Cholinergic eubiosis: A hypothesis on Ivermectin-upregulated Bifidobacterium
Sabine Hazan, Adriana C Vidal, Adonis Sfera
Medical Hypotheses, doi:10.1016/j.mehy.2025.111613
A C T Ivermectin, an anti-parasitic agent extracted from Streptomyces avermitilis, has drawn attention during the COVID-19 pandemic by stirring a controversy regarding its efficacy against the SARS-CoV-2 virus. Some studies supported the use of this drug against SARS-CoV-2, while others demonstrated poor antiviral effect or even detrimental action. However, the controversy aside, whether Ivermectin can restore the depleted levels of beneficial gut microbiota, including Bifidobacterium, remains unanswered. It was established that Ivermectin is a positive allosteric regulator of alpha7 nicotinic acetylcholine receptors, active participants in the cholinergic anti-inflammatory pathway, a component of the gut-brain axis. Alpha7 nicotinic acetylcholine receptors activate gut immunosuppressive CD4 + CD25 + regulatory T cells, increasing the abundance of commensals, including Bifidobacterium and Lactobacillus. Intestinal regulatory T cells are crucial for oral and gastrointestinal tolerance, a physiological mechanism of immune unresponsiveness to food proteins and gut commensal flora. Bifidobacterium upregulates intestinal regulatory T cells, while the latter augments the former in a bidirectional manner, maintaining gut homeostasis. We hypothesize that Ivermectin enhances the cholinergic anti-inflammatory pathway and influences gut immunity and barrier integrity. At the subcellular level, this is accomplished by phosphorylation of signal transducer and activator of transcription 3 (STAT3)/ aryl hydrocarbon receptor (AhR) complex, which increases interleukin 22 and the abundance of beneficial gut microbes, including Bifidobacterium. In return, interleukin 22 and Bifidobacterium-generated interleukin 10 induce STAT3/AhR phosphorylation, producing more interleukin 22 and further upregulation of gut Bifidobacterium. This article uses the term "cholinergic eubiosis" to denote parasympathetic system-mediated increase in commensal levels and restoration of beneficial gut microbes' immune tolerance. As intestinal inflammations are recorded in the Insular Cortex, a brain area responsible for interoception, this hypothesis may explain some beneficial effects of probiotics on neuropathology.
Ethics statement This is a Hypothesis manuscript, thus no human subjects were used/ included in this study, therefore, no Ethics Statement applies. This study received no funding.
CRediT authorship contribution statement
Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Sabine Hazan is CEO of Ventura Clinical Trials and Progenabiome and received no monetary compensation for this study.
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