Elsevier

Life Sciences

Volume 258, 1 October 2020, 118172
Life Sciences

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

https://doi.org/10.1016/j.lfs.2020.118172Get rights and content

Highlights

  • Pharmacological and toxicological chemicals cause direct tissue injury.

  • Conventional mode of action is through oxidative and inflammatory stress.

  • But they also alter gut microbial population, diversity and metabolic functions.

  • Thus, chemical-induced dysbiosis could indirectly result in tissue injury.

Abstract

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.

Introduction

The global burden of metabolic disease is at epidemic proportion. The key concepts of intestinal etiology of metabolic disease have emerged out of our understanding of calorie overload. Purified high fat (HF)-diets can be used to induced various metabolic conditions such as obesity, diabetes and non-alcoholic fatty liver disease in experimental rodent models, which to a larger extent have comparable pathophysiological phenotypes to human metabolic conditions. Data suggested that altered gut microbiota and their increased energy harvesting capacity due to prolonged HF-feeding is associated with weight gain [1] (Fig. 1A). Furthermore, HF diet-induced altered gut microbiota potentiates metabolic endotoxemia that in turn promotes ‘low-grade’ systemic inflammation, a hallmark of obesity and diabetes [2]. Systemic (e.g. toll-like receptor-4) and intestinal (e.g. epithelial tight junction) targets have been identified [3,4], with supportive clinical evidences [5,6], have established that the etiology of metabolic disease are primarily intestine derived where gut microbiota plays profound role in potentiating and mediating metabolic anomalies (Fig. 1B). Thus intestine-centric prophylactic strategies have been proposed to mitigate these metabolic complications along the gut-systemic axis.

Since the advent of our understanding of gut-microbial biotransformation of drugs and phytochemicals responsible for altered bioactivity and bioavailability [7,8], in vivo models have become quintessential for pharmacological exploration of experimental drugs. Indeed, rats and mice collectively corresponds to >77% share of in vivo functional studies [9]. While HF-diet is a gold-standard for investigational chronic metabolic studies, chemical-induced acute metabolic disease models also serve as a reliable and cost-effective means for exploring and understanding the etiology of metabolic complications and for testing of prospective pharmacological drugs.

As discussed below, historically, the mode of actions of chemical-induced metabolic disease models have been attributed to direct tissue toxicity. Especially during the last few decades, our in-depth understanding of redox homeostasis has emphasized the tissue-level effects of the chemical-induced disease models primarily to be oxidative and pro-inflammatory insult-mediated cellular death. For example, carbon tetrachloride (CCl4), that is extensively used to induce liver cirrhosis, triggers oxidative hepatic injury through its derivative trichloromethyl radical. However, recent evidence indicate alternative and additional mechanisms through which CCl4-dependent hepatic injury could be in part associated with alterations in gut microbial phenotype. Indeed, this is true for several of chemical-induced metabolic disease models, indicating the mode of action of these chemicals are in-part dependent on gut microbiota.

The pivotal role of gut microbiota in human health, disease and every other physiological aspect is well established. While recent plethora of evidence suggests important role of intestinal microflora in chemical-induced disease models, a systematic and comprehensive account of those evidences are lacking in the literature. This is concerting since without addressing the microbiota-associated factors in experimental metabolic models, pharmacological studies would only treat symptoms, rather than the root of disease. Thus, this review is aimed to summarize the experimental evidences indicating microbiota-dependent alternative mode of action of metabolic disease models. Collectively, this review of recent evidences supporting microbial interventions in chemical-induced disease models would allow future investigators to emphasize more on microbial effects in pharmacological interventions upstream to tissue-specific metabolic complications and may serve as a reference for future chemical-induced pharmacological interventions.

