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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References
- Inflammatory cytokines in depression: Neurobiological mechanisms and therapeutic implications.Neuroscience. 2013; 246: 199-229
- Alcoholism and inflammation: Neuroimmunology of behavioral and mood disorders.Brain Behav Immun. 2011; 25: S13-S20
- Alcohol in Europe—public health perspective: Report summary.Drugs: Education, Prevention & Policy. 2006; 13: 483-488
- Evidence that chronic alcohol exposure promotes intestinal oxidative stress, intestinal hyperpermeability and endotoxemia prior to development of alcoholic steatohepatitis in rats.J Hepatol. 2009; 50: 538-547
- Increased intestinal permeability to macromolecules and endotoxemia in patients with chronic alcohol abuse in different stages of alcohol-induced liver disease.J Hepatol. 2000; 32: 742-747
- Role of intestinal permeability and inflammation in the biological and behavioral control of alcohol-dependent subjects.Brain Behav Immun. 2012; 26: 911-918
- Probiotics restore bowel flora and improve liver enzymes in human alcohol-induced liver injury: A pilot study.Alcohol. 2008; 42: 675-682
- Intestinal dysbiosis: A possible mechanism of alcohol-induced endotoxemia and alcoholic steatohepatitis in rats.Alcohol Clin Exp Res. 2009; 33: 1836-1846
- Jejunal microflora in patients with chronic alcohol abuse.Hepatogastroenterology. 1984; 31: 30-34
- Enteric dysbiosis associated with a mouse model of alcoholic liver disease.Hepatology. 2011; 53: 96-105
- The bacterial cell envelope.Cold Spring Harb Perspect Biol. 2010; 2: a000414
- Pathogen recognition and innate immunity.Cell. 2006; 124: 783-801
- Pattern recognition receptors and inflammation.Cell. 2010; 140: 805-820
- Signaling to NF-kappaB by Toll-like receptors.Trends Mol Med. 2007; 13: 460-469
- Current views of toll-like receptor signaling pathways.Gastroenterol Res Pract. 2010; 2010: 240365
- CD14, a receptor for complexes of lipopolysaccharide (LPS) and LPS binding protein.Science. 1990; 249: 1431-1433
- MD-2, a molecule that confers lipopolysaccharide responsiveness on toll-like receptor 4.J Exp Med. 189. 1999: 1777-1782
- TRAM couples endocytosis of Toll-like receptor 4 to the induction of interferon-beta.Nat Immunol. 2008; 9: 361-368
- TLR signaling.Semin Immunol. 2007; 19: 24-32
- LPS induction of gene expression in human monocytes.Cell Signal. 2001; 13: 85-94
- LPS-TLR4 signaling to IRF-3/7 and NF-kappaB involves the toll adapters TRAM and TRIF.J Exp Med. 2003; 198: 1043-1055
- Nod2 is a general sensor of peptidoglycan through muramyl dipeptide (MDP) detection.J Biol Chem. 2003; 278: 8869-8872
- Identification of bacterial muramyl dipeptide as activator of the NALP3/cryopyrin inflammasome.Curr Biol. 2004; 14: 1929-1934
- The inflammasomes.Cell. 2010; 140: 821-832
- Diagnostic and Statistical Manual of Mental Disorders.4th ed. APA, Washington, DC1994
- Comparison of two techniques to obtain retrospective reports of drinking behavior from alcohol abusers.Addict Behav. 1982; 7: 33-38
- The loss of metabolic control on alcohol drinking in heavy drinking alcohol-dependent subjects.PLoS ONE. 2012; 7: e38682
- Expression and DNA-binding activity of signal transducer and activator of transcription 3 in alcoholic cirrhosis compared to normal liver and primary biliary cirrhosis in humans.Am J Pathol. 2003; 162: 587-596
- The Obsessive Compulsive Drinking Scale: A self-rated instrument for the quantification of thoughts about alcohol and drinking behavior.Alcohol Clin Exp Res. 1995; 19: 92-99
- A French translation of the Obsessive-Compulsive Drinking Scale for craving in alcohol-dependent patients: A validation study in Belgium, France, and Switzerland.Eur Addict Res. 2000; 6: 51-56
- Pannexin-1 mediates large pore formation and interleukin-1beta release by the ATP-gated P2X7 receptor.EMBO J. 2006; 25: 5071-5082
- Pannexin-1-mediated recognition of bacterial molecules activates the cryopyrin inflammasome independent of Toll-like receptor signaling.Immunity. 2007; 26: 433-443
- Elevated plasma cytokines in autism spectrum disorders provide evidence of immune dysfunction and are associated with impaired behavioral outcome.Brain Behav Immun. 2011; 25: 40-45
- Interleukin-6 (IL-6) plasma levels in depression and schizophrenia: Comparison between the acute state and after remission.Eur Arch Psychiatry Clin Neurosci. 1997; 247: 228-233
- Major depression and activation of the inflammatory response system.Adv Exp Med Biol. 461. 1999: 25-46
- Depressive disorders and immunity: 20 years of progress and discovery.Brain Behav Immun. 2007; 21: 374-383
- Cytokines and alcohol.Alcohol Clin Exp Res. 2006; 30: 720-730
- Increased MCP-1 and microglia in various regions of the human alcoholic brain.Exp Neurol. 2008; 210: 349-358
- Alcoholism: A systems approach from molecular physiology to addictive behavior.Physiol Rev. 2009; 89: 649-705
- Increased tumor necrosis factor production by monocytes in alcoholic hepatitis.Hepatology. 1989; 9: 349-351
- Increased monocyte nuclear factor-kappaB activation and tumor necrosis factor production in alcoholic hepatitis.J Lab Clin Med. 2000; 135: 387-395
- Toll-like receptor 2-dependent bacterial sensing does not occur via peptidoglycan recognition.EMBO Rep. 2004; 5: 1000-1006
- ERK1/2 and Egr-1 contribute to increased TNF-alpha production in rat Kupffer cells after chronic ethanol feeding.Am J Physiol Gastrointest Liver Physiol. 2002; 282: G6-15
- Chronic ethanol increases lipopolysaccharide-stimulated Egr-1 expression in RAW 264.7 macrophages: Contribution to enhanced tumor necrosis factor alpha production.J Biol Chem. 2002; 277: 14777-14785
- Costunolide inhibits interleukin-1beta expression by down-regulation of AP-1 and MAPK activity in LPS-stimulated RAW 264.7 cells.Biochem Biophys Res Commun. 2004; 313: 171-177
- Multiple control of interleukin-8 gene expression.J Leukoc Biol. 2002; 72: 847-855
- JNK pathway is required for TNCB-induced IL-18 expression in murine keratinocytes.Toxicol In Vitro. 2010; 24: 1064-1069
- Distinct effects of protracted withdrawal on affect, craving, selective attention and executive functions among alcohol-dependent patients.Alcohol Alcohol. 2010; 45: 241-246
- Absolute and relative stability of alexithymia in alcoholic inpatients undergoing alcohol withdrawal: Relationship to depression and anxiety.Psychiatry Res. 2008; 157: 105-113
- Is anxious-depression an inflammatory state?.Med Hypotheses. 81. 2013: 577-581
- Mechanisms of neurodegeneration and regeneration in alcoholism.Alcohol Alcohol. 2009; 44: 115-127
- Pivotal role of TLR4 receptors in alcohol-induced neuroinflammation and brain damage.J Neurosci. 2010; 30: 8285-8295
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.