REVIEWS FROM ASN EB 2014 SYMPOSIA
Knud Erik Bach Knudsen* Department of Animal Science, Aarhus University, Tjele, Denmark
ABSTRACT
Whole-grain cereals have a complex dietary fiber (DF) composition consisting of oligosaccharides (mostly fructans), resistant starch, and nonstarch polysaccharides (NSPs); the most important are arabinoxylans, mixed-linkage β(1,3; 1,4)-D-glucan (β-glucan), and cellulose and the noncarbohydrate polyphenolic ether lignin. The highest concentration of NSPs and lignin is found in the outer cell layers of the grain, and refined flour will consequently be depleted of a large proportion of insoluble DF components. The flow and composition of carbohydrates to the large intestine are directly related to the intake of DF. The type and composition of cereal DF can consequently be used to modulate the microbial composition and activity as well as the production and molar ratios of short-chain fatty acids (SCFAs). Arabinoxylans and β-glucan in whole-grain cereals and cereal ingredients have been shown to augment SCFA production, with the strongest relative effect on butyrate. When arabinoxylans were provided as a concentrate, the effect was only on total SCFA production. Increased SCFA production in the large intestine was shown by the concentration in the portal vein, whereas the impact on the concentration in peripheral blood was less because the majority of propionate and butyrate is cleared in the liver. Active microbial fermentation with increased SCFA production reduced the exposure of potentially toxic compounds to the epithelium, potentially stimulating anorectic hormones and acting as signaling molecules between the gut and the peripheral tissues. The latter can have implications for insulin sensitivity and glucose homeostasis. Adv Nutr 2015;6:206–213. Keywords:
whole-grain cereals, complex carbohydrates, short-chain fatty acids, butyrate
Introduction Several epidemiologic studies have indicated that the consumption of whole-grain cereals is protective against several chronic diseases such as cardiovascular diseases, type 2 diabetes, and some forms of cancer (1–4). Whole-grain cereals are a rich source of dietary fiber (DF)5 and bioactive compounds. The DF components, however, are unevenly distributed in the grain; the outer tissues (pericarp/testa, 1
This article is a summary of the symposium "Dietary Whole Grain-Microbiota Interactions: Insights into Mechanisms for Human Health" held 28 April 2014 at the ASN Scientific Sessions and Annual Meeting at Experimental Biology 2014 in San Diego, CA. The symposium was sponsored by the American Society for Nutrition (ASN) and an educational grant from Ingredion. 2 A summary of the symposium "Dietary Whole Grain-Microbiota Interactions: Insights into Mechanisms for Human Health" was published in the September 2014 issue of Advances in Nutrition. 3 Supported by the author’s basic funding from Aarhus University, Department of Animal Science, and funding from the project “Concepts for enhanced butyrate production to improve colonic health and insulin sensitivity” (ButCoIns). 4 Author disclosures: KE Bach Knudsen, no conflicts of interest. 5 Abbreviations used: DF, dietary fiber; GLP-1, glucagon-like peptide 1; NSP, nonstarch polysaccharide; RS, resistant starch; WR, wheat and rye breads. * To whom correspondence should be addressed. E-mail: [email protected].
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aleurone) contain the highest concentrations of DF (3, 5), and depleting the flour of the outer tissues may eliminate ~58% of DF, in particular its insoluble components (3). DFs are the fraction of carbohydrates and lignin that are not degraded by endogenous enzymes in the small intestine (6). Although some degradation occurs in the small intestine, the major portion passes to the large intestine, where it is fermented by the colonic microbiota (7). Fermentation of DF carbohydrates leads to the production of SCFAs, mainly acetate, propionate, and butyrate; gases (hydrogen and methane); and other metabolites (8). The ratio of SCFA production and absorption is dependent on fermentation substrate, the microbial composition, and colonic transit time (9). The substrate dependency has been used as a subject to manipulate the SCFA composition (10, 11). Most SCFAs are absorbed by the colonic epithelium or metabolized by other colonic bacteria, resulting in only 5–10% of SCFAs being excreted in feces (8). SCFAs play an important role in gut and potentially metabolic health (9, 12). The main purpose of the present review is to discuss current ã2015 American Society for Nutrition. Adv. Nutr. 6: 206–213, 2015; doi:10.3945/an.114.007450.
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Microbial Degradation of Whole-Grain Complex Carbohydrates and Impact on Short-Chain Fatty Acids and Health1–4
knowledge concerning the microbial degradation of complex carbohydrates from cereals and influence on SCFA production and impact on health.
Complex Carbohydrates in Whole-Grain Cereals and Refined Products
TABLE 1
Regulation of the Flow of Substrate for Fermentation in the Large Intestine Individuals who have undergone an ileostomy have been used as a model to study and quantify the amount of nutrients that pass from the small to the large intestine and thereby potentially can be available for fermentation (Figure 1). In studies with cereal products (soft and crisp breads and breakfast cereals), there is a strong relation between the intake of DF (NSPs + RS) and the flow of dry solids and carbohydrates to the large intestine (20–24). Carbohydrates account for 30–43% of the dry solids. The structure of the starch granule in cereals (20–30% amylose content) makes starch relatively easily accessible for amylolysis in the small intestine when provided as breads or breakfast cereals. The luminal viscosity created by the soluble b-glucan and arabinoxylans may delay the digestion and absorption processes and thereby impede starch hydrolysis (25, 26). However, most studies showed that, quantitatively, starch digestion was only marginally affected, by 1.3% and 1.9%, after consumption of low- and high-DF diets, respectively (21, 23). This is consistent with studies in ilealcannulated pigs fed wheat or rye breads (27, 28); although intact kernels may reduce the digestibility of starch, the reduction was 0.5% of total 16S ribosomal RNA sequenced across 6 obese male individuals. Five of the top 10 species (Bacteroides vulgatus, Eubacterium rectale, Faecalibacterium pausnitzii, Colinsella aerofaciens, and Ruminococcus 208 Symposium
SCFA Production and Absorption SCFAs are present at concentrations of ~100 mmol/kg colonic material but with a decreasing concentration from the cecum/proximal colon to the distal colon in humans (45) and animals (38). Cecum and proximal colon are the most active site for fermentation and with the lowest pH (5.4–6.4) depending on the rate of fermentation. Acetate accounts for approximately two-thirds of the produced SCFAs and is formed by many of the bacteria groups that inhabit the colon (32) (Figure 2), whereas the number of bacteria
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FIGURE 1 Influence of the intake of NSPs and RS on the ileal flow of dry solids and carbohydrates in subjects who underwent ileostomy. Values are means. CHO, carbohydrates; NSP, nonstarch polysaccharides; RS, resistant starch. Data from references 20–24.
