Alcohol, T. gondii and the natural antibiotic peptide cathelicidin

Alcohol use disorder is both a predisposing risk factor and a trigger for SSDV (Pompili et al. 2010, Kittel et al. 2019, Edwards et al. 2020, Holma et al. 2020). Post-mortem, T. gondii seropositivity was associated with the presence of alcohol in the blood (Samojłowicz et al. 2013, 2017), although no associations were found between T. gondii DNA in the brain and excessive alcohol use (Suvisaari et al. 2017). Yet others’ efforts have been successful obtaining positive results, in particular the group of Alvarado-Esquivel in Mexico. Recently, they reported that in individuals with “alcohol consumption” (at least one alcoholic drink every month) T. gondii IgG (but not IgM) seropositivity was associated with suicidal ideation, but only in women with history of suicide attempts (Alvarado-Esquivel et al. 2021a). Yet a direct comparison of individuals who consume alcohol with those who do not led to unexpected results, with lower consumption of alcohol in T. gondii seropositives (Alvarado-Esquivel et al. 2023). This could be due to pharmacokinetic or pharmacodynamic mechanisms with dopamine production by the parasite in the brain potentially increasing the dopaminergic tone and decreasing the need to rely on alcohol to attain a sufficient hedonic tone in the brain.

A potential “double-hit” hypothesis of both factors interacting as well as increased risk of alcohol or substance use disorder by chronic infection with T. gondii have been considered. The dopaminergic production capability of T. gondii has been thought through as a potential factor leading to alcohol and substance abuse. However, more recently, an increasing number of studies has pointed out the low-grade chronic inflammation as a consequence of drinking (Adams et al. 2020). Additionally, the perturbation of inflammatory homeostasis secondary to alcohol consumption as both an acute and chronic alcohol use potentially results in a diminished efficacy of antimicrobial defense mechanisms (Chan and Levitsky 2016).

Based on an ongoing project we have preliminarily reported that the antimicrobial peptide cathelicidin (active form LL37) level in the blood is decreased in individuals with alcohol use disorder (Postolache et al. 2024). We previously identified, for the first time to our knowledge, a lower expression of cathelicidin in the dorsolateral prefrontal cortex and anterior cingulate cortex in the brain of individuals who died by suicide, relative to psychiatric controls who died from non-suicide related causes (Postolache et al. 2020). Thus, it is theoretically possible that a decrease in antimicrobial peptides’ activity, and in particular decreased LL37, may mediate associations between alcohol use and severity of T. gondii infection and, in particular, its reactivation, potentially leading to increased SSDV risk. This is one of the hypotheses I would like to be able to test in the upcoming years.