Microbes inside--from diversity to function: the case of Akkermansia

Abstract

The human intestinal tract is colonized by a myriad of microbes that have developed intimate interactions with the host. In healthy individuals, this complex ecosystem remains stable and resilient to stressors. There is significant attention on the understanding of the composition and function of this intestinal microbiota in health and disease. Current developments in metaomics and systems biology approaches allow to probe the functional potential and activity of the intestinal microbiota. However, all these approaches inherently suffer from the fact that the information on macromolecules (DNA, RNA and protein) is collected at the ecosystem level. Similarly, all physiological and other information collected from isolated strains relates to pure cultures grown in vitro or in gnotobiotic systems. It is essential to integrate these two worlds of predominantly chemistry and biology by linking the molecules to the cells. Here, we will address the integration of omics- and culture-based approaches with the complexity of the human intestinal microbiota in mind and the mucus-degrading bacteria Akkermansia spp. as a paradigm.

Figure 1

From diversity to function. (a) Schematic outline of the human digestive tract with its characteristics and microbiota. The stomach is characterized by low pH conditions and a short retention time and colonization by bacteria is minimal. The small intestine (duodenum, jejunum and proximal ileum) has a short retention time (2–6 h) and high pH, the residing microflora is exposed to secreted bile salts and pancreatic juices at the proximal part. The lower digestive tract, comprising the terminal ileum and colon, is in contrast characterized by a longer retention time, neutral pH and is the most densely populated by microorganisms. (b) Overview of the major ‘omics' approaches using DNA, RNA, protein or culture-based techniques.

Figure 2

Integrating omics and culturing approaches. All metagenomics and other omics approaches suffer from the fact that information on the macromolecules (DNA, RNA or protein) is collected at the ecosystem level. What needs to be done is to integrate these two worlds of predominantly chemistry and biology by linking the molecules to the cells. Red arrows indicate the experimental approaches related to this integration and the other arrows describe other activities and approaches. See text for further explanations.

Figure 3

Akkermansia muciniphila is universally distributed in intestinal tracts all over the animal kingdom. (a) Phylogenetic tree indicating the position of A. muciniphila among selected full-length 16S rRNA clones from mammalian gut samples. Red colored samples derive from human sources. Thermotoga thermarum is used as an outgroup. The tree was generated using the neighbor joining method. Full details and high-resolution information are provided in Supplementary Figure S1. (b) Schematic representation of the tree in (a) with the five different clades their position and similarity to A. muciniphila. (c) Taxonomic tree of mammals generated using iTol webtool from tree of life project using all available sequences from NCBI (Letunic and Bork). Animal silhouettes indicate single species as a representative of that order. When an animal species from the mammalian orders was positive for Akkermansia-like sequences the animal logo belonging to that order is colored red, when it was negative the animal logo is colored gray. No Akkermansia sequences have been reported yet in any of the animals belonging to the mammalian orders depicted in black.

Figure 4

Akkermansia muciniphila activity and interactions in the intestine. Schematic overview of the metabolic activities of A. muciniphila in the gut and the microbiota and host response as a result of A. muciniphila colonization. As a result of mucus degradation, A. muciniphila produces oligosaccharides and SCFAs. These products can stimulate microbiota interactions and host response. Oligosaccharides and acetate stimulate growth and metabolic activity of bacteria that colonize close to the mucus layer. This may provide colonization resistance to pathogenic bacteria that have to cross the mucus layer to reach the intestinal cells. The propionate produced by Akkermansia-like bacteria can signal to the host via the Gpr43 receptor and other SCFA may also do the same via Gpr41 (Le Poul et al., 2003; Maslowski et al., 2009). This may trigger a cascade of responses in the host expression machinery and together with other signaling pathways has shown to result in immune stimulation and metabolic signaling in monoassociated germ-free mice (Derrien et al., 2011).