The degradation by the microbial community of carbohydrates in the large intestine occurs in a hierarchic fashion: sugar residues = oligosaccharides > starch residues > soluble NSPs > insoluble NSPs. In pigs, almost all sugars, fructans, residual starch, and the soluble DF components (b-glucan and soluble arabinoxylans) are degraded in the cecum and proximal colon where the microbial activity is high (28, 37, 38), whereas insoluble arabinoxylans and cellulose are degraded at more distal locations (28, 37). By linkage composition analyses (39), it was also shown that the aleurone arabinoxylans resemble those of the ileal sample more than the fecal sample, whereas endosperm arabinoxylans had the fecal xylose substitution pattern already in the proximal colon. For pericarp/testa arabinoxylans, the substitution pattern was similar in the ileum, proximal colon, and feces (39). The fecal microbiota profile in healthy adults is generally quite stable over time, but the consumption of selected prebiotics (i.e., nondigestible oligosaccharides and RS) were shown to change the microbial community (40, 41). The fecal microbiota profiles of obese male subjects given diets differing in type and content of DF (RS3, NSPs from wheat bran, and a weight-loss diet) for 3-wk periods tended to group by individuals more than by diets (36). However, marked changes were found in the relative abundance of several dominant phylotypes in response to intake of RS, whereas there was no effect of NSPs from wheat bran (36). The changes occurred within a few days, and they were reversed equally quickly by a subsequent dietary shift. The lack of effect of the NSPs from wheat bran is presumably a consequence of the diverse NSP composition of wheat bran, with no single NSP being dominant (Table 1). Similar results were found by Costabile et al. (42). Feeding wholegrain wheat, however, increased Bifidobacterium spp. and resulted in a higher lactobacilli:enterococci ratio. Another intervention study with whole grain vs. refined wheat documented significantly higher (P 5 0.04) numbers of Bifidobacterium spp. (43). Thus, whole grains have a potential to influence microbial composition, although the effect is less pronounced than when using prebiotics with a dominating polysaccharide (RS, inulin) or oligosaccharide (41, 44).
fermentation of the arabinoxylan concentrate can be expected to be rapid, as indicated by the results in references 49 and 50, and with a decrease in pH mainly in the cecum (48), whereas the fermentation of arabinoxylans from a whole-grain matrix will be slower, with a decrease in pH not only in the cecum but also in the proximal colon (28). pH has been found to play a crucial role for the balance between acetate and butyrate production in the gut (51), and it cannot be excluded that this is a key factor why arabinoxylans fermentation under some conditions leads to enhanced butyrate production. In support of an impact of the wholegrain matrix on butyrate production is a human study in which the subjects consumed wheat and rye breads (WR) that were prepared without (WR2) and with (WR+) xylanases and compared with refined wheat (Table 3) (52). It was found that the concentration of total SCFAs and butyrate in feces was increased after the intervention with the WR diet, but it was only for the WR+ treatment that the effect was significant. Likewise, the concentrations of acetate, propionate, and butyrate in feces all increased when human subjects consumed either wheat arabinoxylan- or inulinenriched bread, but only the butyrate concentration changed significantly with wheat arabinoxylans (53). A range of other in vivo studies (27, 37, 54–58) also pointed toward arabinoxylans as a fermentative substrate that stimulates butyrate
FIGURE 2 A schematic of the gut microbiota involved in the metabolism of SCFAs. Acetate and lactate are shown as intermediates. Representative species and phyla are indicated based on information from cultured microorganisms. CoA, coenzyme A. Reproduced from reference 32 with permission. Carbohydrates and SCFAs 209
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groups that form propionate and butyrate is more restricted (32). There is also a substantial utilization of acetate during butyrate formation (46). As discussed in the previous section, the potential for changing the microbial composition by whole-grain cereals and cereal fractions is lower than by prebiotics with dominating oligo- or polysaccharides. However, several studies showed that b-glucan and arabinoxylans, when present in the whole-grain matrix, can be regulatory factors for SCFA production and profile in the large intestine. An arabinoxylan-rich cereal-based diet was found to stimulate the proliferation of butyrate-producing microorganisms (i.e., F. pausnitzii, Roseburia intestinalis) (46), butyrate production in the large intestine (47), and the net portal absorption of butyrate (48) to a larger extent than a diet with equal amounts of DF in the form of RS (Table 2). A Western-style diet high in refined carbohydrates from sugar and refined wheat flour was used as a reference diet (47, 48). In contrast to these findings, studies in rats and pigs fed an arabinoxylan-rich fraction from wheat did not specifically show enhanced butyrate but only total SCFA production (49, 50). The reasons for this difference in butyrate response between these 2 sets of experiments cannot be determined by any certainty but may be related to the way the arabinoxylans was provided, as a concentrate from wheat (49, 50) or as part of a whole-grain matrix (27, 47, 48). The
TABLE 2 Net portal absorption of total SCFAs and butyrate and butyrate concentrations in the portal vein and mesenteric artery as estimated in conscious catheterized pigs in vivo fed cereal-based diets varying in dietary fiber content and composition1 Diet
RS
nm nm nm 2 5 29 4 18
nm nm nm 6 113 8 nm nm
LF wheat HF wheat bran HF oat bran WSD RSD AXD WFRF WGRRB
Content, g/kg DM Cellulose b-glucan AX 19 28 22 29 34 37 131 20
3 5 40 1 1 16 12 19
33 68 44 18 15 72 53 127
NSP
DF
59 108 113 58 55 144 220 203
64 122 121 70 192 189 234 253
Absorption, mmol/d T-SCFAs Butyrate 720 738 891 888c 1584b 2448a 1595 1845
Butyrate, %
46 77 101 67a 136a 245b 91b 242a
6.3 10.4 11.3 7.5b 8.6b 10.0a 5.7b 13.1a
Butyrate, mmol/L PV MA 29 51 62 34b 75b 133a 52b 141a
6 7 8 3c 6b 8a 10b 25a
Ref (65) (65) (65) (48) (48) (48) (27) (27)
Values are means. Means without a common letter in the same column within each experiment differ, P , 0.05. AX, arabinoxylan; AXD, arabinoxylan-rich diet; DF, dietary fiber; DM, dry matter; HF, high-fiber; LF, low-fiber; MA, mesenteric artery; NDO, nondigestible oligosaccharide; nm, not measured; NSP, nonstarch polysaccharide; PV, portal vein; Ref, reference; RS, resistant starch; RSD, resistant starch diet; T-SCFA, total short-chain fatty acid; WFRF, wheat flour plus refined fiber; WGRRB, whole-grain rye plus rye bran; WSD, Western-style diet.
