The gut microbiota and cardiovascular health benefits: A focus on wholegrain oats

Existing scientific data suggest that a high intake of wholegrain foods contributes to improved gut health and a reduced risk of cardiovascular disease. Wholegrain oats are rich in dietary fibre and an important source of many bioactive components, including minerals, vitamins and phenolic compounds. The oat β‐glucans have been reported to lower low‐density lipoprotein cholesterol through their ability to increase the viscosity of intestinal chime, change the gut microbiota composition and increase the production of short‐chain fatty acids, which may contribute to the inhibition of hepatic cholesterol synthesis. Oats are also a rich source of phenolic acids, which are predominantly bound to cell wall polysaccharides through ester bonds. This bound state within oats means that phenolic acid bioavailability will largely be determined by interactions with the colonic microbiota in the large intestine. However, results from in vitro, animal and human studies have been inconsistent in relation to the impact of oats on the gut microbiota, possibly due to differences in experimental techniques and because compounds in oats, other than β‐glucans, have not been considered. This review focuses on the interaction of oat β‐glucans and phenolic acids with gut microbiota, and the subsequent link to cardiovascular health.


Introduction
A high intake of wholegrains is related to improved gut health (Cooper et al. 2015) and reduced risk of cardiovascular disease (CVD) (Thies et al. 2014b;Aune et al. 2016). The health benefits of wholegrains might be due to effects on inflammation (Nilsson et al. 2008a;Singh et al. 2013), fasting blood glucose (Pick et al. 1996;Jensen et al. 2006) and markers of lipid metabolism (Pins et al. 2002;Behall et al. 2004;Jonnalagadda et al. 2011;Johansson-Persson et al. 2014;Tang et al. 2015;Aune et al. 2016). A recent meta-analysis of observational studies indicates that diets rich in wholegrains are associated with a 21% reduction [relative risk (RR) = 0.79 (95% CI: 0.74, 0.85)] in CVD risk (Ye et al. 2012). However, the median daily wholegrain intake in the UK, estimated from secondary analysis of data from the National Diet and Nutrition Survey Rolling Programme 2008Programme /2009Programme -2010Programme /2011, is 20 g/day for adults and 13 g/day for children, which is higher than in 2000/2001 but remains low and well below the US wholegrain recommendation of 48 g/day (no UK wholegrain dietary reference value exist) (Mann et al. 2015).
It has been suggested that the cardiovascular protective effects of wholegrain oats are mainly due to their dietary fibre content, in particular, soluble oat b-glucans, with established blood cholesterol-and glucoselowering properties (Tappy et al. 1996;Tosh 2013;Whitehead et al. 2014;Tosh & Chu 2015). However, oats are also a rich dietary source of phenolic acids and avenanthramides (a class unique to oats) and several randomised, controlled, crossover studies have suggested that a range of phenolic compounds may be responsible for some of oat's health effects (Lamport et al. 2017;Lockyer et al. 2017;Mills et al. 2017). However, the phenolic acids in oats are linked to cell wall polysaccharides by ester linkages and this means their absorption will be limited until they reach the large intestine where they may undergo extensive bioconversion by colonic microbiota to yield various bioactive metabolites that express local intestinal effects in the gut, and also systemic effects following absorption (Vitaglione et al. 2008;Williamson & Clifford 2017). Previous data have suggested that, in addition to fibre and non-digestible carbohydrates, phenolics may beneficially modulate the gut microbiota composition and activity (Connolly et al. 2012b(Connolly et al. , 2016, which may play role in the prevention of chronic diseases (He & Shi 2017). For example, the secreting metabolites, such as secondary bile acids (BAs), short-chain fatty acids (SCFAs) and trimethylamine-N-oxide (TMAO), act as hormone-like factors and are sensed by dedicated receptor systems in the human host to play a role in the pathogenesis of CVD (Brown & Hazen 2015). In this review, we provide a concise introduction into human gut health and the contribution that the microbiota play in influencing markers of CVD pathophysiology, before outlining the cardiovascular benefits of oat intake and how these are mediated, in part, by the gut microbiome.
Conversely, an unfavourable gut microbiota composition and function (i.e. dysbiosis) can trigger the development of diseases through intestinal-derived endogenous endotoxins, such as lipopolysaccharides, indoxyl sulphate and L-carnitine (Prakash et al. 2011). These metabolites may potentiate the development of acute diseases, such as diarrhoea and chronic diseases, including obesity, metabolic diseases, cancer and CVD (Tang & Hazen 2014;Tuohy et al. 2014;Dao et al. 2015). There has been a long understanding of the interaction between environmental factors and gut microbiota, including that of pH, peristalsis, redox potential and nutrient availability (Nicholson et al. 2012). Dietary changes are thought to be responsible for around 57% of the variation in the gut microbiota, compared with only 12% for genetics (Brown et al. 2012). For example, a study showed that the microbiota of mice fed a low-fat, polysaccharide-rich diet markedly increased in populations of Firmicutes, and decreased in levels of Clostridium, Eubacterium, Enterococcus and Bacteroides spp when the mice were switched to a highsugar/high-fat diet (Turnbaugh et al. 2009;Nguyen et al. 2015). On the other hand, a high-fibre diet can limit the growth of potentially pathogenic E. coli. (Zimmer et al. 2012), which has been observed in humans within 24 hours following a change from a high-fat/low-fibre diet to one which is low-fat/high-fibre (Wu et al. 2011). The role of the gut microbiota in the pathophysiology of cardiovascular disease

