Microbiota-Generated Metabolites Promote Metabolic Benefits via Gut-Brain Neural Circuits
This paper aimed to examine the mechanisms behind the metabolic benefits on body weight and insulin sensitivity with the ingestion of soluble dietary fibers, an energy source for gut microbiota. Soluble fibers are broken further down into SCFAs, specifically propionate and butyrate, which then act to regulate whole-body energy homeostasis and as signaling molecules. The results of this study are broken down below.
The effects of SCFAs on the body initially seems to be paradoxical as an increased energy harvest is seen through the use of butyrate as a major food source for colonocytes and enterocytes. Propionate promotes hepatic gluconeogenesis which can result in insulin resistance and therefore, type II diabetes. If the two products of soluble fiber digestion can be linked to obesity and type II diabetes, through what mechanism do the metabolic benefits occur? In actuality, intestinal gluconeogenesis (IGN) has beneficial effects on energy homeostasis and glucose regulation. This study focused on the role of soluble fiber and/or SCFAs in induction of IGN and whether or not IGN is responsible for the known metabolic benefits.
SCFAs- and FOS-enriched diets increase glucose tolerance and insulin sensitivity in rats
Rats fed a diet including SCFAs and FOS saw less weight gain compared to rats fed a standard diet. Researchers also saw lower fasting basal glucose levels and increased sensitivity to insulin. Through the incorporation of 14C-labelled propionate, there was an increase of 14C-labelled glucose seen in the portal veins when compared to arterial blood which would suggest the effective incorporation of propionate into gluconeogenesis in the small intestine.
Dietary SCFAs and FOS induce IGN and IGN gene expression
Diet incorporation of propionate resulted in the strongest induction of intestinal glucose production, seen by increased expression of G6Pase, PEP carboxykinase, and methylmalonyl-coA mutase activity.
Butyrate directly induces IGN genes:
Butyrate was seen to directly induce IGN genes, even in the presence of Gi and Gq pathway inhibitors (pertussis toxin). A 3-fold increase in intracellular cAMP content was seen in butyrate-treated cells which indicates that butyrate likely works through cAMP mediated induction of two enzymes necessary for gluconeogenesis, glucose-6-phosphate catalytic subunit (G6PC) and phosphoenolpyruvate carboxykinase 1 (PCK1), an already established mechanism.
Propionate induction of IGN is mediated through gut-brain neural communication
Since propionate was shown in the previous section not to directly activate IGN genes, the researchers proposed propionate could work through the gut-neural communication system instead. Denervation, or the blockage of nerve signals, resulted in the loss of beneficial effects previously seen with dietary FOS and SCFAs, such as improved tolerance of glucose and insulin and positive impacts on weight gain. This finding would suggest that the periportal nervous system is critical in mediating the beneficial effects of IGN. FFAR3 activity, a free fatty acid receptor, was measured in the peripheral nervous system through immunofluorescence. The addition of propionate to the portal vein resulted in an increase in G6Pase activity in the jejunum. A combined infusion with β-hydroxybutyrate however, an FFAR antagonist, significantly lowered IGN induction (measured through G6Pase activity). The incorporation of dietary propionate also resulted in increased c-Fos induction, an indicator of neuron activity, in the spinal cord, the parabrachial nucleus, and the hypothalamus
Intestinal gluconeogenesis is a causal factor in the metabolic benefits associated with dietary FOS and SCFAs
IGN deficient mice were utilized through the disruption of G6PC activity. These mice were fed a SCFA- and FOS-enriched diet and the results were compared to that of WT mice. Body weight gain in I-G6PC -/- mice was significantly higher than its WT littermates and an improved tolerance for glucose and insulin was similarly not seen in IGN KO mice. These results would suggest that IGN is necessary for the beneficial impact of a FOS or SCA-enriched diet.
FOS incorporation into diet leads to a shift in microbiota composition
Additional research was done into the effects of FOS supplemented diet on gut microbiota composition through pyrosequencing, in both WT and IGN KO (I-G6PC -/-) mice. The incorporation of an FOS-enriched diet resulted in a significant decrease in Firmicutes but a significant increase in Bacteroidetes in both types of mice, 2 species of microbiota which make up over 80% of the sequences read. A significant increase in Actinobacteria was also seen, but only in I-G6PC -/- mice. As one would expect, FOS incorporation resulted in a significantly higher portal blood SCFA content regardless of phenotype. A significant positive correlation was also seen with the percentage of Bacteroidetes and the concentration of propionate in the plasma.
The SCFAs produced as a result of FOS fermentation through gut microbiota act to significantly lower body weight gain and improve glucose and insulin sensitivity. A major finding of this study was the role propionate plays in direct initiation of gut-brain neural circuits that ultimately promote these metabolic benefits, likely through the activation of FFAR3. In contrast, this study found that butytrate can directly activate IGN genes through a cAMP mediated mechanism does not require a G-coupled signaling pathway. IGN was found to be a causal factor in the metabolic effects associated with this change in diet. These findings will hopefully provide more insight into the use of FOS- and SCFA-enriched diets as potential preventative actions and/or treatments of metabolic diseases.
De Vadder, F., Kovatcheva-Datchary, P., Goncalves, D., Vinera, J., Zitoun, C., Duchampt, A., … Mithieux, G. (2014). Microbiota-Generated Metabolites Promote Metabolic Benefits via Gut-Brain Neural Circuits. Cell, 156(1–2), 84–96. doi:10.1016/j.cell.2013.12.016