Eating foods rich in plant fiber promotes health by changing the composition and metabolic products of gut bacteria.
The health benefits of eating plant fiber have long been appreciated. Epidemiological studies show an inverse relationship between dietary plant fiber and the risk of heart disease, obesity and type-2 diabetes, and consumption of dietary fiber is recommended by the American Dietetic Association and other health organizations. But the biological mechanisms underlying the health effects of dietary fiber have been hard to pin down. Gut microbes are presumed to be involved because they contribute to fiber digestion. Two recent papers in Nature1 and Cell2 shed light on their roles, demonstrating that ingestion of plant fiber induces rapid shifts in the composition and function of the gut microbiota and that metabolites produced by the microbiota support metabolic health by regulating glucose control in the host. These findings may guide efforts to design 'prebiotics'—dietary supplements capable of manipulating the gut microbiota to improve human health.
Fermentation of soluble fibers such as fructo-oligosaccharides and galacto-oligosaccharides by gut bacteria produce the short-chain fatty acids acetate, propionate and butyrate. Although chemically similar, short-chain fatty acids are metabolized differently and exert very different effects on host physiology (Fig. 1). Acetate (the most abundant short-chain fatty acid) is a substrate for hepatic de novo lipogenesis and cholesterol biosynthesis, propionate is a substrate for hepatic gluconeogenesis and butyrate acts as an energy substrate for enterocytes lining the colon. Propionate and butyrate also act as signaling molecules by binding to and activating the G protein–coupled receptors FFAR2 and FFAR3 (free fatty acid receptors).
It is well established that changing the diet changes the composition of the gut microbiota3. David et al.1 explored this phenomenon by measuring the rates at which changes in dietary fiber intake translate into changes in the composition and transcriptional profile of the gut microbiota in humans. To this end they fed ten healthy human volunteers either a plant-based or an animal-based diet for five days. At various points in the study, they analyzed fecal samples by sequencing 16S ribosomal RNA (to determine the relative abundance of different microbes) and by RNA-seq (to determine the relative expression of microbial genes).
Changes in microbial gene expression and community structure were seen within days of starting the diets. In subjects fed the animal-based diet, these changes correlated with a reversible physiological response (weight loss) and an increase in the abundance of bile-tolerant bacteria and of short-chain fatty acids indicative of amino acid fermentation. In contrast, subjects fed the plant-based diet had higher amounts of plant polysaccharide–fermenting bacteria and of short-chain fatty acids derived from carbohydrate fermentation. After the diets were stopped, these parameters quickly reverted to their original states. This study confirmed that the gut microbiota can change rapidly in response to dietary changes and identified some of the molecular mechanisms that may underlie the health benefits of a plant-based diet.
De Vadder et al.2 probed these mechanisms in much greater detail. In particular, they sought to understand precisely how short-chain fatty acids that promote gluconeogenesis—glucose production—can also promote metabolic health. They knew that, unlike hepatic gluconeogenesis, which causes hyperglycemia in diabetic conditions, intestinal gluconeogenesis activates a portal vein glucose sensor4 that sends signals to the brain which beneficially affect food consumption and glucose metabolism. Therefore, they asked whether dietary fiber and short-chain fatty acids boost intestinal gluconeogenesis, and, if so, whether this explains the metabolic benefits of soluble fiber.
Feeding with fructo-oligosaccharides, propionate or butyrate improved glucose tolerance and enhanced intestinal gluconeogenesis in rats. However, propionate and butyrate boosted intestinal gluconeogenesis in different ways. Whereas butyrate acted as a signaling molecule that stimulated expression of intestinal gluconeogenesis genes through cAMP signaling, propionate acted as a substrate, or fuel, for intestinal gluconeogenesis. Propionate also directly activated FFAR3 receptors on peripheral nerves in the portal vein, and periportal nervous deafferentiation prevented propionate-induced stimulation of intestinal gluconeogenesis, suggesting that the effect of propionate on intestinal gluconeogenesis involves gut-brain neural communication. Notably, the improvement in glucose tolerance induced by feeding with fructo-oligosaccharides or short-chain fatty acids required both gut-brain communication (determined using periportal nervous deafferentiation) and intestinal gluconeogenesis (determined using mice harboring a disruption in the G6Pase catalytic subunit in the intestine).
