Intestinal mcirobiota and the development of diet induced obesity: the role of fiber and short chain fatty acids
Final Report Abstract
Background: Obesity and related disorders are caused by a combination of factors including high energy intake, low energy expenditure, and genetic susceptibility. The intestinal microbiota has been implicated in both the promotion and prevention of metabolic diseases. Gut bacteria degrade fermentable dietary fiber to short-chain fatty acids (SCFA) which provide energy to the host and thereby might facilitate obesity development. However, SCFA are also metabolic regulators and ligands of free-fatty acid receptors. Acetate is a precursor of long-chain fatty acid synthesis, whereas propionate is a gluconeogenic substrate. Hence, acetate has been considered to promote obesity, whereas propionate has been suggested to counteract obesity development. Methods: In order to shed light on the controversial function of SCFA in metabolic diseases, we investigated diets with high-fat and low-fat content, with fermentable and non-fermentable fiber, and with high amounts of acetate and propionate in gnotobiotic and conventional mice. In addition, we searched for a route to deliver SCFA to mice that mimics microbial fermentation of fiber in cecum and colon. Results: The fermentable fiber inulin protected mice from HFD-induced obesity, whereas the fermentable fiber guar gum did not do so. Feeding these fibers to mice resulted in differences in the abundance of two Bifidobacterium species. Whether these species played a causal role in the observed metabolic effects remained obscure. Supplementation of the HFD with acetate and propionate prevented severe body-weight gain and diabetes in BL/6 mice, but not in C3H mice, after a long-term intervention. The underlying mechanisms of the beneficial effects of acetate and propionate differed and included modifications in liver and adipose tissue metabolism. In particular propionate exerted a triglyceride lowering effect in the livers of BL/6 and C3H mice after long-term intervention. Furthermore, intestinal propionate was demonstrated to be a precursor of endogenous production of odd-chain fatty acids in mice and humans. Two approaches that aimed to give rise to SCFA formation in cecum and colon of mice failed. First, we were unable to devise a community of intestinal bacteria that produce distinctly more propionate than acetate. Second, we used cellobiose esters of propionate and acetate as a carrier to selectively increase either SCFA in the distal guts of mice. However, owing to the fact that the intestinal acetate concentrations in the mice were very high it was not possible to reach high propionate:acetate ratios by feeding cellobiose-4-propionate esters. Conclusion: Our studies clearly disprove the hypothesis that the fermentation of dietary fiber contributes to obesity and metabolic disease owing to increased SCFA production. Neither intestinal SCFA produced from inulin nor SCFA applied as dietary supplements promoted the development of obesity in C3H and BL/6 mice. In fact, long-term dietary intervention with fermentable inulin or acetate and propionate prevented diet-induced obesity in BL/6 mice. Further studies are needed to assess if these findings are also of relevance for humans.
Publications
- Clostridium ramosum promotes high-fat dietinduced obesity in gnotobiotic mouse models. MBio. 2014;5(5):e01530-14
Woting A, Pfeiffer N, Loh G, Klaus S, Blaut M
(See online at https://doi.org/10.1128/mBio.01530-14) - Alleviation of high fat diet-induced obesity by oligofructose in gnotobiotic mice is independent of presence of Bifidobacterium longum. Mol Nutr Food Res. 2015;59(11):2267-78
Woting A, Pfeiffer N, Hanske L, Loh G, Klaus S, Blaut M
(See online at https://doi.org/10.1002/mnfr.201500249) - Effects of dietary inulin on bacterial growth, short-chain fatty acid production and hepatic lipid metabolism in gnotobiotic mice. J Nutr Biochem. 2015;26(9):929-37
Weitkunat K, Schumann S, Petzke KJ, Blaut M, Loh G, Klaus S
(See online at https://doi.org/10.1016/j.jnutbio.2015.03.010) - Gut microbiota and energy balance: role in obesity. Proc Nutr Soc. 2015;74(3):227-34
Blaut M.
(See online at https://dx.doi.org/10.1017/S0029665114001700) - Importance of propionate for the repression of hepatic lipogenesis and improvement of insulin sensitivity in high-fat diet-induced obesity. Mol Nutr Food Res. 2016;60(12):2611-2621
Weitkunat K, Schumann S, Nickel D, Kappo KA, Petzke KJ, Kipp AP, Blaut M, Klaus S
(See online at https://doi.org/10.1002/mnfr.201600305) - The Intestinal Microbiota in Metabolic Disease. Nutrients. 2016;8(4):202
Woting A., Blaut M.
(See online at https://doi.org/10.3390/nu8040202) - Odd-chain fatty acids as a biomarker for dietary fiber intake: a novel pathway for endogenous production from propionate. Am J Clin Nutr. 2017;105(6):1544-1551
Weitkunat K, Schumann S, Nickel D, Hornemann S, Petzke KJ, Schulze MB, Pfeiffer AF, Klaus S
(See online at https://doi.org/10.3945/ajcn.117.152702) - Reply to TM Venäläinen et al. Am J Clin Nutr. 2017;106(3):954-955
Weitkunat K, Schumann S, Klaus S
(See online at https://dx.doi.org/10.3945/ajcn.117.162594) - Short-chain fatty acids and inulin, but not guar gum, prevent diet-induced obesity and insulin resistance through differential mechanisms in mice. Sci Rep. 2017;7(1):6109
Weitkunat K, Stuhlmann C, Postel A, Rumberger S, Fankhänel M, Woting A, Petzke KJ, Gohlke S, Schulz TJ, Blaut M, Klaus S, Schumann S
(See online at https://doi.org/10.1038/s41598-017-06447-x)
