Oral administration of the commensal Alistipes onderdonkiiprolongs allograft survival

Abstract Intestinal commensals can exert immunomodulatory effects on the host, with beneficial or detrimental consequences depending on underlying diseases. We have previously identified a specific commensal, Alistipes onderdonkii, as mediator of prolonged allograft survival and reduced alloimmunity. Here, we investigated its sufficiency and mechanism of action and found that oral administration of a beneficial A. onderdonkii strain DSM19147 but not a neutral strain, DSM108265, was sufficient to delay minor mismatched skin graft rejection in a TNF-dependent manner. Specifically, DSM19147 decreased TNF production in T cells and antigen-presenting cells, and TNF neutralization prolonged graft survival. Metagenomics and metabolomics analyses between DSM19147 versus strains that did not prolong graft survival identified unique genes and metabolites correlated with the anti-inflammatory effect of DSM19147. Candidate metabolic pathways unique to DSM19147 pointed to sialic acid and KDO2-lipid A modifications. Our findings identify A. onderdonkii DSM19147 as an anti-inflammatory probiotic that improves transplant survival. Supported by NIAID grant 2R01AI115716 to MLA, NIAID grant 1U01AI132898 to MLD and DP, NIDDK grant TL1DK132769 to MR, NIAID grant 5T32AI007090 to MS and MK, and by the Growth, Development, and Disabilities Training Program grant (T32 HD007009) to CM.