What is already known on this topic
Cognitive impairment, a condition characterized by problems in remembering, learning new things, and concentrating, affects up to 19% of people older than 65 years old worldwide. Cognitive impairment is prevalent in aging-related disorders such as Alzheimer’s and Parkinson’s disease, but it can be also associated with other conditions, including immunological, neuropsychiatric, and sleep disorders. Recently, the gut microbiota has emerged as a key mediator of environmental risk factors for cognitive impairment.

What this research adds
Researchers found that a ketogenic diet worsens learning and memory when combined with hypoxia, or low oxygen conditions, in mice. The microbiota of these rodents had high levels of the bacterium Bilophila wadsworthia, and transplanting the animals’ gut bacteria into germ-free mice made them perform poorly in cognitive tests. In their guts, rodents exposed to ketogenic diet and hypoxia had elevated levels of immune cells and inflammatory molecules that are involved in the response against viral infections and some bacterial pathogens. Poor cognitive behavior in mice colonized with B. wadsworthia or exposed to ketogenic diet and hypoxia was associated with altered gene expression and weaker neuron-to-neuron connections in the hippocampus, a brain region involved in learning and memory.

Conclusions
The findings identify specific gut bacteria that could contribute to cognitive impairment by triggering inflammation and neuronal deficits in the hippocampus.

Cognitive impairment, a condition characterized by problems in remembering, learning new things, and concentrating, affects up to 19% of people older than 65 years old worldwide. A study in mice now shows that specific gut bacteria can worsen the cognitive impairment induced by two environmental risk factors for the condition.

The findings, published in Cell Host & Microbe, suggest that the microbiota could contribute to cognitive impairment by triggering inflammation and neuronal deficits in the hippocampus, a brain region involved in learning and memory.

Cognitive impairment is prevalent in aging-related disorders such as Alzheimer’s and Parkinson’s disease, but it can be also associated with other conditions, including immunological, neuropsychiatric, and sleep disorders. Recently, the gut microbiota has emerged as a key mediator of environmental risk factors for cognitive impairment. One such risk factor is hypoxia, or low oxygen conditions, associated with high altitude exposure, sleep apnea, Alzheimer’s disease and other conditions. Another risk factor for cognitive impairment appears to be the high-fat, low-carbohydrate ketogenic diet, which in medicine is used to treat hard-to-control epilepsy.

Working in mice, researchers led by Christine Olson and Elaine Hsiao at the University of California, Los Angeles, assessed the effects of hypoxia and the ketogenic diet on gut microbiota and cognitive behavior. 

Cognitive deficits

First, the researchers induced cognitive impairment in mice by exposing them to acute intermittent hypoxia. Then, they tested the effects of a ketogenic or a control diet on the animals’ learning and memory skills. The ketogenic diet alone had no impact on rodents’ performance in cognitive tests, but it did worsen cognitive behavior when combined with hypoxia. 

The detrimental effects on learning and memory were not observed in mice without a gut microbiota. In contrast, transplanting the microbiota of mice exposed to ketogenic diet and hypoxia into germ-free mice made them perform poorly in cognitive tests. 

The microbiota of the rodents exposed to ketogenic diet and hypoxia had high levels of the bacterium Bilophila wadsworthia, and colonizing new mice with B. wadsworthia alone impaired the animals’ cognitive behavior, the researchers found. Prior work had shown that high-fat diets increase the levels of B. wadsworthia and that the bacterium can induce a type of immune cells, called Th1 cells, that secrete IFN-gamma — an inflammatory molecule that is involved in the response against viral infections and some bacterial pathogens.

Brain function

The researchers found that mice with poor cognitive behavior had higher levels of Th1 cells in their guts. Mice that lacked these immune cells did not experience the learning and memory deficits associated with the ketogenic diet, hypoxia, and B. wadsworthia

What’s more, poor cognitive behavior in mice colonized with B. wadsworthia or exposed to ketogenic diet and hypoxia was associated with altered gene expression and weaker neuron-to-neuron connections in the hippocampus, the researchers found. IFN-gamma reduces neuronal cell proliferation and triggers programmed cell death in the hippocampus, previous research has shown.

The new findings suggest that specific changes in the gut microbiota could contribute to disruptions in brain physiology and cognitive behavior, the researchers say. “We propose that understanding the biological bases for how complex genetic, environmental, and psychosocial factors together predispose to [cognitive impairment] requires consideration of the gut microbiome as an important interface between host genetics and environmental exposures,” they add.

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Giorgia Guglielmi is a freelance science writer based in Cambridge, Massachusetts. She received a PhD in Biology from the European Molecular Biology Laboratory and a Master’s in Science Writing from the Massachusetts Institute of Technology.