In a recent study, a team from the Neurobiota Research Center in Korea has discovered that reducing gut dysbiosis partially alleviates the cognitive impairment associated with Alzheimer’s disease. This may seem puzzling, as the gut and the brain are separate and relatively distant organs, but this research makes sense in the context of chronic inflammation.
Under normal circumstances, inflammation is a short-term measure in response to infection: immune cells are directed towards the inflamed area and handle the infection, and then the inflammation dies down. However, chronic inflammation causes harm to our organs; it is the main form of altered intercellular communication, which is one of the hallmarks of aging. The protein complex NF-kB, the master regulator of inflammation, is the main culprit of inflammaging, and it is specifically discussed in this paper.
From the gut to the brain
The gut and brain are connected through the microbiota-gut-brain (MGB) axis; a panoply of signaling chemicals, metabolites, and other biochemicals are brought from the gut and into the brain. Dysbiosis, therefore, sends inflammatory signals as part of this payload, and gut dysbiosis accompanies both aging and Alzheimer’s disease.
The researchers studied 5XFAD mice, a particular strain designed to mimic Alzheimer’s disease in humans, as well as normal, aged mice. To test their theory, they administered NK46, a strain of Bifidobacterium longum that was specifically chosen for its anti-inflammatory properties, and they tested treated mice, Alzheimer’s mice, and a control group of normal mice. The experiment was a success: the treated mice had less inflammation and performed better on cognitive tests than their untreated counterparts.
To understand the role of commensal gut bacteria on the progression of cognitive decline in Alzheimer’s disease via the microbiota-gut-brain axis, we isolated anti-inflammatory Bifidobacterium longum (NK46) from human gut microbiota, which potently inhibited gut microbiota endotoxin production and suppressed NF-κB activation in lipopolysaccharide (LPS)-stimulated BV-2 cells, and examined whether NK46 could simultaneously alleviate gut dysbiosis and cognitive decline in male 5xFAD-transgenic (5XFAD-Tg, 6 months-old) and aged (18 months-old) mice. Oral administration of NK46 (1 × 109 CFU/mouse/day for 1 and 2 months in aged and Tg mice, respectively) shifted gut microbiota composition, particularly Proteobacteria, reduced fecal and blood LPS levels, suppressed NF-κB activation and TNF-α expression, and increased tight junction protein expression in the colon of 5XFAD-Tg and aged mice. NK46 treatment also alleviated cognitive decline in 5XFAD-Tg and aged mice. Furthermore, NK46 treatment suppressed amyloid-β, β/γ-secretases, and caspase-3 expression and amyloid-β accumulation in the hippocampus of 5XFAD-Tg mice. NK46 treatment also reduced Iba1+, LPS+/CD11b+, and caspase-3+/NeuN+ cell populations and suppressed NF-κB activation in the hippocampus of 5XFAD-Tg and aged mice, while BDNF expression was increased. These findings suggest that the suppression of gut dysbiosis and LPS production by NK46 can mitigate cognitive decline through the regulation of microbiota LPS-mediated NF-κB activation.
This mouse study did not show that gut dysbiosis is a cause of Alzheimer’s disease, nor was it shown that altering bacterial populations can prevent this disease. It seems more likely that the chronic inflammatory signaling associated with gut dysbiosis causes further cognitive impairment, which is something that anti-inflammatory gut bacteria can affect.
However, as the researchers mentioned, this does suggest a link between gut dysbiosis and neuropsychiatric disorders, as this inflammation is a potential cause of neurological damage even in the absence of Alzheimer’s disease. While further research is necessary, this study adds yet another reason why reducing chronic inflammation, particularly in the gut, is a good idea.