Impaired postprandial GLP-2 response enhances endotoxemia, systemic inflammation, and kidney injury in metabolic dysfunction-associated steatohepatitis (MASH): effect of phospholipid curcumin meriva

Gut Microbes. 2024 Jan-Dec;16(1):2424907. doi: 10.1080/19490976.2024.2424907. Epub 2024 Dec 2.

Abstract

We investigate the role of homeostatic mechanisms involved in acute, postprandial nutrient metabolism and nutrient-induced systemic inflammation in CKD presence and progression in Metabolic dysfunction-associated steatohepatitis (MASH). We assessed postprandial incretins (GLP-1 and GIP), intestinotropic hormone GLP-2, endotoxin LPS, Zonulin (a marker of intestinal permeability), hepatokines, adipokines and NF-kB activation in circulating MNCs during a meal tolerance test in 52 biopsy proven MASH patients randomized to curcumin Meriva or placebo and 26 matched controls. At baseline, MASH-CKD had a lower GLP-2 response and a 2-fold higher postprandial LPS and NF-kB activation in MNCs than MASH patients without CKD, but similar remaining postprandial or fasting parameters. Postprandial IAUC GLP-2 predicted the presence of CKD in MASH (OR = 0.43, 95%CI:0.32-0.80, p = 0.008) independently of liver histology and traditional risk factors. After 72 weeks, changes in IAUC GLP-2 independently predicted the presence of CKD (OR = 0.49, 95%CI:0.21-0.73, p = 0.010) and eGFR changes [β(SE) = 0.510(0.007, p = 0.006] at end-of-treatment, In MASH, an impaired GLP-2 response to meals is associated with intestinal barrier dysfunction, endotoxemia and NF-kB-mediated systemic inflammation and may promote renal dysfunction and CKD. These data provide the rationale for evaluating GLP-2 analogues in MASH-related CKD.

Keywords: NF-kB; Steatohepatitis; albuminuria; chemokine; eGFR; postprandial.

Publication types

  • Randomized Controlled Trial

MeSH terms

  • Adult
  • Aged
  • Curcumin* / pharmacology
  • Curcumin* / therapeutic use
  • Endotoxemia* / chemically induced
  • Endotoxemia* / metabolism
  • Fatty Liver / metabolism
  • Female
  • Glucagon-Like Peptide 2* / metabolism
  • Haptoglobins
  • Humans
  • Inflammation* / metabolism
  • Male
  • Middle Aged
  • Postprandial Period*
  • Protein Precursors

Substances

  • Glucagon-Like Peptide 2
  • Curcumin
  • zonulin
  • Haptoglobins
  • Protein Precursors

Grants and funding

This study was funded partly by Indena S.p.A., Milan, Italy, and partly by a grant to RG for the Italian Ministry of University and Research, (MIUR, Rilo, ex 60%, 2023). The sponsor provided funds to acquire kits for biochemical and histological assessments; it had no role in study design, data acquisition and analysis and discussion.