Bacterial Lysate from the Multi-Strain Probiotic SLAB51 Triggers Adaptative Responses to Hypoxia in Human Caco-2 Intestinal Epithelial Cells under Normoxic Conditions and Attenuates LPS-Induced Inflammatory Response

Hypoxia-inducible factor-1alpha (HIF-1alpha), a central player in maintaining gut-microbiota homeostasis, plays a pivotal role in inducing adaptive mechanisms to hypoxia and is negatively regulated by prolyl hydroxylase 2 (PHD2). HIF-1alpha is stabilized through PI3K/AKT signaling regardless of oxygen levels. Considering the crucial role of the HIF pathway in intestinal mucosal physiology and its relationships with gut microbiota, this study aimed to evaluate the ability of the lysate from the multi-strain probiotic formulation SLAB51 to affect the HIF pathway in a model of in vitro human intestinal epithelium (intestinal epithelial cells, IECs) and to protect from lipopolysaccharide (LPS) challenge. The exposure of IECs to SLAB51 lysate under normoxic conditions led to a dose-dependent increase in HIF-1alpha protein levels, which was associated with higher glycolytic metabolism and Llactate production. Probiotic lysate significantly reduced PHD2 levels and HIF-1alpha hydroxylation, thus leading to HIF-1alpha stabilization. The ability of SLAB51 lysate to increase HIF-1alpha levels was also associated with the activation of the PI3K/AKT pathway and with the inhibition of NF-kB, nitric oxide synthase 2 (NOS2), and IL-1 increase elicited by LPS treatment. Our results suggest that the probiotic treatment, by stabilizing HIF-1alpha, can protect from an LPS-induced inflammatory response through a mechanism involving PI3K/AKT signaling.