SARS-CoV-2 Omicron BA.2.86 and JN.1 expand tropism in human proximal intestinal epithelium.

Omicron SARS-CoV-2 has diversified into multiple sub-lineages, complicating assessment of their intrinsic phenotypes due to background population immunity. We compare replication and biological characteristics of variants from BA.1 to JN.1 using human bronchial and lung explants, airway organoids, colon cells, and proximal intestinal enteroids. XBB.1.5 and EG.5.1 achieve higher replication titres in respiratory tissues than BA.2.86 and JN.1, indicating enhanced respiratory fitness. EG.5.1 displays dual cell-entry pathways and greater replication in alveolar epithelial cells, supporting increased lung tropism and pathogenicity. In contrast, BA.2.86 and JN.1 rely on TMPRSS2-mediated entry in airways. Notably, BA.2.86 and JN.1 replicate more efficiently than EG.5.1 in proximal intestinal enteroids in an ACE2- and TMPRSS2-dependent manner, but not in colon cells. JN.1 exhibits elevated intestinal tropism with limited proinflammatory cytokine induction, suggesting potential for faecal transmission. Here we show XBB.1.5 and EG.5.1 greater transmissibility and severity potential whereas BA.2.86 and JN.1 exhibit enhanced intestinal adaptation.