Metabolic Responses to Butyrate Supplementation in LF- and HF-Fed Mice Are Cohort-Dependent and Associated with Changes in Composition and Function of the Gut Microbiota

Abstract

The gut microbiota and associated metabolites have emerged as potential modulators of pathophysiological changes in obesity and related metabolic disorders. Butyrate, a product of bacterial fermentation, has been shown to have beneficial effects in obesity and rodent models of diet-induced obesity. Here, we aimed to determine the beneficial effects of butyrate (as glycerol ester of butyrate monobutyrin, MB) supplementation on metabolic phenotype, intestinal permeability and inflammation, feeding behavior, and the gut microbiota in low-fat (LF)- and high-fat (HF)-fed mice. Two cohorts (separated by 2 weeks) of male C57BL/6J mice (n = 24 in each cohort, 6/group/cohort; 6 weeks old) were separated into four weight-matched groups and fed either a LF (10 % fat/kcal) or HF (45% fat/kcal) with or without supplementation of MB (LF/MB or HF/MB) at 0.25% (w/v) in drinking water for 6 weeks. Metabolic phenotypes (body weight and adiposity), intestinal inflammation, feeding behavior, and fecal microbiome and metabolites were measured. Despite identical genetic and experimental conditions, we found marked differences between cohorts in the response (body weight gain, adiposity, and intestinal permeability) to HF-diet and MB. Notably, the composition of the gut microbiota was significantly different between cohorts, characterized by lower species richness and differential abundance of a large number of taxa, including subtaxa from five phyla, including increased abundance of the genera Bacteroides, Proteobacteria, and Parasutterella in cohort 2 compared to cohort 1. These differences may have contributed to the differential response in intestinal permeability to the HF diet in cohort 2. MB supplementation had no significant effect on metabolic phenotype, but there was a trend to protect from HF-induced impairments in intestinal barrier function in cohort 1 and in sensitivity to cholecystokinin (CCK) in both cohorts. These data support the concept that microbiota composition may have a crucial effect on metabolic responses of a host to dietary interventions and highlight the importance of taking steps to ensure reproducibility in rodent studies.

Butyrate to combat obesity and obesity‐associated metabolic disorders: Current status and future implications for therapeutic use

“…To illustrate, the effects on inflammatory processes and intestinal homeostasis of monobutyrin (a glycerol ester of butyrate) treatment varied between two rat cohorts from identical strains kept under exactly the same experimental circumstances as a result of differential microbial composition and, subsequently, microbial metabolite production. 196 Moreover, preliminary data indicate that obesity prone rats need a higher oral butyrate dose than obesity resistant rats (rats were categorized based on their weight gain after 8 weeks of HFD) to elicit the same response on body weight and glucometabolic parameters. 187 Together, this emphasizes that microbial composition and metabolic phenotype can profoundly impact experimental outcomes.…”

Butyrate ameliorates maternal high-fat diet-induced fetal liver cellular apoptosis

“…HFD can alter the microbiota composition [ 27 ] and prenatal HFD can also change the microbiota in the offspring’s stools [ 30 ]. HFD-driven dysbiosis has been linked to chronic low-grade intestinal inflammation and gut barrier dysfunction [ 28 , 31 ]. There was lower species richness in the HFD group but this richness did not change after butyrate supplementation [ 31 ].…”

“…HFD-driven dysbiosis has been linked to chronic low-grade intestinal inflammation and gut barrier dysfunction [ 28 , 31 ]. There was lower species richness in the HFD group but this richness did not change after butyrate supplementation [ 31 ]. However, it was not possible to collect fetal stool samples for the microbiota study at this GD21 stage.…”

“…Butyrate supplementation had a reduction of liver steatosis and inflammation in HFD fed animals [ 12 ], and had a trend to protect HFD-induced intestinal barrier impairments [ 31 ]. There were no studies investigated the effect of prenatal butyrate in the fetal liver or fetal intestine after maternal HFD.…”

The Short-Chain Fatty Acid Butyrate Attenuates Pulmonary Vascular Remodeling and Inflammation in Hypoxia-Induced Pulmonary Hypertension

“…However, the specific effects of chronic hypoxic exposure on intestinal microbiota composition as well as the identification of butyrogenic bacterial species remain to be a subject of further investigation, considering the importance of a “gut–lung” connection in hypertension [ 8 , 80 ]. In addition, some data provide evidence that exogenous butyrate may increase the abundance of butyrate-producing bacteria in different animal models, suggesting a restoration effect of butyrate on intestinal microbiome composition and homeostasis [ 81 , 82 , 83 , 84 ]. In this regard, the possibility should be explored as to whether butyrate can protect against hypoxia-induced imbalance in gut microbiota in hypoxic PH.…”