Harmaline and the gut-brain-immune axis: a novel therapeutic avenue in neuroinflammation and ulcerative colitis

Chronic inflammatory disorders like neuroinflammatory disorders and ulcerative colitis (UC) have some common pathogenic mechanisms such as persistent activation of nuclear factor-κB (NF-κB), oxidative and nitrosative stress, mitochondrial dysfunction, immune dysregulation, and disruption of the integrity of the epithelial barrier. The gut-brain-immune axis is a bidirectional communication pathway, with growing evidence that intestinal inflammation impairs central neuroimmune responses and vice versa, underscoring the importance of therapeutic interventions that can address and impact these interconnected axes. Harmaline or β-carboline alkaloid, a naturally occurring compound mainly found in Peganum harmala and Banisteriopsis caapi, has gradually gained a lot of interest due to its wide range of pharmacological properties such as anti-inflammatory, antioxidant, neuroprotective, and immunomodulatory. The review focuses on the reported modulation of the major inflammatory pathways, such as inhibition of NF-κB signalling, attenuation of pro-inflammatory cytokine production, regulation of oxidative stress through the Nrf2-dependent pathway, and reversible inhibition of monoamine oxidase-A (MAO-A), by critically evaluating the inflammopharmacological profile of harmaline. All of these molecular activities indicate that harmaline could affect biological activities related to neuroinflammation, intestinal inflammation, and gut-brain-immune communications. Nevertheless, there is limited direct experimental evidence supporting the efficacy of harmaline in disease-specific models of ulcerative colitis, neuroinflammation, and microbiota-associated diseases. Hence, the indicated therapeutic relevance of harmaline has to be considered as hypothesis-generating and mechanistically plausible but for now not experimentally proven in disease-specific contexts. In general, harmaline is a promising mechanistic lead compound to be investigated in future complex inflammatory diseases which involve brain/gut and neuroimmune interactions. Additional research regarding disease-specific efficacy, pharmacokinetic properties, tissue distribution, microbiota-related aspects, dose-response, and safety aspects is needed to evaluate its translatability.