title: Role of inflammatory pathways, blood mononuclear cells, and gut-derived bacterial products in alcohol dependence.
abstract: 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.
authors.affiliation: Institute of Neuroscience and Department of Adult Psychiatry, Brussels, Belgium.
authors.forename: Sophie
authors.initials: S
authors.lastname: Leclercq
authors.affiliation: Institute of Experimental and Clinical Research, Laboratory of Hepato- and Gastroenterology, Brussels, Belgium.
authors.forename: Christine
authors.initials: C
authors.lastname: De Saeger
authors.affiliation: Louvain Drug Research Institute, Metabolism and Nutrition Research Group, Université Catholique de Louvain, Brussels, Belgium.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Delzenne
authors.affiliation: Institute of Neuroscience and Department of Adult Psychiatry, Brussels, Belgium.
authors.forename: Philippe
authors.initials: P
authors.lastname: de Timary
authors.affiliation: Institute of Experimental and Clinical Research, Laboratory of Hepato- and Gastroenterology, Brussels, Belgium. Electronic address: peter.starkel@uclouvain.be.
authors.forename: Peter
authors.initials: P
authors.lastname: Stärkel
mesh_terms: D000328:Adult; D000437:Alcoholism / Q000097:blood* / Q000473:pathology*; D016207:Cytokines / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008070:Lipopolysaccharides / Q000097:blood* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010457:Peptidoglycan / Q000097:blood*; D012333:RNA, Messenger / Q000378:metabolism; D012044:Regression Analysis; D015398:Signal Transduction / Q000502:physiology*; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D016207:Cytokines; D008070:Lipopolysaccharides; D010457:Peptidoglycan; D012333:RNA, Messenger; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D014157:Transcription Factors
keywords: Alcohol craving; MAP kinases; inflammasome; lipopolysaccharides; peptidoglycans; proinflammatory cytokines