An obese-type gut microbiome can lead to neurobehavioral pathology

 Squirrel on high fat diet. (close enough to a mouse!)

Squirrel on high fat diet. (close enough to a mouse!)

Obesity is a complex condition with an extensive range of health complications.  Among many other issues, neurobehavioral deficits in learning, memory, and executive function are observed in this disorder.  However, the cause behind the manifestations of these deficits remains unclear, and new data suggest that obesity by itself may not be the origin of these neurobehavioral complications.  In other words, neurobehavioral deficits may not be caused by obesity, but rather by the microbiome that develops from the high-fat diet that leads to obesity.  A recent study supports this supposition, demonstrating that an “obese-specific” gut microbiome may be the driving force behind these neurobehavioral complications.

Researchers hypothesized that microbiome communities that develop from a sustained high-fat diet could by themselves induce neurobehavioral maladies, independent of diet, adipose fat accumulation, and/or metabolic dysfunction.  To test this theory, the researchers developed a paradigm in which microbiota taken from the gut of obese mice were recolonized in the gut of non-obese mice.  Specifically, mice were split into two groups, and members from each cohort were administered either a standard chow diet or a high-fat chow diet (to induce obesity).  After 10 weeks on their respective diets, the animals were sacrificed and their microbiota bacteria were harvested from cecal and colonic contents.  A third group of mice were administered an intense antibiotic regimen to wipe out their intestinal microbiota populations.  Microbiotas from either the normal chow diet mice or high-fat chow diet mice were subsequently implanted in the microbial-free guts of third group.  These mice were then subject to behavioral examinations and eventually sacrificed for biochemical analysis to characterize disease markers and pathology indications in the brain and gut. 

Behavioral assessments revealed significant increases in anxiety and anxiety-like behaviors concomitant to decreases in memory in mice administered the high-fat diet-associated microbiota.  To validate that differences in gut microbiomes were the root cause, analysis of cecal and fecal samples from mice indicated that the gut microbiomes in both high fat diet and normal diet groups had distinct phylogenetic profiles, demonstrating that microbiota populations from each group were indeed distinct. 

Researchers next analyzed biological protein markers associated endotoxins and inflammation in the gut, as well as markers for injury and inflammation in the brain.  Several inflammatory-associated markers were significantly upregulated in the high-fat diet group, indicating disruption to intestinal permeability and inflammation.  Furthermore, expression of inflammatory protein markers in the brain was significantly increased in the mice with the high-fat diet microbiota, and two proteins known to maintain integrity of brain vasculature were significantly reduced.  Additionally, a protein known to be present during normal synaptic function was significantly reduced. 

Collectively, these data link disturbances in gut and brain physiology resulting in behavioral dysfunction with obese-specific microbiota rather than the state of obesity.  Importantly, however, this study reveals a potential therapeutic target to remedy behavioral disorders that many have previously perceived as a consequence of simply being obese.  

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