A novel ketogenic diet restores SCFA cecum levels and leads to gut microbiota changes correlating with seizure severity and hepatic steatosis development in the rapid kindling rat model of epileptogenesis

We recently described a novel ketogenic diet (KD) with superior anti-seizure efficacy and absence of hepatic steatosis compared to a rodent-adapted classic KD in the rapid kindling rat model of epileptogenesis Since the novel KD had a lower fat content and induced lower plasma ketosis levels than the classic KD, gut microbiota changes were investigated as an alternative mode of action. In contrast to the classic KD, the novel KD was supplemented with a fermentable fiber blend composed of inulin, galacto-oligosaccharides, soy fiber and resistant starch, omega-3 polyunsaturated fatty acids (PUFAs) in exchange for omega-6 PUFAs and was partially depleted of stearic acid in exchange for medium chain fatty acids. 16s rRNA gene sequencing of cecum samples uncovered a distinct gut microbiota signature of the novel KD characterized by (i) a lower unweighted but higher weighted alpha diversity than the classic KD and control diet group, (ii) a separated beta diversity, (iii) increased Bifidobacterium, Clostridium sensu stricto 1 and Muribaculaceae ge abundances, (iv) positively correlating Clostridium sensu stricto I and Muribaculaceae ge abundances with decreased seizure load, and (v) a weakened association of genera, including Bacteroides, Tannerellaceae ge, Escherichia Shigella, Turicibacter, Lachnospiraceae UCG 006, and Roseburia with liver triglyceride accumulation compared to the classic KD. Bifidobacterium, Clostridium sensu stricto I and Muribaculaceae ge abundances correlated positively with omega-3 PUFA plasma levels, while the abundances of genera associated with liver triglyceride content correlated with stearic acid plasma levels, indicating that omega-3 PUFAs and stearic acid, in addition to the fiber blend altered the gut microbiome.