Background
Inflammation might play a role in the development of several psychiatric diseases.
However, the origins of processes that mediate inflammation are unknown. We previously
reported increased intestinal permeability, elevated blood lipopolysaccharide levels,
and low-grade systemic inflammation associated with psychological symptoms of alcohol
dependence in alcohol-dependent subjects. In this study, we tested inflammatory responses
of peripheral blood mononuclear cells (PBMCs) to gut-derived bacterial products during
detoxification and the relationship to alcohol craving.
Methods
In 63 actively drinking noncirrhotic alcohol-dependent subjects, testing was performed
at the beginning (day 2) and end (day 18) of alcohol detoxification and compared with
testing in 14 healthy subjects. Activation of various intracellular signaling pathways
by gut-derived bacterial products was analyzed by quantitative polymerase chain reaction,
Western blotting, and DNA binding assays (for transcription factors). Toll-like receptor
activation was assessed by cell cultures.
Results
In addition to lipopolysaccharides, we showed that peptidoglycans may also cross the
gut barrier to reach the systemic circulation. Both activate their respective Toll-like
receptors in peripheral blood mononuclear cells. Chronic alcohol consumption inhibited
the nuclear factor kappa B proinflammatory cytokine pathway but activated the mitogen-activated
protein kinase/activator protein 1 pathway, together with the inflammasome complex.
This activity resulted in increased messenger RNA and plasma levels of interleukin
(IL)-8, IL-1β, and IL-18. Activated proinflammatory pathways, in particular, IL-8
and IL-1β, were positively correlated with alcohol consumption and alcohol-craving
scores. Short-term alcohol withdrawal was associated with the recovery of lipopolysaccharide-dependent
receptors but not peptidoglycan-dependent receptors.
Conclusions
Lipopolysaccharides and peptidoglycans from the gut microbiota stimulate specific
inflammatory pathways in peripheral blood mononuclear cells that are correlated with
alcohol craving.
Key Words
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Article Info
Publication History
Published online: February 18, 2014
Accepted:
February 3,
2014
Received in revised form:
January 13,
2014
Received:
September 25,
2013
Footnotes
Authors PdT and PS contributed equally to this work.
Identification
Copyright
© 2014 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
