The role of gut microbiome in chemical-induced metabolic and toxicological murine disease models

The role of gut microbiome in human health and disease is well established. While evidence-based pharmacological studies utilize a variety of chemical-induced metabolic and toxicological disease models that in part recapitulate the natural mode of disease pathogenesis, the mode of actions of these disease models are likely underexplored. Conventionally, the mechanistic principles of these disease models are established as direct tissue toxicity through redox imbalance and pro-inflammatory injury. However, emerging evidences suggest that the mode of action of these chemicals could be largely associated with changes in gut microbial populations, diversity and metabolic functions, affecting pathological changes along the gut-liver and gut-pancreas axis. Especially in these disease models, reversal of disease severity or less sensitivity to induced disease pathogenesis has been observed when germ-free or antibiotic-supplemented microbiota-depleted rodents were treated with disease causing chemicals. Thus, by summarizing evidences from in vivo pharmacological interventions, this review revisits the mode of action of carbon tetrachloride-induced cirrhosis, diethylnitrosamine-induced hepatocellular carcinoma, acetaminophen-induced hepatotoxicity and alloxan- and streptozotocin-induced diabetes through the light of gut microbiota. How changes in gut microbiome affects tissue-level toxicity likely through intestinal-level mechanisms like gastrointestinal inflammation and gut barrier dysfunction has also been discussed. Additionally, this review discusses potential pitfalls of inconsistent experimental models that precludes defining the gut microbial effects in evidence-based pharmacology. Collectively, this review emphasizes the underexplored role of microbial intervention in experimental pharmacology and aims to provide direction towards redefining and establishing microbiome-centric alternative mode of action of chemical-induced metabolic and toxicological disease models in pharmacological research.