1
formation, whereas the outcome of in vitro fermentation studies is more variable, with some finding stimulating effects (59, 60) but others not (61). b-Glucan also seems to have the potential to influence SCFA production. In patients with ulcerative colitis who daily consumed 60 g oat bran rich in b-glucan, it was found that the fecal butyrate concentration increased significantly, whereas the remaining fecal SCFA concentrations were unchanged (62). The data from the ulcerative colitis study corroborated studies in rats fed barley b-glucan (63, 64), pigs fed oat bran (37, 55), and portal vein–catheterized pigs fed an oat bran and an oat b-glucan–rich concentrate (65, 66).
SCFA Metabolism DF amount and composition had a profound influence on the net portal absorption of SCFAs, including butyrate (27, 48, 65, 67) (Table 2). Within each experiment, butyrate absorption varied by 2 to 3.6 times between the lowest and highest concentrations due to differences in DF content (48, 65) and composition (27, 67). However, not only did DF content and composition influence total SCFA and butyrate absorption, but there was also a strong relation between net butyrate absorption and the butyrate concentration in the portal vein; for the data presented in Table 2, the correlation was 0.962. This is supported by pig studies in which pigs were deprived of feed for 24 h and then fed a pulse dose of either a barley-based diet rich in b-glucan (68) or a rye-based diet rich in arabinoxylans (27). In these studies, the concentration of butyrate in the portal vein started to increase 4 h postdosing (i.e., the time when the bulk of digesta reaches the large intestine) (27, 68). These data therefore seriously TABLE 3
questioned the general view that butyrate is mainly consumed by the colonic epithelium (69–71). Rather, the liver is the main site for the clearance, with clearance rates of propionate and butyrate of ~94% and ~82%, respectively, and a clearance rate of ~41% for acetate (48). Augmenting DF intake therefore not only increased peripheral acetate but also propionate and butyrate, as shown in studies in pigs (Table 2) and humans (72–75).
Physiologic and Health Effects of SCFAs An unhealthy dietary pattern (i.e., consumption of diets high in fat and refined carbohydrates and low in DF) is regarded to be a significant health risk factor, limiting the production of SCFAs and giving rise to high luminal concentrations of putative risk factors (secondary bile acids, protein degradation products) (28, 49, 76). Diets with a higher DF content stimulate SCFA production and reduce the exposure of colonic epithelium to potentially toxic compounds (28, 49), which have been shown to oppose the induction of DNA stand breaks due to high protein concentrations. Although the study by Belobrajdic et al. (49) did not result in a highest relative proportion of SCFAs, the higher pool size indicates an enhanced total butyrate production, which is of interest because butyrate is believed to play an important role in maintaining colonic health and function. In addition to being an energy source for colonic epithelial cells (70, 71), butyrate can induce changes in gene expression influencing the colonic function, mainly by inhibiting the histone deacetylase (76). In vitro, butyrate was shown to reduce inflammation by inhibition of NF-kB activation and to upregulate PPARg expression (77). Oxidative stress
Fecal SCFA excretions after 3-wk consumption of wheat and rye breads that were prepared without and with xylanases1 Treatment period, mmol/g wet feces
Metabolite
Pre-WR+ (W2 treatment)
WR+ (WR+ treatment)
Pre-WR2 (W2 treatment)
WR2 (WR2 treatment)
Acetic acid Propionic acid Butyric acid Total SCFAs
26.4 (19.5–39.5) 7.9 (6.1–10.7) 10.7 (6.0–19.8) 45.5 (32.3–70.0)
36.6 (24.0–46.7) 11.1 (7.4–14.2) 18.3 (12.4–28.0)* 70.8 (46.8–84.0)*
29.0 (18.0–38.4) 8.5 (5.7–11.0) 11.4 (5.5–18.6) 48.9 (32.0–67.0)
33.8 (26.6–40.3) 9.8 (7.8–11.2) 13.7 (9.4–21.7) 58.5 (40.3–75.1)
Values are medians (IQRs), n = 27. *Different from pre-WR+ period, P , 0.05. Adapted from reference 51 with permission. W2 , wheat flour bread without in situ–produced arabinoxylan oligosaccharides; WR2 , wheat/rye bread without in situ–produced arabinoxylan oligosaccharides; WR+ , wheat/rye bread with in situ–produced arabinoxylan oligosaccharides.
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NDO
Conclusions Whole-grain cereals have a diverse DF composition that can be used to produce diets with the potential to influence microbial composition, the production and molar proportions of SCFAs, and gut and metabolic health.
Acknowledgments The sole author had responsibility for all parts of the manuscript.
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is involved in both inflammation and the initiation and progression of carcinogenesis. During oxidative stress, there is an imbalance between the generation of reactive oxygen species and the antioxidant defense mechanisms, leading to a cascade of reactions in which lipids, proteins, and/or DNA may be damaged (78). Furthermore, butyrate was shown to have a potent effect on the expression of genes involved in regulating cell proliferation, apoptosis, differentiation, and metastasis in a human colonic epithelial cell line (79). It has also been recognized that the binding of SCFAs to free fatty acid receptor (FFAR) 2 and FFAR3 located on colonic L-cells may be involved in controlling anorectic hormones including peptide YY and glucagon-like peptide 1 (GLP-1) (80). Oat b-glucan increased net SCFA absorption in portal vein–catheterized pigs, leading to a decreased apparent insulin production, which was associated with GLP-1 mediation (66); and supplementing a diet with 10% b-glucan increased total SCFA content in the cecum, suppressed central neuronal activity in the hypothalamic appetite centers, and decreased food intake (64). A recent study by Ingerslev et al. (48) in catheterized pigs, however, did not confirm a link between net portal SCFA absorption and the net portal GLP-1 flux but identified a lower insulin flux at higher net portal SCFA absorption. SCFAs are also considered to be signaling molecules between the gut and the peripheral tissues, with implications for insulin sensitivity and glucose homeostasis (12, 74). The mechanisms appear to involve adipocyte cell differentiation, regulation, and metabolism (12, 75). In response to an increased DF intake, there is an increased absorption of SCFAs; and although the major part of propionate and butyrate is cleared in the liver, micromolar concentrations of all 3 SCFAs will reach the peripheral tissues (10) (Table 2). Here, the SCFAs can act as ligands on adipocytes (12, 81) and thereby influence the balance of adipokines released and, in turn, increase adipogenesis and differentiation of fat cells and thus reduce their average size. SCFAs further inhibit lipolysis within adipose tissue as indicated by the reduced plasma concentrations of nonesterified FAs after the intake of fermentable carbohydrates (82–84) and the lower fasting concentrations of nonesterified FAs with higher SCFA production (48). The consequence is reduced availability of FAs for uptake into ectopic fat depots (e.g., liver and pancreas) (12). Overall, the above-mentioned conditions have been linked to improved insulin sensitivity and glucose homeostasis (12, 74, 75, 85, 86).
