The end of 'leaky gut': pathway-specific mechanistic approaches to barrier restoration

For over 50 years, increased intestinal permeability has been associated with diverse inflammatory and systemic diseases. Yet the oversimplified concept of 'leaky gut' as a singular phenomenon has limited both mechanistic understanding and therapeutic development.

It is now recognized that intestinal permeability occurs via two molecularly distinct, differentially regulated trans-tight junction pathways, while a tight junction-independent unrestricted pathway allows flux at sites of epithelial damage. The pore pathway is a high-conductance, size-selective and charge-selective flux route that mediates ion and water flux. Its upregulation can be either protective, as in infectious enterocolitis, or pathogenic, as in immune-mediated disease or, as shown recently, in sepsis. Myosin light chain kinase activation enhances flux across the leak pathway, a low-conductance macromolecular flux route, that promotes progression of immune-mediated diseases. Recently developed molecularly targeted, pathway-specific approaches to barrier restoration are effective and can outperform current therapies without the complications of broad immunosuppression.

The evolving pathway-resolved framework transforms intestinal barrier biology from a descriptive science into mechanism-specific therapeutic approaches that have promise as independent agents and as complements to available immune-targeted therapies.