein and tau protein expression and phosphorylation could be regulated by SCFA in the gut, suggesting a potential direct mechanism linking microbiota metabolites and neuropathology.^12,13 The Mediterranean (MED) diet, which emphasizes increased intake of non-refined grains, fruits and vegetables, legumes, nuts, fish, and lower intake of red meat and processed foods, is associated with improved cognition, reduced dementia risk and leads to increased SCFAs in the gut and bloodstream. ¹⁴ The NU-AGE study has reported on measures of both gut microbiota and cognition, and a sample of 1144 older adults (aged 65–79 years) were randomized to either a MED diet intervention or control diet for 12 months.^15,16 Participants with high MED diet adherence showed significant improvements in global cognition and episodic memory. ¹⁵ In addition, among the 612 non-frail or pre-frail subject from whom microbiome data were collected, the subjects with the greater MED diet adherence had an increased in the microbiome diversity, increased SCFAs detection, and decreased inflammation. ¹⁶ This suggests that greater adherence to a MED diet could modulate the microbiome, and that the response of the microbiome could be associated with an attenuation or reduction in the risk of frailty or cognitive impairment. ¹⁶

Finally, many unknowns and challenges remain in understanding the potential causal relationship between the microbiome and neurodegenerative diseases. Further prospective studies involving patients characterized both clinically and biologically are necessary to determine whether gut microbiota can serve as a relevant biomarker for cognitive diseases, considering key factors of the microbiota-gut-brain axis, such as immune, inflammatory, and neuroendocrine pathways.