New mechanistic study explores the causal role of gut microbiota dysbiosis in metabolic disease

Gut microbiota dysbiosis, which has been defined as “the altered proportion and activity of bacterial groups of gut microbiota”, is suspected to be involved in several metabolic diseases such as hepatic steatosis, type 2 diabetes, and obesity. However, the underlying mechanisms are still a matter of debate.

In a recent study, led by Dr. Matteo Serino from the Institut Nacional de la Santé et de la Recherche Médicale (INASERM) in Toulouse (France), has found that transfer of a dysbiotic microbiota had the capacity to induce metabolic effects that appear beneficial.

To investigate the role of gut microbiota dybiosis in the aetiology of metabolic diseases, the researchers transferred caecal microbiota from either diet-induced and leptin-deficient (ob/ob) obese mice, or lean mice, into healthy mice that had not been treated with antibiotics before (instead of using germ-free mice as recipients of dysbiotic gut microbiota).

Transferring the caecal content from high-fat diet-induced obese mice to conventional mice fed a normal chow (NC) diet led to a significant reduction in fasting glycaemia and a concomitant lower hepatic gluconeogenesis with decreased activity of the key hepatic gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK) and without hepatic damage, compared to control mice (conventional mice inoculated with the vehicle phosphate-buffered saline (PBS ) and conventional mice inoculated with lean gut microbiota). The reduction in hepatic gluconeogenesis was also accompanied by a serum metabolomics signature consisting of increased levels of glucogenic precursors lactate and pyruvate. Both obese-mice and lean-mice gut microbiota transfer had no impact on gut barrier in conventional mice fed NC. Similar effects were also observed when the researchers used gut microbiota from genetically obese mice.

Transfer of high-fat diet-induced obese mice-microbiota into antibiotic-free NC-fed conventional mice changed both the gut microbiota (taxonomy) Actinobacteria were significantly higher in mice receiving the lean gut microbiota, whereas mice inoculated with dysbiotic gut microbiota from high-fat diet-fed mice showed more Firmicutes and the microbiome (function) -the high-fat diet-induced obese mice-microbiota modulated up to twenty microbial pathways, compared to the three microbial pathways found modulated by the lean gut microbiota- of recipient mice, to a greater extent than lean gut microbiota.

In another set of experiments, transfer of dysbiotic gut microbiota from diet-induced (nutritional dysbiosis) and leptin-deficient (ob/ob) (genetic dysbiosis) obese mice to conventional NC and 72% high-fat diet fed-mice led to lower hepatic gluconeogenesis and minor intestinal inflammation. The metabolic impact on white adipose tissue varied depending on the origin of the dysbiosis, as nutritional dysbiosis led to significantly smaller white adipose tissue cell size consistent with higher free fatty acid plasma levels compared to control mice. This was not observed with the inoculation of genetically obese mouse microbiota.

Transfer of dysbiotic gut microbiota into conventional mice changed gut microbiota and microbiome according to the origin of dysbiosis on both NC and 72% high-fat diet. However, transfer of lean-mouse microbiota did not affect either the gut microbiota composition or markers of hepatic gluconeogenesis.

In conclusion, these findings show that transferring a dysbiotic gut microbiota into healthy conventional mice may, surprisingly, have beneficial effects on host liver metabolism. The authors hypothesized that the functional gut barrier and mature immune system of a conventional mouse as compared to germ-free mice could allow a better management of dysbiotic gut microbiota (previous research showing contradictory results was based mainly on transferring dysbiotic gut microbiota in germ-free mice). Further long-term follow-up research will elucidate the mechanisms of metabolic diseases and the role of gut microbiota dysbiosis.

 

 

Reference:

Nicolas S, Blasco-Baque V, Fournel A, et al. Transfer of dysbiotic gut microbiota has beneficial effects on host liver metabolism. Mol Syst Biol. 2017; 13(3):921. doi: 10.15252/msb.20167356.

Andreu Prados
Andreu Prados
Andreu Prados holds a Bachelor of Science Degree in Pharmacy & Human Nutrition and Dietetics. Science writer specialised in gut microbiota and probiotics, working also as lecturer and consultant in nutrition and healthcare. Follow Andreu on Twitter @andreuprados