Investigations of links between the gut microbiome and specific diseases tend to have a causality problem: it’s unclear whether an altered microbiome contributes to the disease or whether the disease alters the collection of microbes.  

A team of researchers led by Serena Sanna and Cisca Wijmenga at the University of Groningen in the Netherlands and Mark McCarthy at the University of Oxford, UK, have addressed this issue using an analytical approach called Mendelian randomization in which genetic variants are treated as manipulations that define experimental groups (1). They have used this technique to show that the microbiome can cause metabolic dysfunction.  

The team also suggested a mechanism by which this occurs: changes in microbial production of short-chain fatty acids (SCFAs). SCFAs are metabolites, or nutritional compounds, that bacteria in the gut microbiome produce. These metabolites are known to act as nutrients for the intestinal cells in the gut and are considered to be associated with decreased risk for chronic disease (2-5). 

The metabolic health of nearly 1,000 people in the Netherlands was found to correlate with the presence of certain bacteria and bacterial metabolic pathways. Most notably, higher fecal levels of butyrate — one type of SCFA produced by gut microbes — predicted better insulin responses. So, the more butyrate your gut is producing, the better your body is able to control your blood sugar. 

The study also showed that participants’ genes partially predicted the level of butyrate production in the gut and predicted each individual’s microbiome structure more broadly, a finding that was then confirmed in a different group of more than 4,000 individuals.  

Then came the test of causality. If altered insulin sensitivity changes the microbiome (rather than the microbiome disrupting insulin pathways in the body), all genetic factors known to influence insulin sensitivity should also predict a person’s butyrate production. But they did not. This suggests that genes associated with both microbiome structure and insulin responses influence gut microbiomes, which in turn disrupt insulin signalling. The team also found that genetic variants causing abnormal production or absorption of another bacteria-derived SCFA, propionate, increased risk of type 2 diabetes.  

These findings pave the way for more personalized treatments of metabolic disease. Scientific advancements, such as those described in the publication shared here, are key to refining personalized nutrition approaches. Integrative Phenomics is constantly working to find evidence-based personalized diet and lifestyle strategies through which we can address the individual microbiome, therefore impacting long-term health.  

1. Sanna, S., van Zuydam, N.R., Mahajan, A. et al. Causal relationships among the gut microbiome, short-chain fatty acids and metabolic diseases. Nat Genet 51, 600–605 (2019). https://doi.org/10.1038/s41588-019-0350-x 
2. Hamer HM, Jonkers D, Venema K, Vanhoutvin S, Troost FJ, Brummer R-J . (2008). Review article: the role of butyrate on colonic function. Aliment Pharmacol Ther 27: 104–119. 
3. Louis P, Hold GL, Flint HJ . (2014). The gut microbiota, bacterial metabolites and colorectal cancer. Nat Rev Microbiol 12: 661–672. 
4. Arora T, Sharma R, Frost G . (2011). Propionate. Anti-obesity and satiety enhancing factor? Appetite 56: 511–515. 
5. Frost G, Sleeth ML, Sahuri-Arisoylu M, Lizarbe B, Cerdan S, Brody L et al. (2014). The short-chain fatty acid acetate reduces appetite via a central homeostatic mechanism. Nat Commun 5: 3611.