Zonulin as Gatekeeper in Gut-Brain Axis: Dysregulation in Glioblastoma

Novel biomarkers and therapeutic strategies for glioblastoma, the most common malignant brain tumor with an extremely unfavorable prognosis, are urgently needed. Recent studies revealed a significant upregulation of the protein zonulin in glioblastoma, which correlates with patient survival. Originally identified as pre-haptoglobin-2, zonulin modulates both the intestinal barrier and the blood-brain barrier by disassembling tight junctions. An association of zonulin with various neuroinflammatory diseases has been observed. It can be suggested that zonulin links a putative impairment of the gut-brain barrier with glioblastoma carcinogenesis, leading to an interaction of the gut microbiome, the immune system, and glioblastoma. We therefore propose three interconnected hypotheses: (I) elevated levels of zonulin in glioblastoma contribute to its aggressiveness; (II) upregulated (serum-) zonulin increases the permeability of the microbiota-gut-brain barrier; and (III) this creates a carcinogenic and immunosuppressive microenvironment preventing the host from an effective antitumor response. The role of zonulin in glioblastoma highlights a promising field of research that could yield diagnostic and therapeutic options for glioblastoma patients and other diseases with a disturbed microbiota-gut-brain barrier.