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23. Pettersson D, Åman P, Bach Knudsen KE, Lundin E, Zhang J-X, Hallmans G, Härkönen H. Intake of rye bread by ileostomists increases ileal excretion of fiber polysaccharide components and organic acids but does not increase plasma or urine lignans and isoflavonoids. J Nutr 1996;126:1594–600. 24. Sundberg B, Wood P, Lia Å, Andersson H, Sandberg A-S, Hallmans G, Åman P. Mixed-linked b-glucan from breads of different cereals is partly degraded in the human ileostomy model. Am J Clin Nutr 1996;64:878–85. 25. Le Gall M, Eybye KL, Bach Knudsen KE. Molecular weight changes of arabinoxylans of wheat and rye incurred by the digestion processes in the upper gastrointestinal tract of pigs. Livest Sci 2010;134:72–5. 26. Lærke HN, Pedersen C, Mortensen MA, Theil PK, Larsen T, Bach Knudsen KE. Rye bread reduces plasma cholesterol levels in hypercholesterolaemic pigs when compared to wheat at similar dietary fibre level. J Sci Food Agric 2008;88:1385–93. 27. Bach Knudsen KE, Serena A, Kjaer AK, Jørgensen H, Engberg R. Rye bread enhances the production and plasma concentration of butyrate but not the plasma concentrations of glucose and insulin in pigs. J Nutr 2005;135:1696–704. 28. Glitsø LV, Brunsgaard G, Hojsgaard S, Sandstrom B, Bach Knudsen KE. Intestinal degradation in pigs of rye dietary fibre with different structural characteristics. Br J Nutr 1998;80:457–68. 29. Kasprzak MM, Lærke HN, Bach Knudsen KE. Effects of isolated and complex dietary fiber matrices in breads on carbohydrate digestibility and physiocochemical properties of ileal effluent from pigs. J Agric Food Chem 2012;60:12469–76. 30. Bach Knudsen KE, Hessov I. Recovery of inulin from Jerusalem artichoke (Helianthus tuberosus L.) in the small intestine of man. Br J Nutr 1995;74:101–13. 31. Flint HJ, Duncan SH, Scott KP, Louis P. Interactions and competition within the microbial community of the human colon: links between diet and health. Environ Microbiol 2007;9:1101–11. 32. Louis P, Scott KP, Duncan SH, Flint HJ. Understanding the effects of diet on bacterial metabolism in the large intestine. J Appl Microbiol 2007;102:1197–208. 33. Flint HJ, Scott KP, Louis P, Duncan SH. The role of the gut microbiota in nutrition and health. Nat Rev Gastroenterol Hepatol 2012;9:577–89. 34. Scott KP, Gratz SW, Sheridan PO, Flint HJ, Duncan SH. The influence of diet on the gut microbiota. Pharmacol Res 2013;69:52–60. 35. Tap J, Mondot S, Levenez F, Pelletier E, Caron C, Furet JP, Ugarte E, Munoz-Tamayo R, Paslier DL, Nalin R, et al. Towards the human intestinal microbiota phylogenetic core. Environ Microbiol 2009;11:2574–84. 36. Walker AW, Ince J, Duncan SH, Webster LM, Holtrop G, Ze X, Brown D, Stares MD, Scott P, Bergerat A, et al. Dominant and diet-responsive groups of bacteria within the human colonic microbiota. ISME J 2011; 5:220–30. 37. Bach Knudsen KE, Borg Jensen B, Hansen I. Digestion of polysaccharides and other major components in the small and large intestine of pigs fed on diets consisting of oat fractions rich in b-D-glucan. Br J Nutr 1993;70:537–56. 38. Bach Knudsen KE, Jensen BB, Andersen JO, Hansen I. Gastrointestinal implications in pigs of wheat and oat fractions. 2. Microbial activity in the gastrointestinal tract. Br J Nutr 1991;65(2):233–48. 39. Glitsø LV, Gruppen H, Schols HA, Højsgaard S, Sandström B, Bach Knudsen KE. Degradation of rye arabinoxylans in the large intestine of pigs. J Sci Food Agric 1999;79:961–9. 40. Davis LM, Martinez I, Walter J, Goin C, Hutkins RW. Barcoded pyrosequencing reveals that consumption of galactooligosaccharides results in a highly specific bifidogenic response in humans. PLoS ONE 2011;6: e25200. 41. Martínez I, Kim J, Duffy PR, Schlegel VL, Walter J. Resistant starches types 2 and 4 have differential effects on the composition of the fecal microbiota in human subjects. PLoS ONE 2010;5:e15046. 42. Costabile A, Klinder A, Fava F, Napolitano A, Fogliano V, Leonard C, Gibson GR, Tuohy KM. Whole-grain wheat breakfast cereal has a prebiotic effect on the human gut microbiota: a double-blind, placebocontrolled, crossover study. Br J Nutr 2008;99:110–20.
