The link between inflammation, bugs, the intestine and the brain in alcohol dependence

S Leclercq, P de Timary, N M Delzenne, P Stärkel, S Leclercq, P de Timary, N M Delzenne, P Stärkel

Abstract

In recent years, some new processes have been proposed to explain how alcohol may influence behavior, psychological symptoms and alcohol seeking in alcohol-dependent subjects. In addition to its important effect on brain and neurotransmitters equilibrium, alcohol abuse also affects peripheral organs including the gut. By yet incompletely understood mechanisms, chronic alcohol abuse increases intestinal permeability and alters the composition of the gut microbiota, allowing bacterial components from the gut lumen to reach the systemic circulation. These gut-derived bacterial products are recognized by immune cells circulating in the blood or residing in target organs, which consequently synthesize and release pro-inflammatory cytokines. Circulating cytokines are considered important mediators of the gut-brain communication, as they can reach the central nervous system and induce neuroinflammation that is associated with change in mood, cognition and drinking behavior. These observations support the possibility that targeting the gut microbiota, by the use of probiotics or prebiotics, could restore the gut barrier function, reduce systemic inflammation and may have beneficial effect in treating alcohol dependence and in reducing alcohol relapse.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Activation of Toll-like receptors (TLRs) and Nod-like receptors (NLRs) by pathogen-associated molecular patterns (PAMPs) and damage-associated molecular pattern (DAMPs). Extracellular or intracellular binding of PAMP and DAMP to their receptors activates inflammatory pathways, dependent or independent of MyD88, which leads to the nuclear translocation and DNA binding of transcription factors (NFκB, AP-1 and IRF), resulting in the upregulation of pro-inflammatory cytokines, chemokines and type I interferons. Numerous bacterial, viral and host-derived ligands can activate the NLRP3 inflammasome complex constituted by the enzyme pro-caspase-1. Activation of caspase-1 is necessary to produce biologically active cytokines IL-1β and IL-18. IL, interleukin.
Figure 2
Figure 2
Chronic alcohol abuse is associated with gut barrier alteration, dysbiosis and immune activation. Alcohol-dependent subjects present with increased intestinal permeability (leaky gut) and altered gut microbiota composition and functionality. This favors the translocation of gut-derived bacterial components, such as lipopolysaccharides (LPS) and peptidoglycan (PGN), from the gut lumen to the systemic circulation and other organs. Bacterial ligands are recognized by Toll-like receptors (TLRs) expressed by immune cells and induce an inflammatory response.
Figure 3
Figure 3
Gut-to-brain pathways of communication. Gut-derived bacterial components (LPS and PGN) activate the immune cells localized in the systemic circulation (peripheral blood mononuclear cells—PBMCs), or in target organs such as the gut or the liver that also release pro-inflammatory cytokines. These peripheral circulating cytokines are important mediators of the gut–brain axis as they can reach the central nervous system (CNS) and induce de novo the synthesis of cytokines within the brain. Brain cytokines are thought to mediate changes in mood, cognitive function and drinking behavior. Afferent vagus nerve fibers express the IL-1β receptor and can also convey the peripheral inflammatory message to the CNS and influence brain function and behavior. Other potential mechanisms of gut–brain communication involving the secretion of neurotransmitters, short-chain fatty acids (SCFAs) and the tryptophan/kynurenine (TRP/KYN) are also depicted. IL, interleukin; LPS, lipopolysaccharide; PGN, peptidoglycans.

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