Complex carbohydrate utilization by gut bacteria modulates host food preference.

The gut microbiota interacts directly with dietary nutrients and has the ability to modify host feeding behavior, but the underlying mechanisms remain poorly understood. Select gut bacteria digest complex carbohydrates that are non-digestible by the host and liberate metabolites that serve as additional energy sources and pleiotropic signaling molecules. Here we use a gnotobiotic mouse model to examine how differential fructose polysaccharide metabolism by commensal gut bacteria influences host preference for diets containing these carbohydrates. Bacteroides thetaiotaomicron and Bacteroides ovatus selectively ferment fructans with different glycosidic linkages: B. thetaiotaomicron ferments levan with ß2-6 linkages, whereas B. ovatus ferments inulin with ß2-1 linkages. Since inulin and levan are both fructose polymers, inulin and levan diet have similar perceptual salience to mice. We find that mice colonized with B. thetaiotaomicron prefer the non-fermentable inulin diet, while mice colonized with B. ovatus prefer the non-fermentable levan diet. Knockout of bacterial fructan utilization genes abrogates this preference, whereas swapping the fermentation ability of B. thetaiotaomicron to inulin confers host preference for the levan diet. Bacterial fructan fermentation and host behavioral preference for the non-fermentable fructan are associated with increased neuronal activation in the arcuate nucleus of the hypothalamus, a key brain region for appetite regulation. These results reveal that selective nutrient metabolism by gut bacteria contributes to host associative learning of dietary preference, and further informs fundamental understanding of the biological determinants of food choice.

Ketogenic diet therapy for pediatric epilepsy is associated with alterations in the human gut microbiome that confer seizure resistance in mice.

The gut microbiome modulates seizure susceptibility and the anti-seizure effects of the ketogenic diet (KD) in animal models, but whether these relationships translate to KD therapies for human epilepsy is unclear. We find that the clinical KD alters gut microbial function in children with refractory epilepsy. Colonizing mice with KD-associated microbes promotes seizure resistance relative to matched pre-treatment controls. Select metagenomic and metabolomic features, including those related to anaplerosis, fatty acid ß-oxidation, and amino acid metabolism, are seen with human KD therapy and preserved upon microbiome transfer to mice. Mice colonized with KD-associated gut microbes exhibit altered hippocampal transcriptomes, including pathways related to ATP synthesis, glutathione metabolism, and oxidative phosphorylation, and are linked to susceptibility genes identified in human epilepsy. Our findings reveal key microbial functions that are altered by KD therapies for pediatric epilepsy and linked to microbiome-induced alterations in brain gene expression and seizure protection in mice.

Interactions between the gut microbiome and ketogenic diet in refractory epilepsy.

Epilepsy is one of the most common neurological diseases globally, afflicting approximately 50 million people worldwide. While many antiepileptic drugs exist, an estimated one-third of individuals do not respond to available medications. The high fat, low carbohydrate ketogenic diet (KD) has been used to treat refractory epilepsy in cases when existing antiepileptic drugs fail. However, there are many variations of the KD, each of which varies greatly in its efficacy and side effects. Increasing evidence suggests that interactions between the KD and gut microbiome may modulate the effects of the diet on host physiology. Herein, we review existing evidence of microbiome differences in epileptic individuals compared to healthy controls. We highlight in particular both clinical and animal studies revealing effects of the KD on the composition and function of the microbiome, as well as proof-of-concept animal studies that implicate the microbiome in the antiseizure effects of the KD. We further synthesize findings suggesting that variations in clinical KD formulations may differentially influence host physiology and discuss the gut microbial interactions with specific dietary factors that may play a role. Overall, understanding interactions between the gut microbiota and specific nutritional components of clinical KDs could reveal foundational mechanisms that underlie the effectiveness, variability, and side effects of different KDs, with the potential to lead to precision nutritional and microbiome-based approaches to treat refractory epilepsy.

Hypoxia-Inducible Factor 1 Alpha Is Dispensable for Host Defense of Group B Streptococcus Colonization and Infection.

Group B Streptococcus (GBS) is a leading cause of neonatal morbidity and mortality, and the primary source of exposure is the maternal vagina. Intrapartum antibiotic prophylaxis for GBS-positive mothers has reduced the incidence of GBS early-onset disease, however, potential long-lasting influence of an antibiotic-altered neonatal microbiota, and the frequent clinical sequelae in survivors of invasive GBS infection, compels alternative treatment options for GBS. Here, we examined the role of transcription factor hypoxia-inducible factor 1 alpha (HIF-1α), widely recognized as a regulator of immune activation during infection, in the host response to GBS. Given the importance of endogenous HIF-1α for innate immune defense, and the potential utility of HIF-1α stabilization in promoting bacterial clearance, we hypothesized that HIF-1α could play an important role in coordinating host responses to GBS in colonization and systemic disease. Counter to our hypothesis, we found that GBS infection did not induce HIF-1α expression in vaginal epithelial cells or murine macrophages, nor did HIF-1α deficiency alter GBS colonization or pathogenesis in vivo. Furthermore, pharmacological enhancement of HIF-1α did not improve control of GBS in pathogenesis and colonization models, while displaying inhibitory effects in vaginal epithelial cytokines and immune cell killing in vitro. Taken together, we conclude that HIF-1α is not a prominent aspect of the host response to GBS colonization or invasive disease, and its pharmacological modulation is unlikely to provide significant benefit against this important neonatal pathogen.

Ketone Bodies Exert Ester-Ordinary Suppression of Bifidobacteria and Th17 Cells.

The ketogenic diet is used to treat neurological and metabolic symptoms of disease, but the extent of its influences across organ systems remains unclear. Ang et al., 2020 reveal that ketone bodies induced by the diet inhibit specific bacteria of the gut microbiota and suppress pro-inflammatory T cells in the intestine.

Emerging roles for the intestinal microbiome in epilepsy.

The gut microbiome is emerging as a key regulator of brain function and behavior and is associated with symptoms of several neurological disorders. There is emerging evidence that alterations in the gut microbiota are seen in epilepsy and in response to seizure interventions. In this review, we highlight recent studies reporting that individuals with refractory epilepsy exhibit altered composition of the gut microbiota. We further discuss antibiotic treatment and infection as microbiome-related factors that influence seizure susceptibility in humans and animal models. In addition, we evaluate how the microbiome may mediate effects of the ketogenic diet, probiotic treatment, and anti-epileptic drugs on reducing both seizure frequency and severity. Finally, we assess the open questions in interrogating roles for the microbiome in epilepsy and address the prospect that continued research may uncover fundamental insights for understanding risk factors for epilepsy, as well as novel approaches for treating refractory epilepsy.