75. Robertson MD, Bickerton AS, Dennis AL, Vidal H, Frayn KN. Insulinsensitizing effects of dietary resistant starch and effects on skeletal muscle and adipose tissue metabolism. Am J Clin Nutr 2005;82 (3):559–67. 76. Hamer HM, Jonkers D, Venema K, Vanhoutvin S, Troost FJ, Brummer RJ. Review article: the role of butyrate on colonic function. Aliment Pharmacol Ther 2008;27:104–19. 77. Kinoshita M, Suzuki Y, Saito Y. Butyrate reduces colonic paracellular permeability by enhancing PPARgamma activation. Biochem Biophys Res Commun 2002;293(2):827–31. 78. Hamer HM, Jonkers DM, Bast A, Vanhoutvin SA, Fischer MA, Kodde A, Troost FJ, Venema K, Brummer RJ. Butyrate modulates oxidative stress in the colonic mucosa of healthy humans. Clin Nutr 2009;28 (1):88–93. 79. Daly K, Shirazi-Beechey SP. Microarray analysis of butyrate regulated genes in colonic epithelial cells. DNA Cell Biol 2006;25:49–62. 80. Sleeth ML, Thompson EL, Ford HE, Zac-Varghese SE, Frost G. Free fatty acid receptor 2 and nutrient sensing: a proposed role for fibre, fermentable carbohydrates and short-chain fatty acids in appetite regulation. Nutr Res Rev 2010;23:135–45. 81. Brown AJ, Goldsworthy SM, Barnes AA, Eilert MM, Tcheang L, Daniels D, Muir AI, Wigglesworth MJ, Kinghorn I, Fraser NJ, et al. The orphan G protein-coupled receptors GPR41 and GPR43 are activated by propionate and other short chain carboxylic acids. J Biol Chem 2003;278: 11312–9. 82. Ferchaud-Roucher V, Pouteau E, Piloquet H, Zair Y, Krempf M. Colonic fermentation from lactulose inhibits lipolysis in overweight subjects. Am J Physiol Endocrinol Metab 2005;289:E716–20. 83. Brighenti F, Benini L, Del Rio D, Casiraghi C, Pellegrini N, Scazzina F, Jenkins DJA, Vantini I. Colonic fermentation of indigestible carbohydrates contributes to the second-meal effect. Am J Clin Nutr 2006; 83:817–22. 84. Robertson MD, Bickerton AS, Dennis AL, Vidal H, Frayn KN. Insulinsensitizing effects of dietary resistant starch and effects on skeletal muscle and adipose tissue metabolism. Am J Clin Nutr 2005;82:559–67. 85. Gao Z, Yin J, Zhang J, Ward RE, Martin RJ, Lefevre M, Cefalu WT, Ye J. Butyrate improves insulin sensitivity and increases energy expenditure in mice. Diabetes 2009;58:1509–17. 86. Robertson MD, Currie JM, Morgan LM, Jewell DP, Frayn KN. Prior short-term consumption of resistant starch enhances postprandial insulin sensitivity in healthy subjects. Diabetologia 2003;46:659–65.
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62. Hallert C, Bjorck I, Nyman M, Pousette A, Granno C, Svensson H. Increasing fecal butyrate in ulcerative colitis patients by diet: controlled pilot study. Inflamm Bowel Dis 2003;9:116–21. 63. Berggren AM, Björck IME, Nyman EMGL, Eggum BO. Short-chain fatty acid content and pH in caecum of rats given various sources of carbohydrates. J Sci Food Agric 1993;63:397–406. 64. Arora T, Loo RL, Anastasovska J, Gibson GR, Tuohy KM, Sharma RK, Swann JR, Deaville ER, Sleeth ML, Thomas EL, et al. Differential effects of two fermentable carbohydrates on central appetite regulation and body composition. PLoS ONE 2012;7:e43263. 65. Bach Knudsen KE, Canibe N, Jørgensen H. Quantification of the absorption of nutrients deriving from carbohydrate assimilation: model experiment with catheterised pigs fed on wheat and oat based rolls. Br J Nutr 2000;84:449–58. 66. Hooda S, Matte JJ, Vasanthan T, Zijlstra RT. Dietary oat beta-glucan reduces peak net glucose flux and insulin production and modulates plasma incretin in portal-vein catheterized grower pigs. J Nutr 2010;140:1564–9. 67. Theil PK, Jorgensen H, Serena A, Hendrickson J, Bach Knudsen KE. Products deriving from microbial fermentation are linked to insulinaemic response in pigs fed breads prepared from whole-wheat grain and wheat and rye ingredients. Br J Nutr 2011;105:373–83. 68. Bach Knudsen KE, Serena A, Canibe N, Juntunen KS. New insight into butyrate metabolism. Proc Nutr Soc 2003;62:81–6. 69. Cummings JH, Pomare EW, Branch WJ, Naylor CPE, MacFarlane GT. Short chain fatty acids in human large intestine, portal, hepatic and venous blood. Gut 1987;28:1221–7. 70. Roediger WEW. Oxidative and synthetic functions of n-butyrate in colonocytes. Dis Colon Rectum 1992;35:511–2. 71. Scheppach W, Weiler F. The butyrate story: old wine in new bottles? Curr Opin Clin Nutr Metab Care 2004;7:563–7. 72. Hartvigsen ML, Laerke HN, Overgaard A, Holst JJ, Bach Knudsen KE, Hermansen K. Postprandial effects of test meals including concentrated arabinoxylan and whole grain rye in subjects with the metabolic syndrome: a randomised study. Eur J Clin Nutr 2014;68:567–74. 73. Nilsson AC, Ostman EM, Knudsen KE, Holst JJ, Bjorck IM. A cerealbased evening meal rich in indigestible carbohydrates increases plasma butyrate the next morning. J Nutr 2010;140:1932–6 . 74. Priebe MG, Wang H, Weening D, Schepers M, Preston T, Vonk RJ. Factors related to colonic fermentation of nondigestible carbohydrates of a previous evening meal increase tissue glucose uptake and moderate glucose-associated inflammation. Am J Clin Nutr 2010;91:90–7.