Prebiotic effects
Shifts in the gut microbiota composition have been associated with a wide variety of diseases, including CVD (Garcia-Mantrana et al. 2018). The promotion of the growth of specific beneficial gut microbiota is believed to have preventative effects on CVD due to the influence of these bacteria on human physiology/ metabolism, including the ability to reduce total serum cholesterol, low-density lipoprotein (LDL) cholesterol and inflammation (Sun & Buys 2015;Ejtahed et al. 2011). Dietary substrates which induce changes in the growth of favourable bacteria are referred to as 'prebiotics', which pass largely unmetabolised in the upper gastrointestinal tract and are selectively utilised by host microorganisms conferring a health benefit (Gibson et al. 2017). Established prebiotics are carbohydratebased but other substances, such as polyphenols (Tzounis et al. 2011;Queipo-Ortuño et al. 2012) and polyunsaturated fatty acids (Kankaanpaa et al. 2001;Peluso et al. 2014), might also fit the updated definition as they can affect the gut microbiome, although more studies are needed to show subsequent health effects. Prebiotics may reduce risk factors of CVD through the stimulation of growth of Bifidobacterium and Lactobacillus, and the subsequent production of SCFAs (LeBlanc et al. 2017), or possibly through the reduction in plasma cholesterol (Hooper et al. 2002) and/or fasting plasma glucose and insulin (Ooi & Liong 2010;Saini et al. 2010;Ruan et al. 2015). Furthermore, consumption of prebiotics has been linked to improved intestinal function, such as reduced gastrointestinal inflammation (Laparra & Sanz 2010;Vieira et al. 2013) and mineral absorption, and modulation of energy metabolism, satiety and immune function (Gibson & Roberfroid 1995;Gibson 1998;Pereira & Gibson 2002;Nicholson et al. 2012).

Structural effects
The large gut's enormous surface area helps to absorb nutrients, water and electrolytes from food but at the same time, it needs to provide a tight barrier against harmful substances and pathogens. One way in which the gut microbiota may confer health effects is via their potential to maintain large gut integrity (Konig et al. 2016). Gut hyperpermeability (leaky gut) results from structural changes induced by Gram-negative bacteria, which allows bacterial cell wall products, such as lipopolysaccharide and peptidoglycans, to enter into the bloodstream and activate macrophages. Also, gut microbiota-derived lipopolysaccharide can induce foam cell formation, and this can reduce reverse cholesterol transport and increase insulin resistance, hyperlipidaemia, vascular inflammation (Aki et al. 2008) and thus increase CVD risk.

