Involvement of Gut Microbial Metabolites Derived from Diet on Host Energy Homeostasis.

Due to the excess energy intake, which is a result of a high fat and high carbohydrate diet, dysfunction of energy balance leads to metabolic disorders such as obesity and type II diabetes mellitus (T2DM). Since obesity can be a risk factor for various diseases, including T2DM, hypertension, hyperlipidemia, and metabolic syndrome, novel prevention and treatment are expected. Moreover, host diseases linked to metabolic disorders are associated with changes in gut microbiota profile. Gut microbiota is affected by diet, and nutrients are used as substrates by gut microbiota for produced metabolites, such as short-chain and long-chain fatty acids, that may modulate host energy homeostasis. These free fatty acids are not only essential energy sources but also signaling molecules via G-protein coupled receptors (GPCRs). Some GPCRs are critical for metabolic functions, such as hormone secretion and immune function in various types of cells and tissues and contribute to energy homeostasis. The current studies have shown that GPCRs for gut microbial metabolites improved host energy homeostasis and systemic metabolic disorders. Here, we will review the association between diet, gut microbiota, and host energy homeostasis.

Fructooligosaccharides Intake during Pregnancy Improves Metabolic Phenotype of Offspring in High Fat Diet-Induced Obese Mice.

SCOPE: Obesity and metabolic diseases are closely associated, and individuals who become obese are also prone to type 2 diabetes and cardiovascular disorders. Gut microbiota is mediated by diet and can influence host metabolism and the incidence of metabolic disorders. Recent studies have suggested that improving gut microbiota through a fructooligosaccharide (FOS)-supplemented diet may ameliorate obesity and other metabolic disorders. Although accumulating evidence supports the notion of the developmental origins of health and disease, the underlying mechanisms remain obscure. METHODS AND RESULTS: ICR mice are fed AIN-93G formula-based cellulose -, FOS-, acetate-, or propionate-supplemented diets during pregnancy. Offspring are reared by conventional ICR foster mothers for 4 weeks; weaned mice are fed high fat diet for 12 weeks and housed individually. The FOS and propionate offspring contribute to suppressing obesity and improving glucose intolerance. Gut microbial compositions in FOS-fed mothers and their offspring are markedly changed. However, the beneficial effect of FOS diet on the offspring is abolished when antibiotics are administered to pregnant mice. CONCLUSION: The findings highlight the link between the maternal gut environment and the developmental origin of metabolic syndrome in offspring. These results open novel research avenues into preemptive therapies for metabolic disorders by targeting the maternal gut microbiota.

Host metabolic benefits of prebiotic exopolysaccharides produced by Leuconostoc mesenteroides.

Fermented foods demonstrate remarkable health benefits owing to probiotic bacteria or microproducts produced via bacterial fermentation. Fermented foods are produced by the fermentative action of several lactic acid bacteria, including Leuconostoc mesenteroides; however, the exact mechanism of action of these foods remains unclear. Here, we observed that prebiotics associated with L. mesenteroides-produced exopolysaccharides (EPS) demonstrate substantial host metabolic benefits. L. mesenteroides-produced EPS is an indigestible α-glucan, and intake of the purified form of EPS improved glucose metabolism and energy homeostasis through EPS-derived gut microbial short-chain fatty acids, and changed gut microbial composition. Our findings reveal an important mechanism that accounts for the effects of diet, prebiotics, and probiotics on energy homeostasis and suggests an approach for preventing lifestyle-related diseases by targeting bacterial EPS.

An ex vivo organ culture screening model revealed that low temperature conditions prevent side effects of anticancer drugs.

Development of chemotherapy has led to a high survival rate of cancer patients; however, the severe side effects of anticancer drugs, including organ hypoplasia, persist. To assume the side effect of anticancer drugs, we established a new ex vivo screening model and described a method for suppressing side effects. Cyclophosphamide (CPA) is a commonly used anticancer drug and causes severe side effects in developing organs with intensive proliferation, including the teeth and hair. Using the organ culture model, we found that treatment with CPA disturbed the growth of tooth germs by inducing DNA damage, apoptosis and suppressing cellular proliferation and differentiation. Furthermore, low temperature suppressed CPA-mediated inhibition of organ development. Our ex vivo and in vitro analysis revealed that low temperature impeded Rb phosphorylation and caused cell cycle arrest at the G1 phase during CPA treatment. This can prevent the CPA-mediated cell damage of DNA replication caused by the cross-linking reaction of CPA. Our findings suggest that the side effects of anticancer drugs on organ development can be avoided by maintaining the internal environment under low temperature.

An environmental pollutant, 9,10-phenanthrenequinone, activates human TRPA1 via critical cysteines 621 and 665.

Transient receptor potential ankyrin 1 (TRPA1) is activated by noxious cold, mechanical stimulation, and irritant chemicals. In our recent study, 9, 10-phenanthrenequinone (9,10-PQ) is the most potent irritant for activation of NRF2 among 1395 cigarette smoke components and it may be, therefore, important to find its additional targets. Here, we show that 9,10-PQ functions as an activator of TRPA1 in human embryonic kidney (HEK) cells expressing human wild-type TRPA1 (HEK-wTRPA1) and human alveolar A549 (A549) cells. Application of 9,10-PQ at 0.1-10 µmol/L induced a concentration-dependent Ca2+ response as well as inward currents at -50 mV in HEK-wTRPA1 cells. The current response was blocked by TRPA1 antagonists, HC-030031 (HC) and A-967079. To test whether 9,10-PQ affects the cysteine residues of TRPA1, we expressed mutant TRPA1 channels in HEK cells (HEK-muTRPA1) in which six different cysteine residues were replaced with serine. Among them, a mutation of cysteine 621 (C621S) abolished the 9,10-PQ-induced Ca2+ and current responses. The channel activity induced by 9,10-PQ was also abolished in excised inside-out patches isolated from HEK-muTRPA1 cells with the C621S substitution. Although a mutation of cysteine 665 (C665S) reduced the 9,10-PQ-induced response, channel sensitization by pretreatment with Cu2+ plus 1,10-phenanthroline and by internal dialysis of 3 µmol/L Ca2+ restored the response. However, a double mutant with C621S and C665S substitutions had little response to 9,10-PQ, even when sensitized by Ca2+ dialysis. In A549 cells, 9,10-PQ induced an HC-sensitive Ca2+ response. Our findings demonstrate that 9,10-PQ activation of human TRA1 is dependent on cysteine residues 621 and 665.