Mouse Models for Human Intestinal Microbiota Research: a Critical Evaluation

Cell. Mol. Life Sci. (2018) 75:149–160 https://doi.org/10.1007/s00018-017-2693-8 Cellular and Molecular LifeSciences MULTI-AUTHOR REVIEW Mouse models for human intestinal microbiota research: a critical evaluation Floor Hugenholtz1,3 · Willem M. de Vos1,2 Received: 25 September 2017 / Accepted: 29 September 2017 / Published online: 9 November 2017 © The Author(s) 2017. This article is an open access publication Abstract Since the early days of the intestinal microbi- data. This may afect the reproducibility of mouse micro- ota research, mouse models have been used frequently to biota studies and their conclusions. Hence, future studies study the interaction of microbes with their host. However, should take these into account to truly show the efect of to translate the knowledge gained from mouse studies to diet, genotype or environmental factors on the microbial a human situation, the major spatio-temporal similarities composition. and diferences between intestinal microbiota in mice and humans need to be considered. This is done here with spe- Keywords Microbiome · Metagenome · Phylogeny · cifc attention for the comparative physiology of the intes- Murine models · Reproducibility · Diet tinal tract, the efect of dietary patterns and diferences in genetics. Detailed phylogenetic and metagenomic analysis showed that while many common genera are found in the Introduction human and murine intestine, these difer strongly in abun- dance and in total only 4% of the bacterial genes are found In adult life, a healthy human may harbor several hundreds to share considerable identity. Moreover, a large variety of diferent microbial species in their intestine, which col- of murine strains is available yet most of the microbiota lectively encode more than 100-fold more non-redundant research is performed in wild-type, inbred strains and their genes than there are in the human genome [1–3]. The com- transgenic derivatives. It has become increasingly clear that position of the intestinal microbiota is driven by factors such the providers, rearing facilities and the genetic background as diet, antibiotic therapy, maternal microbiota and genotype of these mice have a signifcant impact on the microbial [4–9]. Since the intestinal tract is the main point of contact composition and this is illustrated with recent experimental of the host immune system and microorganisms, the role of microbiota in both local and systemic immune function Electronic supplementary material The online version of this plays an important role in immunity and health [10]. Early article (doi:10.1007/s00018-017-2693-8) contains supplementary comparative analyses of the intestinal microbiota of human material, which is available to authorized users. and other animals have shown that each mammalian species harbors a distinct microbial composition and can be grouped * Willem M. de Vos [email protected] based on their microbial community and diet [11]. Carni- vores, omnivores and herbivores could be distinguished by 1 Laboratory of Microbiology, Wageningen University, increasing microbiota diversity, which probably refects the Stippeneng 4, Building 124, 6708 WE Wageningen, large variety of plant-derived carbohydrates in the diet of The Netherlands 2 herbivores. The diferences in composition and diversity of Research Programme Unit Immunobiology, Department intestinal tract microbiota in these animal groups indicate of Bacteriology and Immunology, Helsinki University, P.O. Box 21, 00014 Helsinki, Finland that both diet and host collectively afect the microbial composition [11–13]. 3 Present Address: Division of Infectious Diseases, Department of Medicine, Academic Medical Centre, University Studies of the local microbiota at diferent locations along of Amsterdam, Amsterdam, The Netherlands the human intestinal tract require rather invasive sampling Vol.:(0123456789)1 3 150 F. Hugenholtz, W. M. de Vos methods. Pioneering studies have used these and provided example of an anecdotal development is that of Miss Abbie the frst molecular biogeography of the human intestinal E.C. Lathrop who started breeding mice in the early 1900s microbiota by addressing colonic and ileal sites [14, 15]. in Granby MA, USA [19]. In a couple of years, her busi- However, these approaches cannot be scaled for practical ness had grown into an operation with over ten thousand and ethical reasons. While ethical considerations nowadays mice that were used to be sold as pets but also provided also apply to rodent models, these provide an easy way to laboratories in the area for scientifc studies. Subsequently, collect many samples from diferent sites, allow multiple she also started inbreeding mice, avoiding mixing her mice comparisons at large scale, and have the great advantage with wild mice [20, 21]. These inbred mice are the ances- to ofer a wide range of diferent genotypic backgrounds. tors of the most commonly used strain C57BL/6 created in Moreover, rodents and specifcally mice have become the William Castle’s lab (Fig. 1). Since