As often mentioned in these GEITP pages –– the microbiome (gut bacteria, which actually comprise more than 90% of all the DNA in us) has become increasingly realized to play an important role in gene-environment interactions. In today’s topic, the TRAIT (phenotype) is ketogenic diet-mediated protection again epileptic seizures (caused when the brain has a sudden burst of electrical activity). The genotype in specific patients unfortunately causes them to be highly susceptible to seizures. The environmental effect is the response, or lack of response, “to be cured” by this particular diet.
The ketogenic diet is well known as a successful treatment for many who have refractory epilepsy (i.e. when various medicines are tried, and they do not bring seizures under control; sometimes called drug-resistant epilepsy), but the mechanisms underlying the neuroprotective effects of the ketogenic diet remain unclear. Authors [see attached article] show that the gut microbiome is transformed by the ketogenic diet and the microbiome is required for protection –– in two mouse models –– against sudden electrically-induced seizures. Mice, when treated with antibiotics or reared in a germ-free facility, are resistant to the ketogenic diet-mediated seizure protection.
Enrichment of the microbiome with two ketogenic diet-associated bacterial species, restores seizure protection. Furthermore, transplantation of either of these two ketogenic diet-mediated gut bacterial species each confer seizure protection to mice fed a control diet. Alterations in metabolic profile –– seen in the lumen of the colon, blood serum, and brain hippocampal region –– all are correlated with seizure protection, including decreases in systemic g-glutamylated amino acids and elevated hippocampal g-aminobutyric acid (GABA)/glutamate levels. Bacterial cross-feeding decreases g-glutamyltranspeptidase (GGT) activity, and inhibiting this g-glutamylation promotes seizure protection in the intact animal. This fascinating study reveals that the gut microbiome can modulate the host in protection vs resistance to intractible epilepsy.
Cell June 2o18; 173: 1728–1741
I thought of one more worthwhile point to add: The “ketogenic diet” is, in fact, a form of treatment, although it is not specifically a DRUG. However, I would regard this as “being within the realm of gene-drug interactions”. I predict that, in the near future, that we will see a flurry of publications on “gene responses” to a drug (in humans as well as mice) –– showing that alterations in the individual’s microbiome can lead to serious consequences on the drug response, i.e. the phenotype.
This is funny—I just recently listened to a podcast on the origins of the ketogenic diet. I had no idea that it helped some people with seizures..!!
I also have a new faculty member who is interested in the gut-lung interaction. He has sent me some research projects—but everything is exploratory and correlational. Frank McCormack wants mechanisms in proposals, and perhaps we don’t know enough yet, about the gut microbiome, to propose mechanisms. I have a “gut feeling” (pun intended) that the immune system is the intermediary. (EK)