Pharmacological Research 66 (2012) 443–447 Contents lists available at SciVerse ScienceDirect Pharmacological Research jo ur n al hom epage: www.elsevier.com/locate/yphrs Perspective The human gastrointestinal microbiota—An unexplored frontier for pharmaceutical discovery  Guus Roeselers a,∗ , Jildau Bouwman a , Koen Venema b , Roy Montijn a a Microbiology & Systems Biology, TNO, Utrechtseweg 48, 3704 HE Zeist, The Netherlands b Pharmacokinetics & Human Studies, TNO, Utrechtseweg 48, 3704 HE Zeist, The Netherlands a r t i c l e i n f o Article history: Received 11 September 2012 Accepted 11 September 2012 Keywords: Drugs Gut Human microbiome Metagenomics Microbial ecology a b s t r a c t The mammalian gastrointestinal tract (GIT) harbors microorganisms (the microbiota) of vast phylogentic, genomic, and metabolic diversity, and recent years have seen a rapid development in the techniques for studying these complex microbial ecosystems. It is increasingly apparent that the GIT microbiota plays an intricate role in host health and disease. Targeted strategies for modulating human health through the modification of the GIT microbiota, however, are developing and in their infancy. This perspective article discusses the rationale, benefits and limitations of using the GIT microbiota as a pharmacological and nutritional target in the treatment of various diseases and disorders linked to imbalances in our microbiota. © 2012 Elsevier Ltd. All rights reserved. 1. Background Mammals have evolved strategies to co-exist at all stages of their life cycle with the diverse microorganisms within their envi- ronment. Early stages of vertebrate development typically occur in the protected confines of the chorion, an environment free of microorganisms. Upon leaving this germ-free environment at birth, mammals’ external surfaces are rapidly colonized by communities of opportunistic microorganisms acquired from maternal (faecal, vaginal) and environmental sources, before a more stable adult-like microbiota develops after weaning [1]. Notably, type of delivery (natural vs. cesarean) and feeding (breast vs. milk formula feed- ing) play major roles in determining the colonization succession [2] The mature vertebrate gastrointestinal tract (GIT) harbors an astonishing complex consortium of trillions of microbes, including Bacteria, Archaea, Eukarya, and their viruses [3–5], pro- viding an overwhelming catalogue of cellular functions as was recently shown by metagenome analysis of over 100 individuals [6]. This myriad of microorganisms, that outnumbers the host cells by a factor of 10 [7], is for the most part, considered beneficial (if not crucial) for host health [8–10]. Accumulating evidence indicates that this intestinal ecosystem plays an impor-  Perspective articles contain the personal views of the authors who, as experts, reflect on the direction of future research in their field. ∗ Corresponding author. E-mail addresses: guus@roeselers.com, guus.roeselers@tno.nl (G. Roeselers). tant role in the host GIT development, metabolism, and immune function. 2. GIT development Newborns leave the environment of the chorion with a struc- turally and functionally immature GIT [11], which postnatal development is influenced by a number of factors [12], including exposure to a developing GIT microbial community [13]. Com- parisons of germ-free (GF) with conventional animals reveal the central role of gut microbiota in the structural and functional devel- opment of the GIT. The ceca of GF mice are often greatly enlarged, often leading to reproductive and functional gastrointestinal disor- ders [14]. The GF gut presents an increased enterochromaffin cell area and fewer intraepithelial lymphocytes and reduced Peyer’s patches [15,16], while the intestinal surface area is reduced [17] and villus thickness decreased, resulting from reduced cell regeneration [18] and increased cell cycle time [19]. Stappenbeck et al. [20] compared the intestinal capillary networks of germ-free mice with those of ex-germ-free animals colonized during or after completion of postnatal gut development. Adult germ-free mice displayed reduced capillary networks. The authors demonstrated that this ‘developmental program’ can be restarted and completed within 10 days after colonization with a GIT microbiota harvested from conventionally raised mice, or with Bacteroides thetaiotaomicron, a key member of the normal mouse/human GIT microbiota [21]. The GIT microbiota is essential for both morphological and immunological maturation of the intestinal barrier [22]. 1043-6618/$ – see front matter © 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.phrs.2012.09.007