Knud Erik Bach Knudsen* Department of Animal Science, Aarhus University, Tjele, Denmark
ABSTRACT
Whole-grain cereals have a complex dietary fiber (DF) composition consisting of oligosaccharides (mostly fructans), resistant starch, and nonstarch polysaccharides (NSPs); the most important are arabinoxylans, mixed-linkage β(1,3; 1,4)-D-glucan (β-glucan), and cellulose and the noncarbohydrate polyphenolic ether lignin. The highest concentration of NSPs and lignin is found in the outer cell layers of the grain, and refined flour will consequently be depleted of a large proportion of insoluble DF components. The flow and composition of carbohydrates to the large intestine are directly related to the intake of DF. The type and composition of cereal DF can consequently be used to modulate the microbial composition and activity as well as the production and molar ratios of short-chain fatty acids (SCFAs). Arabinoxylans and β-glucan in whole-grain cereals and cereal ingredients have been shown to augment SCFA production, with the strongest relative effect on butyrate. When arabinoxylans were provided as a concentrate, the effect was only on total SCFA production. Increased SCFA production in the large intestine was shown by the concentration in the portal vein, whereas the impact on the concentration in peripheral blood was less because the majority of propionate and butyrate is cleared in the liver. Active microbial fermentation with increased SCFA production reduced the exposure of potentially toxic compounds to the epithelium, potentially stimulating anorectic hormones and acting as signaling molecules between the gut and the peripheral tissues. The latter can have implications for insulin sensitivity and glucose homeostasis. Adv Nutr 2015;6:206–213. Keywords:
whole-grain cereals, complex carbohydrates, short-chain fatty acids, butyrate
Introduction Several epidemiologic studies have indicated that the consumption of whole-grain cereals is protective against several chronic diseases such as cardiovascular diseases, type 2 diabetes, and some forms of cancer (1–4). Whole-grain cereals are a rich source of dietary fiber (DF)5 and bioactive compounds. The DF components, however, are unevenly distributed in the grain; the outer tissues (pericarp/testa, 1
This article is a summary of the symposium "Dietary Whole Grain-Microbiota Interactions: Insights into Mechanisms for Human Health" held 28 April 2014 at the ASN Scientific Sessions and Annual Meeting at Experimental Biology 2014 in San Diego, CA. The symposium was sponsored by the American Society for Nutrition (ASN) and an educational grant from Ingredion. 2 A summary of the symposium "Dietary Whole Grain-Microbiota Interactions: Insights into Mechanisms for Human Health" was published in the September 2014 issue of Advances in Nutrition. 3 Supported by the author’s basic funding from Aarhus University, Department of Animal Science, and funding from the project “Concepts for enhanced butyrate production to improve colonic health and insulin sensitivity” (ButCoIns). 4 Author disclosures: KE Bach Knudsen, no conflicts of interest. 5 Abbreviations used: DF, dietary fiber; GLP-1, glucagon-like peptide 1; NSP, nonstarch polysaccharide; RS, resistant starch; WR, wheat and rye breads. * To whom correspondence should be addressed. E-mail: [email protected].
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aleurone) contain the highest concentrations of DF (3, 5), and depleting the flour of the outer tissues may eliminate ~58% of DF, in particular its insoluble components (3). DFs are the fraction of carbohydrates and lignin that are not degraded by endogenous enzymes in the small intestine (6). Although some degradation occurs in the small intestine, the major portion passes to the large intestine, where it is fermented by the colonic microbiota (7). Fermentation of DF carbohydrates leads to the production of SCFAs, mainly acetate, propionate, and butyrate; gases (hydrogen and methane); and other metabolites (8). The ratio of SCFA production and absorption is dependent on fermentation substrate, the microbial composition, and colonic transit time (9). The substrate dependency has been used as a subject to manipulate the SCFA composition (10, 11). Most SCFAs are absorbed by the colonic epithelium or metabolized by other colonic bacteria, resulting in only 5–10% of SCFAs being excreted in feces (8). SCFAs play an important role in gut and potentially metabolic health (9, 12). The main purpose of the present review is to discuss current ã2015 American Society for Nutrition. Adv. Nutr. 6: 206–213, 2015; doi:10.3945/an.114.007450.
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Microbial Degradation of Whole-Grain Complex Carbohydrates and Impact on Short-Chain Fatty Acids and Health1–4
knowledge concerning the microbial degradation of complex carbohydrates from cereals and influence on SCFA production and impact on health.
Complex Carbohydrates in Whole-Grain Cereals and Refined Products
TABLE 1
Regulation of the Flow of Substrate for Fermentation in the Large Intestine Individuals who have undergone an ileostomy have been used as a model to study and quantify the amount of nutrients that pass from the small to the large intestine and thereby potentially can be available for fermentation (Figure 1). In studies with cereal products (soft and crisp breads and breakfast cereals), there is a strong relation between the intake of DF (NSPs + RS) and the flow of dry solids and carbohydrates to the large intestine (20–24). Carbohydrates account for 30–43% of the dry solids. The structure of the starch granule in cereals (20–30% amylose content) makes starch relatively easily accessible for amylolysis in the small intestine when provided as breads or breakfast cereals. The luminal viscosity created by the soluble b-glucan and arabinoxylans may delay the digestion and absorption processes and thereby impede starch hydrolysis (25, 26). However, most studies showed that, quantitatively, starch digestion was only marginally affected, by 1.3% and 1.9%, after consumption of low- and high-DF diets, respectively (21, 23). This is consistent with studies in ilealcannulated pigs fed wheat or rye breads (27, 28); although intact kernels may reduce the digestibility of starch, the reduction was 0.5% of total 16S ribosomal RNA sequenced across 6 obese male individuals. Five of the top 10 species (Bacteroides vulgatus, Eubacterium rectale, Faecalibacterium pausnitzii, Colinsella aerofaciens, and Ruminococcus 208 Symposium
SCFA Production and Absorption SCFAs are present at concentrations of ~100 mmol/kg colonic material but with a decreasing concentration from the cecum/proximal colon to the distal colon in humans (45) and animals (38). Cecum and proximal colon are the most active site for fermentation and with the lowest pH (5.4–6.4) depending on the rate of fermentation. Acetate accounts for approximately two-thirds of the produced SCFAs and is formed by many of the bacteria groups that inhabit the colon (32) (Figure 2), whereas the number of bacteria
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FIGURE 1 Influence of the intake of NSPs and RS on the ileal flow of dry solids and carbohydrates in subjects who underwent ileostomy. Values are means. CHO, carbohydrates; NSP, nonstarch polysaccharides; RS, resistant starch. Data from references 20–24.
