Modeling microbiota-associated human diseases: from minimal models to complex systems

Abstract

Alterations in the intestinal microbiota are associated with various human diseases of the digestive system, including obesity and its associated metabolic diseases, inflammatory bowel diseases (IBD), and colorectal cancer (CRC). All three diseases are characterized by modifications of the richness, composition, and metabolic functions of the human intestinal microbiota. Despite being multi-factorial diseases, studies in germ-free animal models have unarguably identified the intestinal microbiota as a causal driver of disease pathogenesis. However, for an increased mechanistic understanding of microbial signatures in human diseases, models require detailed refinement to closely mimic the human microbiota and reflect the complexity and range of dysbiosis observed in patients. The transplantation of human fecal microbiota into animal models represents a powerful tool for studying the causal and functional role of the dysbiotic human microbiome in a pathological context. While human microbiota-associated models were initially employed to study obesity, an increasing number of studies have applied this approach in the context of IBD and CRC over the past decade. In this review, we discuss different approaches that allow the functional validation of the bacterial contribution to human diseases, with emphasis on obesity and its associated metabolic diseases, IBD, and CRC. We discuss the utility of simple models, such as in vitro fermentation systems of the human microbiota and ex vivo intestinal organoids, as well as more complex whole organism models. Our focus here lies on human microbiota-associated mouse models in the context of all three diseases, as well as highlighting the advantages and limitations of this approach.

Keywords: Human microbiota-associated mouse models; colorectal cancer; fecal microbiota transplantation; host-microbiota interactions; inflammatory bowel diseases; metabolic diseases; obesity.

Figure 1

The number of publications related to the contribution of the intestinal microbiota to human diseases in the last two decades, grouped per year. Data were obtained by searching PubMed (https://pubmed.ncbi.nlm.nih.gov/) with the term “gut microbiota”, and each human pathology indicated (retrieved 21 December 2021): Obesity, type 2 diabetes (T2D), inflammatory bowel disease (IBD), colorectal cancer (CRC), asthma, allergy, rheumatoid arthritis (RA), and autism.

Figure 2

The number of publications using human microbiota-associated mouse models to study the contribution of the intestinal microbiota to IBD, obesity and its associated metabolic diseases, and CRC in the last decade grouped per year. Data were obtained by searching PubMed (https://pubmed.ncbi.nlm.nih.gov/) with the term “human fecal microbiota transplantation” or “colonized germ-free” or “Human microbiota-associated mice” and each human pathology indicated (retrieved 21 December 2021): obesity, inflammatory bowel disease (IBD), and colorectal cancer (CRC).

Figure 3

Preclinical models for the study of human microbiome-associated diseases. Overview schematic summarizing the different models of choice to study functional host-microbiota interactions, with their advantages and disadvantages, in human diseases of the digestive system, such as obesity and related metabolic disorders, inflammatory bowel diseases, and colorectal cancer. Depicted are: (A) in vitro fermentation systems; (B) ex vivo intestinal organoids; and (C) in vivo HMA mouse models. GF: Germ-free.