Illustration of a Novel Gut-Brain Axis of Alcohol Withdrawal, Withdrawal-Associated Depression, Craving and Alcohol-Severity Index in Alcohol Use Disorder Patients

Abstract

Pathways underlying the gut-brain axis and pro-inflammatory cytokine production influence brain functions and behavior. Alcohol use disorder (AUD) patients exhibit domains such as alcohol withdrawal, depression, and craving; and the gut-immune response may play a significant role in these domains of AUD. This study examined the role of intestinal permeability, pro-inflammatory cytokines, and hormones levels on the domains of AUD.Forty-eight AUD patients [male (n=34) and female (n=14)] aged 23-63 yrs. were grouped categorically using the Clinical Institute Withdrawal Assessment of alcohol scale (CIWA) as either clinically significant CIWA group (CS-CIWA [score>10] Gr.1 [n=22]), and clinically not-significant group (NCS-CIWA [score≤10] Gr.2 [n=26]). A sub-set of 13 AUD patient were also tested for reward response for drug-seeking using Penn-Alcohol Craving Score (PACS). Clinical data and blood samples were collected upon enrollment. Blood samples were analyzed for pro-inflammatory cytokines, and hormones, and markers of intestinal permeability. CIWA, 90-day timeline followback (TLFB90), and lifetime drinking history (LTDH) were also collected for comparison.As expected, recent and chronic heavy drinking were significantly higher in Gr.1: HDD90 (heavy drinking days), NDD90 (number of drinking days), as was LTDH, especially in Gr.1 females. Further, in Gr.1, adiponectin (associated with withdrawal) was significantly higher; and numerically higher levels of lipopolysaccharide (LPS) and LPS-binding protein (LBP) were also reported. Gr.1 patients exhibited higher effects of association on the withdrawal-associated depression domain for the parameters of LPS, sCD14, IL-6 and IL-8. Leptin also showed a significantly high effect of association with HDD90 in those AUD patients with craving. The craving domain (assessed by PACS, Penn-Alcohol Craving Scale) could be described as a gut-immune-brain model by the gut-dysregulation (LBP and Leptin) markers, and specific pro-inflammatory activity (IL-1β and TNF-α). Such pathway model describes the heavy drinking phenotype, HDD90 with even higher effects (R2=0.955, p=0.006) in the AUD patients who had higher ratings for craving (PACS>5).Interaction of gut-dysfunction, cytokines involved in both inflammation and in mediating-chemotactic activity constitute a novel pathophysiological gut-brain axis for withdrawal, and alcohol-associated depression and craving domains of AUD. AUD patient with higher craving show higher reinforcing effects of the gut-brain axis response for heavy drinking.