The degradation by the microbial community of carbohydrates in the large intestine occurs in a hierarchic fashion: sugar residues = oligosaccharides > starch residues > soluble NSPs > insoluble NSPs. In pigs, almost all sugars, fructans, residual starch, and the soluble DF components (b-glucan and soluble arabinoxylans) are degraded in the cecum and proximal colon where the microbial activity is high (28, 37, 38), whereas insoluble arabinoxylans and cellulose are degraded at more distal locations (28, 37). By linkage composition analyses (39), it was also shown that the aleurone arabinoxylans resemble those of the ileal sample more than the fecal sample, whereas endosperm arabinoxylans had the fecal xylose substitution pattern already in the proximal colon. For pericarp/testa arabinoxylans, the substitution pattern was similar in the ileum, proximal colon, and feces (39). The fecal microbiota profile in healthy adults is generally quite stable over time, but the consumption of selected prebiotics (i.e., nondigestible oligosaccharides and RS) were shown to change the microbial community (40, 41). The fecal microbiota profiles of obese male subjects given diets differing in type and content of DF (RS3, NSPs from wheat bran, and a weight-loss diet) for 3-wk periods tended to group by individuals more than by diets (36). However, marked changes were found in the relative abundance of several dominant phylotypes in response to intake of RS, whereas there was no effect of NSPs from wheat bran (36). The changes occurred within a few days, and they were reversed equally quickly by a subsequent dietary shift. The lack of effect of the NSPs from wheat bran is presumably a consequence of the diverse NSP composition of wheat bran, with no single NSP being dominant (Table 1). Similar results were found by Costabile et al. (42). Feeding wholegrain wheat, however, increased Bifidobacterium spp. and resulted in a higher lactobacilli:enterococci ratio. Another intervention study with whole grain vs. refined wheat documented significantly higher (P 5 0.04) numbers of Bifidobacterium spp. (43). Thus, whole grains have a potential to influence microbial composition, although the effect is less pronounced than when using prebiotics with a dominating polysaccharide (RS, inulin) or oligosaccharide (41, 44).
fermentation of the arabinoxylan concentrate can be expected to be rapid, as indicated by the results in references 49 and 50, and with a decrease in pH mainly in the cecum (48), whereas the fermentation of arabinoxylans from a whole-grain matrix will be slower, with a decrease in pH not only in the cecum but also in the proximal colon (28). pH has been found to play a crucial role for the balance between acetate and butyrate production in the gut (51), and it cannot be excluded that this is a key factor why arabinoxylans fermentation under some conditions leads to enhanced butyrate production. In support of an impact of the wholegrain matrix on butyrate production is a human study in which the subjects consumed wheat and rye breads (WR) that were prepared without (WR2) and with (WR+) xylanases and compared with refined wheat (Table 3) (52). It was found that the concentration of total SCFAs and butyrate in feces was increased after the intervention with the WR diet, but it was only for the WR+ treatment that the effect was significant. Likewise, the concentrations of acetate, propionate, and butyrate in feces all increased when human subjects consumed either wheat arabinoxylan- or inulinenriched bread, but only the butyrate concentration changed significantly with wheat arabinoxylans (53). A range of other in vivo studies (27, 37, 54–58) also pointed toward arabinoxylans as a fermentative substrate that stimulates butyrate
FIGURE 2 A schematic of the gut microbiota involved in the metabolism of SCFAs. Acetate and lactate are shown as intermediates. Representative species and phyla are indicated based on information from cultured microorganisms. CoA, coenzyme A. Reproduced from reference 32 with permission. Carbohydrates and SCFAs 209
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groups that form propionate and butyrate is more restricted (32). There is also a substantial utilization of acetate during butyrate formation (46). As discussed in the previous section, the potential for changing the microbial composition by whole-grain cereals and cereal fractions is lower than by prebiotics with dominating oligo- or polysaccharides. However, several studies showed that b-glucan and arabinoxylans, when present in the whole-grain matrix, can be regulatory factors for SCFA production and profile in the large intestine. An arabinoxylan-rich cereal-based diet was found to stimulate the proliferation of butyrate-producing microorganisms (i.e., F. pausnitzii, Roseburia intestinalis) (46), butyrate production in the large intestine (47), and the net portal absorption of butyrate (48) to a larger extent than a diet with equal amounts of DF in the form of RS (Table 2). A Western-style diet high in refined carbohydrates from sugar and refined wheat flour was used as a reference diet (47, 48). In contrast to these findings, studies in rats and pigs fed an arabinoxylan-rich fraction from wheat did not specifically show enhanced butyrate but only total SCFA production (49, 50). The reasons for this difference in butyrate response between these 2 sets of experiments cannot be determined by any certainty but may be related to the way the arabinoxylans was provided, as a concentrate from wheat (49, 50) or as part of a whole-grain matrix (27, 47, 48). The
TABLE 2 Net portal absorption of total SCFAs and butyrate and butyrate concentrations in the portal vein and mesenteric artery as estimated in conscious catheterized pigs in vivo fed cereal-based diets varying in dietary fiber content and composition1 Diet
RS
nm nm nm 2 5 29 4 18
nm nm nm 6 113 8 nm nm
LF wheat HF wheat bran HF oat bran WSD RSD AXD WFRF WGRRB
Content, g/kg DM Cellulose b-glucan AX 19 28 22 29 34 37 131 20
3 5 40 1 1 16 12 19
33 68 44 18 15 72 53 127
NSP
DF
59 108 113 58 55 144 220 203
64 122 121 70 192 189 234 253
Absorption, mmol/d T-SCFAs Butyrate 720 738 891 888c 1584b 2448a 1595 1845
Butyrate, %
46 77 101 67a 136a 245b 91b 242a
6.3 10.4 11.3 7.5b 8.6b 10.0a 5.7b 13.1a
Butyrate, mmol/L PV MA 29 51 62 34b 75b 133a 52b 141a
6 7 8 3c 6b 8a 10b 25a
Ref (65) (65) (65) (48) (48) (48) (27) (27)
Values are means. Means without a common letter in the same column within each experiment differ, P , 0.05. AX, arabinoxylan; AXD, arabinoxylan-rich diet; DF, dietary fiber; DM, dry matter; HF, high-fiber; LF, low-fiber; MA, mesenteric artery; NDO, nondigestible oligosaccharide; nm, not measured; NSP, nonstarch polysaccharide; PV, portal vein; Ref, reference; RS, resistant starch; RSD, resistant starch diet; T-SCFA, total short-chain fatty acid; WFRF, wheat flour plus refined fiber; WGRRB, whole-grain rye plus rye bran; WSD, Western-style diet.
1
formation, whereas the outcome of in vitro fermentation studies is more variable, with some finding stimulating effects (59, 60) but others not (61). b-Glucan also seems to have the potential to influence SCFA production. In patients with ulcerative colitis who daily consumed 60 g oat bran rich in b-glucan, it was found that the fecal butyrate concentration increased significantly, whereas the remaining fecal SCFA concentrations were unchanged (62). The data from the ulcerative colitis study corroborated studies in rats fed barley b-glucan (63, 64), pigs fed oat bran (37, 55), and portal vein–catheterized pigs fed an oat bran and an oat b-glucan–rich concentrate (65, 66).
