Tryptophan in diet, gut bacteria protect against E. coli infection

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Gut germs and a fare rich | successful nan amino acerb tryptophan tin play a protective domiciled against pathogenic E. coli, which tin origin terrible tummy upset, cramps, fever, intestinal bleeding and renal failure, according to a study published March 13 successful Nature.

The investigation reveals really dietary tryptophan -- an amino acerb recovered mostly successful animal products, nuts, seeds, full grains and legumes -- tin beryllium surgery down by gut germs into mini molecules called metabolites. It turns retired a fewer of these metabolites tin hindrance to a receptor connected gut epithelial (surface) cells, triggering a pathway that yet reduces nan accumulation of proteins that E. coli usage to connect to nan gut lining wherever they origin infection. When E. coli neglect to connect and colonize nan gut, nan pathogen benignly moves done and passes retired of nan body.

The investigation describes a antecedently chartless domiciled successful nan gut for a receptor, DRD2. DRD2 has different been known arsenic a dopamine (neurotransmitter) receptor successful nan cardinal and peripheral tense systems.

"It's really 2 wholly different areas that this receptor could play a domiciled in, which was not appreciated anterior to our findings," said Pamela Chang, subordinate professor of immunology successful nan College of Veterinary Medicine and of chemic biology successful nan College of Arts and Sciences. "We fundamentally deliberation that DRD2 is moonlighting successful nan gut arsenic a microbial metabolite sensor, and past its downstream effect is to thief protect against infection."

Samantha Scott, a postdoctoral interrogator successful Chang's lab, is first writer of nan study, "Dopamine Receptor D2 Confers Colonization Resistance via Microbial Metabolites."

Now that Chang, Scott and colleagues person identified a circumstantial pathway to thief forestall E. coli infection, they whitethorn now statesman studying nan DRD2 receptor and components of its downstream pathway for therapeutic targets.

In nan study, nan researchers utilized mice infected pinch Citrobacter rodentium, a bacterium that intimately resembles E. coli, since definite pathogenic E. coli don't infect mice. Through experiments, nan researchers identified that location was little pathogen and inflammation (a motion of an progressive immune strategy and infection) aft mice were fed a tryptophan-supplemented diet. Then, to show that gut germs were having an effect, they gave nan mice antibiotics to deplete microbes successful nan gut, and recovered that nan mice were infected by C. rodentium successful spite of eating a tryptophan diet, confirming that protection from tryptophan was limited connected nan gut bacteria.

Then, utilizing wide spectrometry, they ran a surface to find nan chemic identities of tryptophan metabolites successful a gut sample, and identified 3 specified metabolites that were importantly accrued erstwhile fixed a tryptophan diet. Again, based connected pathogen levels and inflammation, erstwhile these 3 metabolites unsocial were fed to nan mice, they had nan aforesaid protective effect arsenic giving nan mice a afloat tryptophan diet.

Switching gears, nan researchers utilized bioinformatics to find which proteins (and receptors) mightiness hindrance to nan tryptophan metabolites, and from a agelong database they identified 3 related receptors wrong nan aforesaid family of dopamine receptors. Using a quality intestinal compartment statement successful nan lab, they were capable to isolate receptor DRD2 arsenic nan 1 that had nan protective effect against infection successful nan beingness of tryptophan metabolites.

Having identified nan metabolites and nan receptor, they analyzed nan downstream pathway of DRD2 successful quality gut epithelial cells. Ultimately, they recovered that erstwhile nan DRD2 pathway was activated, nan host's expertise to nutrient an actin regulatory macromolecule was compromised. C. rodentium (and E. coli) require actin to connect themselves to gut epithelial cells, wherever they colonize and inject virulence factors and toxins into nan cells that origin symptoms. But without actin polymerization they can't connect and nan pathogen passes done and clears.

The experiments revealed a caller domiciled of dopamine receptor DRD2 successful nan gut that controls actin proteins and affects a antecedently chartless pathway for preventing a pathogenic bacteria's expertise to colonize nan gut.

Jingjing Fu, a erstwhile postdoctoral interrogator successful Chang's lab, is simply a co-author.

The study was supported by nan Arnold and Mabel Beckman Foundation, a President's Council of Cornell Women Affinito-Stewart Grant, nan National Institutes of Health and a Cornell Institute of Host-Microbe Interactions and Disease Postdoctoral Fellowship.