From gut to liver: organoids as platforms for next-generation toxicology assessment vehicles for xenobiotics

Abstract

Traditional toxicological assessment relied heavily on 2D cell cultures and animal models of study, which were inadequate for the precise prediction of human response to chemicals. Researchers have now shifted focus on organoids for toxicological assessment. Organoids are 3D structures produced from stem cells that mimic the shape and functionality of human organs and have a number of advantages compared to traditional models of study. They have the capacity to replicate the intricate cellular microenvironment and in vivo interactions. They offer a physiologically pertinent platform that is useful for the researchers to monitor cellular responses in a more realistic manner and evaluate drug toxicity. Additionally, organoids can be created from cells unique to a patient, allowing for individualized toxicological research and providing understanding of the inter-individual heterogeneity in drug responses. Recent developments in the use of gut and liver organoids for assessment of the xenobiotics (environmental toxins and drugs) is reviewed in this article. Gut organoids can reveal potential damage to the digestive system and how xenobiotics affect nutrient absorption and barrier function. Liver is the primary site of detoxification and metabolism of xenobiotics, usually routed from the gut. Hence, these are linked and crucial for evaluating chemical or pollutant induced organ toxicity, forecasting their metabolism and pharmacokinetics. When incorporated into the drug development process, organoid models have the potential to improve the accuracy and efficiency of drug safety assessments, leading to safer and more effective treatments. We also discuss the limitations of using organoid-based toxicological assays, and future prospects, including the need for standardized protocols for overcoming reproducibility issues.

1. Introduction

Organoids are multicellular, three-dimensional cultures made from stem cells. They assemble themselves into structures with cell types specific to each organ and imitate some of the in vivo cell structure and functions of the original organ [1, 2]. Organoids have a lot of potential for use in basic research and personalized therapy as our knowledge of organogenesis and tissue engineering develops [3]. Organoids also serve as disease models and facilitate drug screening through genetic alterations, exposure to disease-relevant stimuli, and toxicity and efficacy testing of medicinal substances, providing a closer-to-natural system than 2D cultures or animal models.

This is because the traditional two-dimensional (2D) cell cultures failed to replicate the natural cell morphology and interactions found in vivo as they lose their normal shape, undergo aberrant splitting and flattening, and disrupt the differentiation phenotype over time [4]. This limits their relevance for studying human biology and disease mechanisms. Epidemiological studies also have their own limitations as they rely on observational data and can be influenced by confounding factors, such as lifestyle, genetics, and co-exposures [5, 6]. Establishing causal relationships between environmental toxicant exposure and health outcomes can be complex and may require large sample sizes and long-term follow-up [7, 8]. Additionally, epidemiological studies lack mechanistic insights into the toxicity of environmental pollutants.

Systems toxicology approaches, which model the absorption, distribution, metabolism, and excretion (ADME) of chemicals, can also be limited in their predictive accuracy [9]. Similarly, animal models remain widely used in toxicology research but they have intrinsic drawbacks in predicting human responses to toxins due to species-specific differences in anatomy, physiology, and metabolism [10, 11]. These differences often lead to discrepancies in toxicity outcomes, making the extrapolation of animal data to human health risks challenging and potentially unreliable. Hence, 3D cultures or organoids are a promising alternative for overcoming these limitations [12]. By better recapitulating human tissue architecture and cellular interactions, they can significantly contribute to toxicological studies aimed at cellular.