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

Abstract

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.

Keywords: blood–brain barrier; glioblastoma; pre-haptoglobin; zonulin.

Figure 1

While zonulin (Pre-Hp2) increases permeability of tight junctions, its “mature” form Hp2 prevents oxidative stress [10,14,21,22,23]. Created with BioRender.com.

Figure 2

Zonulin induces glioblastoma aggressiveness [9,27,28]. Created with BioRender.com.

Figure 3

Zonulin as dysregulated gatekeeper of the microbiota–gut–brain axis in glioblastoma [9,10,13,14,23,30,34,42,73]. Created with BioRender.com.

Figure 4

Elevated zonulin levels create a carcinogenic environment in a vicious cycle [9,42,43,55]. Created with BioRender.com.