In mice, diets high in fat cause similar levels of gut imbalance, metabolic problems, and cognitive decline whether or not they also contain high amounts of carbohydrates, suggesting that...
Mechanism
Synthesis from 1 study
Eating a high-fat diet changes gut bacteria and makes the intestine leaky, letting bacterial toxins into the blood. These toxins damage the energy parts of cells, causing them to spill their DNA into surrounding tissue. This leaked DNA tricks the body into starting a strong inflammatory response...
Most probable mechanism
Eating a lot of fat changes the gut bacteria in a way that makes the intestinal lining leaky. This lets bacterial toxins enter the bloodstream, which damages the energy factories inside cells, causing them to release their own DNA into the surrounding fluid. This misplaced DNA tricks the immune system into thinking there's an infection, so it turns on powerful inflammatory signals. These signals spread to the brain, where they activate immune cells that damage nerve cells in the memory center, leading to trouble with learning and remembering things. Adding sugar doesn't make this worse than fat alone.
Dietary fat alters gut microbiota composition, reducing beneficial microbes and increasing pro-inflammatory bacterial strains
Dysbiosis increases intestinal permeability, allowing microbial products such as lipopolysaccharide to enter systemic circulation
Systemic microbial toxins induce mitochondrial stress in peripheral and central cells, reducing expression of TFAM, a key regulator of mitochondrial DNA maintenance
Mitochondrial dysfunction leads to release of mitochondrial DNA into the cytosol, where it acts as a damage-associated molecular pattern
Cytosolic mitochondrial DNA activates the AIM2 inflammasome, leading to caspase-1-mediated cleavage and release of interleukin-1β and interleukin-18
Cytosolic mitochondrial DNA also activates cGAS, which produces cGAMP to stimulate STING, resulting in IRF3 phosphorylation and type I interferon production
Pro-inflammatory cytokines and type I interferons cross the blood-brain barrier or activate resident microglia and astrocytes, initiating neuroinflammation
Chronic neuroinflammation triggers intrinsic apoptotic pathways in hippocampal neurons, resulting in neuronal loss
Loss of hippocampal neurons and disruption of synaptic plasticity impair memory formation and cognitive function
Evidence from Studies
Supporting (1)
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