A LPS Structure/Function analysis in metabolic diseases – LPS-MD-SF

Large sets of data have been accumulated over the course of the last 5 years describing the important role of the lipopolysaccharides [(LPS)/CD14-TLR4] dyad in the control of the onset of metabolic diseases. A change to high-fat diet is associated with a change in intestinal human and animal microflora, leading to an increased ratio of Gram negative to Gram positive bacteria, thereby increasing the probability of LPS diffusion into the blood. This concept is responsible at least in part for the initiation of the low grade metabolic inflammation characterizing obesity and type 2 diabetes and linking the major role played by intestinal microbiota to metabolic diseases. Importantly, although LPSs share a common architecture, they vary with each species of a genus and each structural detail exert a strong influence on the activities. LPS are made of a lipid moiety called lipid A carrying most of the biological activities of the molecule. This moiety is substituted by a core oligosaccharide, itself carrying the O-specific antigens made of repetitive oligosaccharide subunits. The latter is the most variable LPS moiety also called O-chain, and the number and structure of its units is highly variable. Another important source of heterogeneity is the number of fatty acids in the lipid A moiety, this, added to the length of their carbon chains are crucial points for the recognition of the molecule at the level of LPS receptors leading to inflammatogenic activities. Therefore, we are planning to determine i. whether type 2 diabetes is associated with structural changes in plasma LPS and what are the corresponding mechanisms,
ii. whether there is a differential distribution of LPS within their main transporters: the lipoproteins.
To answer these questions two Teams are gathering their skills and specialties: - Team 1 is specialized in LPS structural analysis in connection to biological activities, having a unique expertise in France for detection and analyses of LPS structures.
Team 2, which discovered the increase of LPS diffusion into the blood of diabetes patients, has unique mouse models, as well as, in vivo, and in vitro lipidomics and phenotyping procedures to determine the causal link between the onset of metabolic diseases and LPSs.
The preliminary data demonstrate that changes in LPS moieties are related to different inflammatory actions and that Rasltonia is a genus present in large amount in the adipose tissues from obese patients at risk to become type 2 diabetic.
These joint efforts should allow a better understanding of the relationship between the structure of the LPSs and their function in diabetes. This project should lead to the identification of targets and biomarkers for the treatment and early diagnosis of metabolic diseases.