Background: Persistent Inflammation, Immunosuppression, and Catabolism Syndrome (PICS) severely affects patients' quality of life and social reintegration, and is a major concern in critical care medicine. Methods: in our study, cecal ligation and puncture (CLP) was used to establish a PICS mice model. The effects of hyaluronic acid (HA) with different molecular weights (3 kDa and 1600 kDa) on the health of PICS mice were evaluated by histopathological analysis. Pulmonary microbial composition and structure were analyzed by 16S rRNA gene sequencing, and the correlation between gut and lung microbiota was assessed using Pearson correlation analysis. Results: both 3 kDa and 1600 kDa HA alleviated PICS by regulating gut-lung axis microbiota dysbiosis, with a significantly stronger gut-lung microbiota correlation in the 3 kDa HA group, and 1600 kDa HA was superior to 3 kDa HA in weakening gut-lung microbial interaction, suggesting that the difference in their blocking ability may account for the distinct therapeutic effects.