Like David et al.1, De Vadder et al.2 used 16S ribosomal RNA sequencing to track changes in the gut microbiota composition. Notably, they found that, unlike wild-type mice fed fructo-oligosaccharides, mice lacking G6Pase in their intestine enjoyed none of the metabolic benefits of fructo-oligosaccharide intake even though fructo-oligosaccharide provoked very similar shifts in the gut microbiota composition in the two strains of mice. These results indicate that the beneficial effects of diet on metabolic health may require not only a favorable gut microbiota composition but also intestinal gluconeogenesis.
A century ago, Metchnikoff distinguished putrefactive from saccharolytic gut bacteria and associated the latter, particularly lactic acid bacteria, with beneficial health effects5. His observations laid the foundation for the idea of using probiotics and prebiotics to counteract the detrimental effects of Western diet and lifestyle. Numerous studies have pointed to the potential of using prebiotic supplements that stimulate specific gut bacteria to achieve defined health outcomes. For example, ingestion of starch products that escape digestion in the small intestine of healthy individuals ('resistant starch') leads to reproducible shifts in gut microbiota toward saccharolytic microbes3, similar to what David et al.1 observed for a plant-based diet. Resistant starch feeding can also improve insulin sensitivity in healthy adults6. Dietary supplementation with oligosaccharides such as fructo-oligosaccharides and galacto-oligosaccharides reproducibly increases the proportion of bifidobacteria in human stool7. Bifidobacteria have been associated with health benefits in the young and elderly, and clinical trials have shown that fructo-oligosaccharides and galacto-oligosaccharides can prevent atopic eczema in infants8.
The findings of David et al.1 and De Vadder et al.2 could inform efforts to design health-promoting dietary supplements. Several supplementation strategies can be proposed. The probiotic approach would provide specific groups of saccharolytic bacteria known to produce beneficial metabolites. The prebiotic approach would supplement the diet with fibers that favor the growth of beneficial resident gut bacteria. These two strategies are not mutually exclusive and could be combined. A third approach would be to exploit the mechanistic detail outlined in the studies by providing the microbial metabolite directly as a 'postbiotic'. This approach may be of interest to the pharmaceutical industry. The challenge will be to identify synthetic FFAR3 agonists that have an improved pharmacodynamic profile over simple and cost-effective oral short-chain fatty acid supplementation. The probiotic, prebiotic and postbiotic approaches are not as distinct as they might seem. As a case in point, Bifidobacterium longum, when administered as a probiotic in a mouse model of pathogenic Escherichia coli infection, defends the host by using a carbohydrate transporter that allows it to produce the short-chain fatty acid acetate, which enhances barrier function of the gut epithelium, thereby blocking the transit of the lethal Shiga toxin into the bloodstream9.
Questions remain about the translational relevance of the new studies. For example, the contribution of intestinal gluconeogenesis to human health in different scenarios is still uncertain10. Regardless, the work of David et al.1 and De Vadder et al.2 provides a fascinating view of the effects of diet-derived short-chain fatty acids on distant organs. Because acetate, propionate, butyrate and isovalerate are the most abundant metabolites in human feces11 and—with the exception of butyrate, which is mostly consumed by enterocytes—are also released into the bloodstream, it is perhaps not surprising that diet-derived short-chain fatty acids exert beneficial effects on tissues other than the gut and the brain. In one recent example, the existence of a gut-lung axis was suggested by a study showing in a mouse model of allergic airway inflammation that a high-fiber diet reduced airway inflammation whereas a low-fiber diet exacerbated it12. Notably, ingestion of propionate decreased lung inflammation in an FFAR3-dependent manner and reduced the ability of dendritic cells from the lung-draining lymph nodes to provoke pro-allergenic phenotypes in T lymphocytes. Although short-chain fatty acids were not detected in the lung, propionate enhanced production of dendritic cells in the bone marrow; once in the lung, the newly generated dendritic cells activated pro-allergenic T cells less efficiently.
With its versatile metabolic capability, the gut microbiota acts as an important conduit between diet and host physiology. The findings of David et al.1 and De Vadder et al.2 are a step toward understanding this complex ecosystem and provide additional support for the proposition that intentional modulation of the gut microbiota is a valid strategy for improving human health.
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Scientific Reports (2016)