Optogenetic operated probiotics to regulate host metabolism by mimicking enteroendocrine

Abstract

The enteroendocrine system plays an important role in metabolism. The gut microbiome regulates enteroendocrine in an extensive way, arousing attention in biomedicine. However, conventional strategies of enteroendocrine regulation via gut microbiome are usually non-specific or imprecise. Here, an optogenetic operated probiotics system was developed combining synthetic biology and flexible electronics to achieve in situ controllable secretion to mimic enteroendocrine. Firstly, optogenetic engineered Lactococcus lactis (L. lactis) were administrated in the intestinal tract. A wearable optogenetic device was designed to control optical signals remotely. Then, L. lactis could secrete enteroendocrine hormone according to optical signals. As an example, optogenetic L. lactis could secrete glucagon-like peptide-1(GLP-1) under the control of the wearable optogenetic device. To improve the half-life of GLP-1 in vivo, the Fc domain from immunoglobulin was fused. Treated with this strategy, blood glucose, weight and other features were relatively well controlled in rats and mice models. Furthermore, up-conversion microcapsules were introduced to increase the excitation wavelength of the optogenetic system for better penetrability. This strategy has biomedical potential in metabolic diseases therapy by mimicking enteroendocrine.

Light-regulated gene expression in Bacteria: Fundamentals, advances, and perspectives

“…Similarly, EL222 was used in Sinorhizobium meliloti (Pirhanov et al, 2021). Applications of none of these three optogenetic circuits are restricted to Gram-negative bacteria but extend to for instance bacilli e.g., B. subtilis (Castillo-Hair et al, 2019), and Lactococcus lactis (Pan et al, 2021;Pan et al, 2022;Zhang et al, 2021). While in most of these studies the optogenetic setups were used essentially unmodified, other reports required the optimization of plasmid backbones, promoters, ribosome-binding sites, and chromophore supply to elicit and boost light-dependent gene-expression responses (Castillo-Hair et al, 2019;Hueso-Gil et al, 2020).…”

“…Light-responsive bacteria were also considered as potential therapeutics for other diseases and disorders. Again with the probiotic L. lactis as the chassis, the pDawn circuit was used to control the expression of the hormone glucagon-like peptide 1 (GLP-1) (Zhang et al, 2021(Zhang et al, , 2022. Upon oral administration, the Lactococci stayed viable in the rat intestinal tract for several days.…”

“…In a type-II diabetes rat model, the light-induced GLP-1 production thus lowered the blood glucose levels. Compared to constitutive expression and application of GLP-1, the optogenetically stimulated, intermittent hormone production may reduce the metabolic burden and side effects caused by GLP-1 (Zhang et al, 2021). The application of lightresponsive L. lactis proved versatile and adaptable to other ends (Pan et al, 2022).…”