Time-restricted feeding (TRF) is a potent dietary intervention for improving metabolic diseases, including metabolic dysfunction-associated steatotic liver disease/metabolic dysfunction-associated steatohepatitis (MASLD/MASH). However, the mechanism of this efficacy has remained elusive. Here, we show that TRF improves MASLD, which is associated with a significant enrichment of Ruminococcus torques (R. torques). Mechanistically, R. torques suppresses the intestinal HIF-2α-ceramide pathway via the production of 2-hydroxy-4-methylpentanoic acid (HMP). We identify rtMor as a 4-methyl-2-oxopentanoate reductase that synthesizes HMP in R. torques. Finally, we show that either the colonization of R. torques or oral HMP supplementation can ameliorate inflammation and fibrosis in a MASH mouse model. These findings identify R. torques and HMP as potential TRF mimetics for the treatment of metabolic disorders.

The gut microbiota has been found to play an important role in the progression of metabolic dysfunction-associated steatohepatitis (MASH), but the mechanisms have not been established. Here, by developing a click-chemistry-based enrichment strategy, we identified several microbial-derived bile acids, including the previously uncharacterized 3-succinylated cholic acid (3-sucCA), which is negatively correlated with liver damage in patients with liver-tissue-biopsy-proven metabolic dysfunction-associated fatty liver disease (MAFLD). By screening human bacterial isolates, we identified Bacteroides uniformis strains as effective producers of 3-sucCA both in vitro and in vivo. By activity-based protein purification and identification, we identified an enzyme annotated as β-lactamase in B. uniformis responsible for 3-sucCA biosynthesis. Furthermore, we found that 3-sucCA is a lumen-restricted metabolite and alleviates MASH by promoting the growth of Akkermansia muciniphila. Together, our data offer new insights into the gut microbiota-liver axis that may be leveraged to augment the management of MASH.

Polythiourethanes (PTU) and polythioesters (PTE) derived from renewable sources are emerging sustainable polymers for their excellent degradability and recyclability. However, P(TU-alt-TE) copolymers have been rare and challenging to synthesize. Here, we report the efficient synthesis of novel P(TU-alt-TE) copolymers via the alternating copolymerization of N-thiocarboxyanhydrides (NTA)/episufides (ES) and provide mechanistic insight into the alternating chain propagation process via density functional theory (DFT) calculation. The incorporation of ESs into traditional peptide backbone is capable of adjusting the glass transition temperature below thermal decomposition temperature, which confers better thermal processability by regulating the rigidity of the backbone and the hydrogen bond interaction among the polymer chains. Crosslinked PTUs with tailored properties are accessible by altering the feeding ratio of NTAs and (bifunctional) ESs. Moreover, the thiourethane in the backbone can endow interesting underwater adhesion properties to the materials. Considering the broad scope of NTA and ES monomers, this method is expected to provide a promising and general route to a wide range of P(TU-alt-TE) copolymers with diverse properties.

The rapid and controlled synthesis of high molecular weight (MW) polysarcosine (pSar), a potential polyethylene glycol (PEG) alternative, via the ring-opening polymerization (ROP) of N-carboxyanhydride (NCA) is rare and challenging. Here, we report carboxylic acid-catalyzed well-controlled ROP of Sar-NCA, which accelerates the polymerization rate up to 50 times, and enables the robust synthesis of pSar with unprecedented high molecular weight (MW) up to 586 kDa (DP ~ 8200) and exceptionally narrow dispersity (Ð) below 1.02. Density functional theory (DFT) calculations combined with mechanistic experiments identify the carbamic acid as dormant species before generating the secondary amine for chain propagation, and elucidate the role of carboxylic acid as a bifunctional catalyst that significantly facilitates proton transfer processes and avoids charge separation. High MW pSar demonstrates improved thermal and mechanical properties over low MW pSar. This work provides a simple yet highly efficient approach to ultra-high MW pSar and generates new fundamental understandings useful not only for the ROP of Sar-NCA but also other NCAs.