François Trottein

The age‐related decline in immunity reduces the effectiveness of vaccines in older adults. Immunosenescence is associated with chronic, low‐grade inflammation, and the accumulation of senescent cells. The latter express Bcl‐2 family members (providing resistance to cell death) and exhibit a pro‐inflammatory, senescence‐associated secretory phenotype (SASP). Preexisting senescent cells cause many aging‐related disorders and therapeutic means of eliminating these cells have recently gained attention. The potential consequences of senescent cell removal on vaccine efficacy in older individuals are still ignored. We used the Bcl‐2 family inhibitor ABT‐263 to investigate the effects of pre‐vaccination senolysis on immune responses in old mice. Two different ovalbumin (OVA)‐containing vaccines (containing a saponin‐based or a CpG oligodeoxynucleotide adjuvant) were tested. ABT‐263 depleted senescent cells (apoptosis) and ablated the basal and lipopolysaccharide‐induced production of SASP‐related factors in old mice. Depletion of senescent cells prior to vaccination (prime/boost) had little effect on OVA‐specific antibody and T‐cell responses (slightly reduced and augmented, respectively). We then used a preclinical melanoma model to test the antitumor potential of senolysis before vaccination (prime with the vaccine and OVA boost by tumor cells). Surprisingly, ABT‐263 treatment abrogated the vaccine's ability to protect against B16 melanoma growth in old animals, an effect associated with reduced antigen‐specific T‐cell responses. Some, but not all, of the effects were age‐specific, which suggests that preexisting senescent cells were partly involved. Hence, depletion of senescent cells modifies immune responses to vaccines in some settings and caution should be taken when incorporating senolytics into vaccine‐based cancer therapies.

The gut microbiota is now considered as a key player in the development of metabolic dysfunction. Therefore, targeting gut microbiota dysbiosis has emerged as a new therapeutic strategy, notably through the use of live gut microbiota-derived biotherapeutics. We previously highlighted the anti-inflammatory abilities of two Parabacteroides distasonis strains. We herein evaluate their potential anti-obesity abilities and show that the two strains induced the secretion of the incretin glucagon-like peptide 1 in vitro and limited weight gain and adiposity in obese mice. These beneficial effects are associated with reduced inflammation in adipose tissue and the improvement of lipid and bile acid metabolism markers. P. distasonis supplementation also modified the Actinomycetota, Bacillota and Bacteroidota taxa of the mice gut microbiota. These results provide better insight into the capacity of P. distasonis to positively influence host metabolism and to be used as novel source of live biotherapeutics in the treatment and prevention of metabolic-related diseases.