Establishment of a gut-on-a-chip device with controllable oxygen gradients to study the contribution of Bifidobacterium bifidum to inflammatory bowel disease

Abstract

Supplemental Bifidobacterium has been shown to aid in the prevention, alleviation, and treatment of inflammatory bowel disease (IBD), but the progression and mechanisms are largely unstudied, partly because of a lack of appropriate models. In vitro human gut models must accurately recreate oxygen concentration gradients consistent with those in vivo to mimic gene expression, metabolism, and host–microbiome interactions. A non-equipment-intensive and inexpensive method for constructing the gut-on-a-chip with physiological oxygen concentration gradients remains challenging. Here, we propose a simple strategy using numerical simulations in a dual-channel gut-on-a-chip to guide chip design and achieve controllable oxygen gradients. By varying the size of microchannels, blocking the oxygen penetration of the polydimethylsiloxane layer at a given location, and controlling the flow of hypoxic/aerobic media, this strategy creates steep gradients across the intestinal epithelium. IBD symptoms were induced on the chip by tumor necrosis factor-α and lipopolysaccharide treatment. Bifidobacterium bifidum has been validated to contribute to the stability of the intestinal epithelial barrier, including preventing epithelial barrier disruption and promoting the repair of damaged intestinal epithelial cell monolayers. These effects may be associated with the co-localization of Bifidobacterium bifidum and ZO-1. This simple but robust approach for designing microfluidic devices is applicable to various organs-on-chips in which fluid dynamics and concentration profiles between different media must be considered. With the customized chip, the integration of activated Bifidobacterium bifidum provides an initial step toward developing a multi-factorial IBD platform. The approach could be scaled up for disease modeling, high-throughput drug screening and personalized medicine.