Human gut microbiome: hopes, threats and promises

Abstract

The microbiome has received increasing attention over the last 15 years. Although gut microbes have been explored for several decades, investigations of the role of microorganisms that reside in the human gut has attracted much attention beyond classical infectious diseases. For example, numerous studies have reported changes in the gut microbiota during not only obesity, diabetes, and liver diseases but also cancer and even neurodegenerative diseases. The human gut microbiota is viewed as a potential source of novel therapeutics. Between 2013 and 2017, the number of publications focusing on the gut microbiota was, remarkably, 12 900, which represents four-fifths of the total number of publications over the last 40 years that investigated this topic. This review discusses recent evidence of the impact of the gut microbiota on metabolic disorders and focus on selected key mechanisms. This review also aims to provide a critical analysis of the current knowledge in this field, identify putative key issues or problems and discuss misinterpretations. The abundance of metagenomic data generated on comparing diseased and healthy subjects can lead to the erroneous claim that a bacterium is causally linked with the protection or the onset of a disease. In fact, environmental factors such as dietary habits, drug treatments, intestinal motility and stool frequency and consistency are all factors that influence the composition of the microbiota and should be considered. The cases of the bacteria Prevotella copri and Akkermansia muciniphila will be discussed as key examples.

Keywords: diabetes mellitus; intestinal microbiology; obesity.

Figure 1

Relative sizes of major host cells and their components versus those of bacteria and viruses.

Figure 2

Major mechanisms involved in the crosstalk between microbes and host: impact of metabolism. The balance between healthy and pathological situations (eg, metabolic disorders) is crucial. This is under the tight influence of several factors including the genes, food and drugs. This left part of the figure shows that in healthy situation, the composition of the gut microbiome is associated with a higher mucus layer thickness, the production of antimicrobial signals and different short-chain fatty acids such as butyrate and propionate. Both butyrate and propionate bind to G protein coupled receptors (GPR)-43 and GPR-41 expressed on the enteroendocrine L-cells thereby stimulating the secretion of gut peptides such as glucagon-like peptide-1 (GLP-1) and peptide YY (PYY). This effect contributes to reduce food intake and to improve glucose metabolism. Propionate can also bind to GPR-43 expressed on lymphocytes in order to maintain appropriate immune defence. Butyrate activates peroxisome proliferator-activated receptor-γ (PPAR-γ) leading to beta-oxidation and oxygen consumption, a phenomenon contributing to maintain anaerobic condition in the gut lumen. As depicted on the right part of the figure, during metabolic disorders, changes in the gut microbiome are linked with a lower mucus thickness, decreased antimicrobial defense and butyrate and propionate production. As a consequence, L-cells secrete less gut peptides. The lack of PPAR-γ activation lead to higher oxygen available for the microbiota at the proximity of the mucosa and increases the proliferation of Enterobacteriaceae. The decrease in propionate also contribute to the lower abundance of specific T cells (mucosal-associated invariant T cells (MAIT) and Treg) in the lamina propria of the gut. Altogether, such changes in the microbial environment and metabolites induce a leakage of pathogen associated molecular patterns (PAMPs) such as the lipopolysaccharide (LPS) that are increased in the blood, and trigger low-grade inflammation.

Figure 3

Association between Akkermansia muciniphila and several diseases: what is known? What are the major confounding factors. The picture illustrated different pathological situations where the abundance of the bacteria A. muciniphila has been found to be increased or decreased. It also highlight several confounding factors associated with the modulation of the gut microbiota and eventually the abundance of A. muciniphila according to the health situation and shows the current data for which a proof-of-concept of the link between the disease and the presence of the bacteria has been made.