around 1910, these mice most studied disease models for pharmaceutical research were inbred, with over two generations per year; thus, many [16]. Mice models have also been used to study the interac- of the presently available mice have been inbred for over tion of intestinal microbes and its host since the early days 150 generations on average [22]. Also the 129, C3H and when large scale studies became feasible due the develop- BALB/c have a similar origin, where the latter two were a ment of molecular and high throughput approaches [17]. Ini- cross between progenitors of the C57 line and Bagg albino’s tially, most attention has focused on germ-free mice models from H. Bagg (Fig. 1). Some strains were developed much and provided basic insights in initial host–microbe interac- later, like the NOD inbred strain, which was derived from an tion [18]. However, increasingly mice are used as models to outbred colony of Swiss Webster mice. Ohtori developed the study dietary efects, disease development, and the impact of inbred CTS strain from this colony [18]. And in 1980, the microbial therapies. However, in order to translate such gen- F6 of the CTS strain selected for diabetes was taken sepa- erated knowledge from mouse to man, the similarities and rate and the F20 developed spontaneous insulin-dependent diferences between their intestinal microbiota need to be diabetes, and named NOD [23]. The advantages of using considered and these are reviewed here with specifc atten- mice models appealed to many scientists, from that time tion to the historic development of inbred mouse models, the till now, since they are relatively small, easy to maintain in impact of genomics and the diference in intestinal anatomy. large numbers, and can be inbred or genetically modifed to be used as models to study human diseases. It has been estimated that presently over 90% of the rodents used for History of mouse models pharmaceutical research are mice [16]. The majority of presently employed murine strains, i.e., strains belonging to the species Mus musculus, have a com- The mouse versus the human genome mon origin that goes back over 100 years ago and derive from Asian or European fancy mice, usually yellow, white Lineages of men and mouse are separated by more than or with another appealing color, that had been developed as 90 million years of evolution, yet more than 85% of the pets as early as 1200 BC in China (Fig. 1). The best recorded genomic sequences between mouse and human are still Fig. 1 A simplifed family tree of the main mouse strains used in intestinal microbiota research. Solid lines indicate inbreeding and dotted lines indi- cated outbreeding of a mouse line. When lines are connected a cross or a new line was created by selection. Data adapted from [20, 21] 1 3 151 Mouse models for human intestinal microbiota research: a critical evaluation conserved [24, 25]. One of the major divergences that diversity in GI tract and to relate this back to the human occurred in the genomes in the course of this evolutionary situation [22]. time span is found in the primary sequence of regulatory ele- Mice are exclusive herbivores, while humans can be her- ments. Recent detailed genomic and transcriptomic analysis bivores, carnivores and everything in between, depending on revealed that half of the transcription factor binding sites culture, food supply and many other factors. It appears that of the murine genome does not appear to have orthologous there are considerable anatomical, histological and physi- sequences present in the human genome [26]. However, the ological features of the intestinal tract that are shared. The regulatory networks among transcription factors are highly main diference is the size of the intestinal tract in relation conserved between mice and humans [27]. In contrast, the to the total size of the species but there are many distinct overall gene expression and its regulation were found to be diferences throughout the intestinal tract, which should be considerably diferent between the two species. However, it considered during experimental design and interpretation should be emphasized that most human functional studies (Fig. 2). have been performed with cell lines and it is known that One of the most remarkable diferences to be noted at the their expression patterns may difer from the large variety of beginning of the tract, is the presence of a non-glandular tissue-specifc expression in the human body. Comparative forestomach in mice that is absent in humans. This fores- genomic studies do not sufer from that bias and have shown tomach is lined with keratinizing squamous mucosa and that the immune system and its regulation has dramatically covers two-thirds of the entire stomach. The forestomach changed during evolution, indicating a rapid but species- has no secretory activity and is used for food storage [30] specifc adaption of this system in the diferent species [28]. and is covered with a bioflm comprised of strains of various As the intestinal tract is the site of the majority of innate and Lactobacillus spp.

Load more