Pathogenic infections can lead to metabolic alterations that result in maladies such as cachexia, or muscle wasting. Antibiotics can be prescribed to treat a variety of intestinal diseases or inflammatory conditions, but these agents can also disrupt the natural microbiome ecology that could perhaps provide benefits to protecting against metabolic dysregulations. On top of this, harnessing components of the microbiome with respect disease tolerance is an avenue under continuous exploration. Within this contextual framework, researchers from The Salk Institute for Biological Studies in La Jolla, CA investigated to see whether components of the microbiome could have a protective effect on metabolic dysregulation brought on by gut trauma and/or infection.
To initiate the investigation, the researchers used an induced-injury model known as the dextran sulfate sodium (DSS) intestinal injury model to create symptoms associated with inflammatory bowel disease/Crohn’s disease. DSS was applied to mice in two cohorts procured from two distinct laboratories (Jackson labs [Jax] and UC Berkeley lab [CB]). This treatment was administered to C57 mice followed by an administration of an antibiotic cocktail of ampicillin, vancomycin, neomycin, and metronidazole (AVNM) to provide remedy for the injury. The AVNM cocktail had no impact on the severity of DSS in mice procured from Jackson labs, whereas mice procured from UC Berkeley colonies demonstrated significantly less muscle wasting. This observation led to the hypothesis that microbiota composition differences between both cohorts of mice drove this observation.
After examining cecal content from AVNM-CB and AVNM-Jax mice, it was determined that the CB mice had a higher composition of E. coli compared to the Jax mice. Building on the original supposition, the researchers then administered E. coli to Jax mice, and upon DSS administration, they demonstrated significantly less wasting pathology as compared to the vehicle control groups (i.e., DSS treatment without being administered E. coli). The researchers further investigated whether E. coli had a protective effect in response to infectious microbes in addition to induced-DSS injury, and Jax mice were infected with Salmonella Typhimurium or Burkholderia thailandensis. There was no significant difference in alterations in host metabolism, caloric uptake, or inflammation between E. coli-administered groups and controls. However, the E. coli group demonstrated increased signaling in the insulin-like growth factor 1/phosphatidylinositol 3-kinase/AKT pathway in skeletal muscle, a pathway implicated in the prevention of muscle wasting. This finding effectively provides mechanistic evidence of protecting against muscle wasting.
Together, these findings provide additional evidence that support the microbiome’s role in tempering inflammatory disease or injury. Further delineation of molecular pathways associated with these maladies will advance our understanding and treatment of disease.