Section snippets

Diet-induced metabolic disease model- the benchmark of microbiome research

Diet has emerged as the key modulator of gut microbiota and diet-induced metabolic disease models are considered as the gold-standard for in vivo pharmacological investigation of new drugs. Substantial evidence show that 60% (w/w) HF diet-induce an array of metabolic abnormalities including obesity, fatty-liver and insulin resistance (IR) [[10], [11], [12], [13], [14]]. On HF-diet, hyperglycemia appears at 4-wk [15], fat-accumulation accelerates at 8-wk [16] and histopathological symptoms of

Carbon tetrachloride (CCl4)-induced liver cirrhosis

The classical CCl4-induced hepatotoxicity (Fig. 2) is mediated by trichloromethyle radical (CCl3radical dot) that is generated through cytochrome P450-dependent reductive dehalogenation of CCl4 [26,27]. CCl3radical dot triggers a cascade of intracellular changes that ultimately leads to oxidative and inflammatory stress-mediated hepatotoxicity. Further downstream generation of highly reactive trichloromethylperoxy radical (CCl3OOradical dot) induces direct intracellular injury, exacerbating the hepatoxicity. Although, CCl4 in

Diethylnitrosamine (DEN)-induced hepatocellular carcinoma (HCC)

DEN is a hepatocellular carcinogen that potentiates HCC along the inflammation-fibrosis-cancer axis [50] (Fig. 3). DEN is one of the most reliable hepatocellular carcinogen that is used alone or in combination with other hepatotoxins (e.g. CCl4) or chronic inducers of metabolic anomalies (e.g. HF diet) to study an array of pathological, inflammatory and oncological parameters related to HCC [51]. HCC development depends on rodent age and sex, where younger and male mice are more susceptible to

Acetaminophen-induced hepatotoxicity

Acetaminophen, commonly known as Paracetamol, is an analgesic and antipyretic drug, overdose of which is attributed to >40% of all cases of drug-induced hepatotoxicity in the United States [64]. Key symptoms of acetaminophen-overdose include mild hepatitis, cholestasis and asymptomatic transaminase elevations, and could account for about 50% cases of acute liver failure [65]. Acetaminophen is frequently used in evidence-based in vivo pharmacology as hepatotoxic agent to evaluate the

Alloxan-induced diabetes

Alloxan (5,5-dihydroxyl pyrimidine-2,4,6-trione) is a urea derivative and a glucose analogue, that is extensively used as an insulin-dependent diabetogenic agent in pharmacological studies [77]. The diabetogenic activity of alloxan is through direct pancreatic β-cell toxicity (Fig. 5), thereby lowering insulin production and increasing systemic glucose load. In particular alloxan-treatment induce two separate pathological events viz. selective inhibition of glucose-induced insulin secretion and

Streptozotocin (STZ)-induced diabetes

STZ is a cytotoxic glucose analogue, that has been initially used as chemotherapeutic alkylating agent for treating metastasizing pancreatic islet cell tumors [95]. Since the discovery of its diabetogenic properties, STZ is extensively used to induce experimental diabetes in pharmacological studies (Fig. 6). The central element of STZ-induced diabetes is GLUT 2-dependent uptake into pancreatic β-cells and subsequent induction of apoptosis via DNA fragmentation due to the nitrosourea moiety in

Conclusions and perspectives

Data obtained from HF-induced obese murine model has been the primary source of knowledge of intestinal bacterial ecology. Yet, no absolute microbial marker of ‘dysbiosis’ and that of ‘healthy microbiota’ exists. Thus, it would be partially unfair to compare the intestinal-level microbial changes of clinical or HF-induced metabolic conditions to that of chemical-induced ones. In line, although the aforementioned evidences of chemical-induced disease models indicate a central role of gut

Abbreviations

    O2

    superoxide radical

    OH

    hydroxyl radical

    ALT

    alanine aminotransferase

    CCl3radical dot

    trichloromethyle radical

    CCl3OOradical dot

    trichloromethylperoxy radical

    CCl4

    carbon tetrachloride

    CD

    cognitive dysfunction

    CYP2E1

    cytochrome P450 2E1

    DEN

    diethylnitrosamine

    F:B

    Firmicutes-to-Bacteroidetes ratio

    Fe2+

    ferrous ion

    GF

    germ free

    GLP-1

    glucagon-like peptide-1

    GLT2

    glucose transporter 2

    GSH

    Glutathione

    GSSH

    Glutathione oxidized

    H2O2

    hydrogen peroxide

    HCC

    hepatocellular carcinoma

    HF

    high fat

    IL

    interleukin

    IR

    insulin resistance

    JAK/STAT

    janus kinases/signal

Declaration of competing interest

The author declares that he has no conflict of interest.

Acknowledgements

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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