A Nine-Strain Bacterial Consortium Improves Portal Hypertension and Insulin Signaling and Delays NAFLD Progression In Vivo

Abstract

The gut microbiome has a recognized role in Non-alcoholic fatty liver disease (NAFLD) and associated comorbidities such as Type-2 diabetes and obesity. Stool transplantation has been shown to improve disease by restoring endothelial function and insulin signaling. However, more patient-friendly treatments are required. The present study aimed to test the effect of a defined bacterial consortium of nine gut commensal strains in two in vivo rodent models of Non-alcoholic steatohepatitis (NASH): a rat model of NASH and portal hypertension (PHT), and the Stelic animal (mouse) model (STAM™). In both studies the consortium was administered orally q.d. after disease induction. In the NASH rats, the consortium was administered for 2 weeks and compared to stool transplant. In the STAM™ study administration was performed for 4 weeks, and the effects compared to vehicle or Telmisartan at the stage of NASH/early fibrosis. A second group of animals was followed for another 3 weeks to assess later-stage fibrosis. In the NASH rats, an improvement in PHT and endothelial function was observed. Gut microbial compositional changes also revealed that the consortium achieved a more defined and richer replacement of the gut microbiome than stool transplantation. Moreover, liver transcriptomics suggested a beneficial modulation of pro-fibrogenic pathways. An improvement in liver fibrosis was then confirmed in the STAM™ study. In this study, the bacterial consortium improved the NAFLD activity score, consistent with a decrease in steatosis and ballooning. Serum cytokeratin-18 levels were also reduced. Therefore, administration of a specific bacterial consortium of defined composition can ameliorate NASH, PHT, and fibrosis, and delay disease progression.

Gut–Liver Axis Dysregulation in Portal Hypertension: Emerging Frontiers

“…The link between the GM and endothelium and PH was also suggested by the paper of Pinheiro et al [53], reporting that a distinctive bacterial consortium exhibits the potential to ameliorate MASLD, type-2 diabetes, and obesity by reinstating endothelial function, improving insulin signaling, and retarding the progression of these conditions. The authors underscore that metabolic dysregulation is a shared characteristic of MASLD.…”

Faecal Microbiota Transplantation, Paving the Way to Treat Non-Alcoholic Fatty Liver Disease

“…There was no difference in glucose and insulin levels, HOMA-IR or cholesterol in any group. However, in the stelic animal (mouse) model (STAM™) study, where a consortium was administrated during 4 weeks, an improvement in NAS was observed, consisting in a decrease in steatosis and ballooning, and in liver fibrosis [ 95 ].…”