Cholinergic eubiosis: A hypothesis on Ivermectin-upregulated Bifidobacterium
Year: 2025
Type: article
Abstract: Ivermectin is an allosteric modulator of α7nAChR, enhancing the effect of nicotinic vagal innervation. Immune cells, including monocytes and Tregs express α7nAChRs and are part of the CAP. ACh promotes STAT3/AhR phosphorylation upon which both transcription factors enter the nucleus, inducing the transcription of many genes, including cytokine IL22, and increasing the abundance of Bifidobacterium and Lactobacillus . Some Bifidobacterium spp . generate IL10. IL22 and microbial IL10 phosphorylate STAT3/AhR, generating a self-enhancing immunosuppressant loop and protecting the gut barrier and microbiota, a phenomenon, we call cholinergic eubiosis. Hypothesis : Ivermectin (IVM) augments cholinergic signaling that in return phosphorylate STAT3/AhR complex, increasing the expression of IL-22, the abundance of Bifidobacteria and protection against inflammation. α7nAChR: alpha-7-nicotinic acetylcholine receptor; CAP: cholinergic anti-inflammatory pathway;Ach: acetylcholine; STAT3: signal transducer and activator of transcription 3; AhR: aryl hydrocarbon receptor; IL: interleukin; IVM: Ivermectin. • We hypothesize that Ivermectin enhances the cholinergic anti-inflammatory pathway and influences gut immunity. • At the subcellular level, pSTAT3 increases IL-22 and the abundance of Bifidobacterium and Lactobacillus. • Combined, cholinergic eubiosis can explain IVM-mediated upregulation of beneficial gut microbes, including Bifidobacterium. 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.
Source: Medical Hypotheses
Authors: Sabine Hazan, Adriana C. Vidal, Adonis Sfera
Institutions: ProgenaBiome (United States), Patton State Hospital
Language: English
Subfield: Neurology
Field: Neuroscience
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $2,820
OpenAlex ID: W4408981175