SCFA Metabolism DF amount and composition had a profound influence on the net portal absorption of SCFAs, including butyrate (27, 48, 65, 67) (Table 2). Within each experiment, butyrate absorption varied by 2 to 3.6 times between the lowest and highest concentrations due to differences in DF content (48, 65) and composition (27, 67). However, not only did DF content and composition influence total SCFA and butyrate absorption, but there was also a strong relation between net butyrate absorption and the butyrate concentration in the portal vein; for the data presented in Table 2, the correlation was 0.962. This is supported by pig studies in which pigs were deprived of feed for 24 h and then fed a pulse dose of either a barley-based diet rich in b-glucan (68) or a rye-based diet rich in arabinoxylans (27). In these studies, the concentration of butyrate in the portal vein started to increase 4 h postdosing (i.e., the time when the bulk of digesta reaches the large intestine) (27, 68). These data therefore seriously TABLE 3
questioned the general view that butyrate is mainly consumed by the colonic epithelium (69–71). Rather, the liver is the main site for the clearance, with clearance rates of propionate and butyrate of ~94% and ~82%, respectively, and a clearance rate of ~41% for acetate (48). Augmenting DF intake therefore not only increased peripheral acetate but also propionate and butyrate, as shown in studies in pigs (Table 2) and humans (72–75).
Physiologic and Health Effects of SCFAs An unhealthy dietary pattern (i.e., consumption of diets high in fat and refined carbohydrates and low in DF) is regarded to be a significant health risk factor, limiting the production of SCFAs and giving rise to high luminal concentrations of putative risk factors (secondary bile acids, protein degradation products) (28, 49, 76). Diets with a higher DF content stimulate SCFA production and reduce the exposure of colonic epithelium to potentially toxic compounds (28, 49), which have been shown to oppose the induction of DNA stand breaks due to high protein concentrations. Although the study by Belobrajdic et al. (49) did not result in a highest relative proportion of SCFAs, the higher pool size indicates an enhanced total butyrate production, which is of interest because butyrate is believed to play an important role in maintaining colonic health and function. In addition to being an energy source for colonic epithelial cells (70, 71), butyrate can induce changes in gene expression influencing the colonic function, mainly by inhibiting the histone deacetylase (76). In vitro, butyrate was shown to reduce inflammation by inhibition of NF-kB activation and to upregulate PPARg expression (77). Oxidative stress
Fecal SCFA excretions after 3-wk consumption of wheat and rye breads that were prepared without and with xylanases1 Treatment period, mmol/g wet feces
Metabolite
Pre-WR+ (W2 treatment)
WR+ (WR+ treatment)
Pre-WR2 (W2 treatment)
WR2 (WR2 treatment)
Acetic acid Propionic acid Butyric acid Total SCFAs
26.4 (19.5–39.5) 7.9 (6.1–10.7) 10.7 (6.0–19.8) 45.5 (32.3–70.0)
36.6 (24.0–46.7) 11.1 (7.4–14.2) 18.3 (12.4–28.0)* 70.8 (46.8–84.0)*
29.0 (18.0–38.4) 8.5 (5.7–11.0) 11.4 (5.5–18.6) 48.9 (32.0–67.0)
33.8 (26.6–40.3) 9.8 (7.8–11.2) 13.7 (9.4–21.7) 58.5 (40.3–75.1)
Values are medians (IQRs), n = 27. *Different from pre-WR+ period, P , 0.05. Adapted from reference 51 with permission. W2 , wheat flour bread without in situ–produced arabinoxylan oligosaccharides; WR2 , wheat/rye bread without in situ–produced arabinoxylan oligosaccharides; WR+ , wheat/rye bread with in situ–produced arabinoxylan oligosaccharides.
1
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NDO
Conclusions Whole-grain cereals have a diverse DF composition that can be used to produce diets with the potential to influence microbial composition, the production and molar proportions of SCFAs, and gut and metabolic health.
Acknowledgments The sole author had responsibility for all parts of the manuscript.
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is involved in both inflammation and the initiation and progression of carcinogenesis. During oxidative stress, there is an imbalance between the generation of reactive oxygen species and the antioxidant defense mechanisms, leading to a cascade of reactions in which lipids, proteins, and/or DNA may be damaged (78). Furthermore, butyrate was shown to have a potent effect on the expression of genes involved in regulating cell proliferation, apoptosis, differentiation, and metastasis in a human colonic epithelial cell line (79). It has also been recognized that the binding of SCFAs to free fatty acid receptor (FFAR) 2 and FFAR3 located on colonic L-cells may be involved in controlling anorectic hormones including peptide YY and glucagon-like peptide 1 (GLP-1) (80). Oat b-glucan increased net SCFA absorption in portal vein–catheterized pigs, leading to a decreased apparent insulin production, which was associated with GLP-1 mediation (66); and supplementing a diet with 10% b-glucan increased total SCFA content in the cecum, suppressed central neuronal activity in the hypothalamic appetite centers, and decreased food intake (64). A recent study by Ingerslev et al. (48) in catheterized pigs, however, did not confirm a link between net portal SCFA absorption and the net portal GLP-1 flux but identified a lower insulin flux at higher net portal SCFA absorption. SCFAs are also considered to be signaling molecules between the gut and the peripheral tissues, with implications for insulin sensitivity and glucose homeostasis (12, 74). The mechanisms appear to involve adipocyte cell differentiation, regulation, and metabolism (12, 75). In response to an increased DF intake, there is an increased absorption of SCFAs; and although the major part of propionate and butyrate is cleared in the liver, micromolar concentrations of all 3 SCFAs will reach the peripheral tissues (10) (Table 2). Here, the SCFAs can act as ligands on adipocytes (12, 81) and thereby influence the balance of adipokines released and, in turn, increase adipogenesis and differentiation of fat cells and thus reduce their average size. SCFAs further inhibit lipolysis within adipose tissue as indicated by the reduced plasma concentrations of nonesterified FAs after the intake of fermentable carbohydrates (82–84) and the lower fasting concentrations of nonesterified FAs with higher SCFA production (48). The consequence is reduced availability of FAs for uptake into ectopic fat depots (e.g., liver and pancreas) (12). Overall, the above-mentioned conditions have been linked to improved insulin sensitivity and glucose homeostasis (12, 74, 75, 85, 86).
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