The role of proinflammatory response and the kynurenine pathway in the association between childhood maltreatment and lifetime substance use disorder

Introduction: Childhood maltreatment (CM) is a risk factor for adult psychiatric and substance use disorders (SUD). Retrospectively assessed CM has been linked to increased proinflammatory cytokines, including IL-6. Induced by inflammation, the neurotoxic branch of the kynurenine pathway has been implicated in psychiatric disorders and SUD. This study explored proinflammatory responses and kynurenine metabolites following acute stress in participants with, and without, prospectively recorded CM, with or without, lifetime SUD. Methods: The study included 89 participants, divided into 4 groups based on the presence or absence of prospectively assessed CM and lifetime SUD: CM + SUD, n = 24, CM only, n = 20, SUD only, n = 22, and healthy controls (HC), n = 23. Participants underwent an acute stress task. Blood was collected at five time-points measuring IL-6 and kynurenine metabolites. Linear mixed models assessed the effects of CM, SUD, and time on IL-6 and kynurenine metabolite levels. Results: Participants with prospectively recorded CM had higher baseline IL-6 compared to those without CM (mean difference = 0.37, 95% CI = 0.09-0.57, p = 0.008). Stress increased IL-6 in all participants (p < 0.001), with no significant group differences. We found no association between CM exposure and KYNA or QUIN concentrations. Participants with SUD, irrespective of CM-status, had a lower KYNA/QUIN ratio (mean difference: 0.02, 95% CI: 0.00-0.04, p = 0.047). Discussion: Our findings of low-grade proinflammatory activity support the hypothesis that CM contributes to long-term immune system alterations, but these findings do not support the role of the kynurenine pathway in this process. However, increased neurotoxicity through kynurenine metabolism was associated to SUD-diagnosis.