AUTHOR=Vatsalya Vatsalya , Verster Joris C. , Sagaram Manasa , Royer Amor J. , Hu Huirong , Parthasarathy Ranganathan , Schwandt Melanie L. , Kong Maiying , Ramchandani Vijay A. , Feng Wenke , Agrawal Ruchita , Zhang Xiang , McClain Craig J. 

TITLE=Novel paradigms for the gut–brain axis during alcohol withdrawal, withdrawal-associated depression, and craving in patients with alcohol use disorder

JOURNAL=Frontiers in Psychiatry

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/psychiatry/articles/10.3389/fpsyt.2023.1203362

DOI=10.3389/fpsyt.2023.1203362

ISSN=1664-0640

ABSTRACT=<sec><title>Introduction</title><p>Patients with alcohol use disorder (AUD) exhibit symptoms such as alcohol withdrawal, depression, and cravings. The gut-immune response may play a significant role in manifesting these specific symptoms associated with AUD. This study examined the role of gut dysfunction, proinflammatory cytokines, and hormones in characterizing AUD symptoms.</p></sec><sec><title>Methods</title><p>Forty-eight AUD patients [men (<italic>n</italic> = 34) and women (<italic>n</italic> = 14)] aged 23–63 years were grouped using the Clinical Institute Withdrawal Assessment of Alcohol Scale (CIWA) as clinically significant (CS-CIWA [score &gt; 10] [<italic>n</italic> = 22]) and a clinically not-significant group (NCS-CIWA [score ≤ 10] [<italic>n</italic> = 26]). Clinical data (CIWA, 90-day timeline followback [TLFB90], and lifetime drinking history [LTDH]) and blood samples (for testing proinflammatory cytokines, hormones, and markers of intestinal permeability) were analyzed. A subset of 16 AUD patients was assessed upon admission for their craving tendencies related to drug-seeking behavior using the Penn-Alcohol Craving Score (PACS).</p></sec><sec><title>Results</title><p>CS-CIWA group patients exhibited unique and significantly higher levels of adiponectin and interleukin (IL)-6 compared to NCS-CIWA. In the CS group, there were significant and high effects of association for the withdrawal score with gut-immune markers (lipopolysaccharide [LPS], adiponectin, IL-6, and IL-8) and for withdrawal-associated depression with gut-immune markers (scored using MADRS with LPS, soluble cells of differentiation type 14 [sCD14], IL-6, and IL-8). Craving (assessed by PACS, the Penn-Alcohol Craving Scale) was significantly characterized by what could be described as gut dysregulation (LBP [lipopolysaccharide binding protein] and leptin) and candidate proinflammatory (IL-1β and TNF-α) markers. Such a pathway model describes the heavy drinking phenotype, HDD90 (heavy drinking days past 90 days), with even higher effects (R<sup>2</sup> = 0.955, <italic>p</italic> = 0.006) in the AUD patients, who had higher ratings for cravings (PACS &gt; 5).</p></sec><sec><title>Discussion</title><p>The interaction of gut dysfunction cytokines involved in both inflammation and mediating activity constitutes a novel pathophysiological gut–brain axis for withdrawal symptoms and withdrawal-associated depression and craving symptoms in AUD. AUD patients with reported cravings show a significant characterization of the gut–brain axis response to heavy drinking.</p></sec><sec><title>Trial registration</title><p><ext-link ext-link-type="uri" xlink:href="https://ClinicalTrials.gov" xmlns:xlink="http://www.w3.org/1999/xlink">ClinicalTrials.gov</ext-link>, identifier: NCT# 00106106.</p></sec>