Akkermansia muciniphila- and Pathogenic Bacteria-Derived Endotoxins Differently Regulate Human Dendritic Cell Generation and γδ T Lymphocyte Activation

Lipopolysaccharide (LPS) is a potent endotoxin released at high concentrations in acute infections, causing massive host inflammatory response. Accumulating evidence indicates that dysbiosis-associated chronic low levels of circulating LPS can sustain a prolonged sterile low-grade inflammation that increases the risk of several non-communicable diseases. Interventions aimed at increasing the abundance of beneficial/probiotic bacteria, including Akkermansia muciniphila, result in reduced inflammation, favoring metabolic and immune health. Immunosuppression is a common feature in conditions of chronic inflammation, and dendritic cells (DCs) represent key targets given their ability to shift the balance toward immunity or tolerance. In this study, the effects of low concentrations of LPS from pathogenic (Escherichia coli and Salmonella enterica) and probiotic (Akkermansia muciniphila) bacterial species on human DC generation and functions were compared. We report that monocyte precursor priming with Escherichia coli and Salmonella enterica LPS forces the differentiation of PD-L1-expressing DCs, releasing high levels of IL-6 and IL-10, and impairs their capacity to drive full TCR-Vδ2 T cell activation. Conversely, comparable concentrations of Akkermansia muciniphila promoted the generation of DCs with preserved activating potential and immunostimulatory properties. These results shed light on potential mechanisms underlying the impact of low endotoxemia on disease risk and pathogenesis, and increase our understanding of the immunomodulatory effects of Akkermansia muciniphila