Bile acid synthesis/clearance/metabolism
BAs have indirect (through cholesterol metabolic pathways) and direct effects (through interaction with myocytes) on blood cholesterol levels, atherosclerotic plaque formation and myocardial function and thus are hypothesised to reduce CVD risk (Khurana et al. 2011). Figure 1 illustrates the pathways of BA synthesis and cholesterol biotransformation in the liver (Ridlon et al. 2006). Primary BAs are further metabolised via conjugation to glycine or taurine in the liver, synthesised to bile salts and transported to the gallbladder. Following a meal and the release of cholecystokinin from the duodenum, the gallbladder contracts resulting in bile salts flowing into the duodenum, which in turn promotes the absorption of dietary lipids (Wahlstrom et al. 2016). The bacteria in the lower intestine are capable of converting primary BAs, by deconjugation and hydroxyl group oxidation at C-3, C-7, and C-12, and 7a/b-dehydroxylation, to secondary BAs, which predominate in human faeces (Sagar et al. 2015;Wahlstrom et al. 2016). Even though some are lost in faeces, most BAs are absorbed in the ileum and return to the liver where they are deconjugated and released into the small intestine (Ridlon et al. 2006). The genera of the gut microbiota involved in BA metabolism are Bacteroides, Bifidobacterium, Clostridium, Lactobacillus and Eubacterium (G erard 2014). BA metabolites resulting from microbial transformation may act as signalling molecules and regulate cardiovascular function through the TGR5 (G-coupled protein receptor) and FXR (farnesoid x receptor), thus potentially inhibiting inflammation and maintaining epithelial cell integrity (Miyazaki-Anzai et al. 2014), and modifying vascular tone (Nie et al. 2015;Wahlstrom et al. 2016). Furthermore, Bacteroides fragilis, B. vulgatus, Clostridium perfringens, Listeria monocytogenes and several species of Lactobacillus and Bifidobacterium interfere with cholesterol absorption from the gut by deconjugating bile salts, via bile salt hydrolases (Jones et al. 2008), which means cholesterol is less easily absorbed and more likely to be excreted in faeces, resulting in lowered blood cholesterol (Hofmann 1999;Ridlon et al. 2006;Nicholson et al. 2012;Tuohy et al. 2014).

Short-chain fatty acids
SCFAs are the major end product of both carbohydrate and amino acid bacterial fermentation in the human large intestine (Morrison & Preston 2016). The main SCFAs are acetate, propionate and butyrate; less common are formate, valerate, caproate and branched-chain fatty acids (Macfarlane & Macfarlane 2003;Nicholson et al. 2012). Butyrate can be metabolised by colonocytes or absorbed and metabolised further in the liver, where they are metabolised (R ıos-Covi an et al. 2016). SCFAs can act as an energy source for gut epithelial cells, improve intestinal defence against pathogens, modulate inflammation and possibly influence satiety (Russell et al. 2013). Butyrate may play a key role in regulating gene expression, inflammation and maintaining homeostasis of colonic mucosa through stimulating the production and release of the gut hormone glucagon-like peptide-2 (GLP-2) in enteroendocrine L cells (Tappenden et al. 2003;Hamer et al. 2008;Louis & Flint 2009). In addition, SCFAs decrease systemic levels of blood lipids by inhibiting hepatic cholesterol synthesis and/or redistributing cholesterol from plasma to the liver (Pereira & Gibson 2002). SCFAs are also thought to bind to specific G protein-coupled receptors, leading to the favourable regulation of lipid and glucose metabolism in the context of CVD (den Besten et al. 2013;Canfora et al. 2015;Kasubuchi et al. 2015). Another gut microbiota metabolism-dependent effect is the microbial conversion of choline and L-carnitine to trimethylamine (TMA) to TMAO. TMAO is thought to increase atherosclerotic CVD by altering cholesterol transport, potentially increasing macrophage activation (Randrianarisoa et al. 2016).

Oat components
Oats (Avena sativa) are unique among cereals due to their multifunctional characteristics and nutritional profile (Table 1). They supply protein, carbohydrate (primarily starch), crude fat, dietary fibre, unique antioxidants and vitamins and minerals (Welch 1994;Sadiq Butt et al. 2008;Menon et al. 2016). Oats have been grown for thousands of years, mainly as an animal feed crop, but during the 19th century, oats gained recognition as a 'healthy' food (Menon et al. 2016). Numerous reviews suggest that diets rich in oats may reduce inflammatory bowel disease and coeliac disease (Haboubi et al. 2006;Thies et al. 2014), attenuate CVD progression (Ruxton & Derbyshire 2008;Thies et al. 2014), and regulate glucose control in type 2 diabetes (Connolly et al. 2012b;Hou et al. 2015).
The nutrient profile and quality of oats depend on several factors, such as growth environment, genotype and the interaction between environment and genotype (Peterson et al. 2005). The main constituent (60%) of oat grains is starch (rapidly digestible, slowly digestible and resistant), located in the

Oat phytochemicals
Dietary phenolics, such as hydroxycinnamic, hydroxybenzoic acids and avenanthramides, are natural phenolic components in oats . They are found in three different forms within the oat food matrix: as soluble free acids; as soluble conjugates esterified to low molecular weight components such as sugars; and as insoluble bound acids esterified to high molecular weight components, including lignin, cell wall polysaccharides such as arabinoxylan (Stevenson et al. 2012) and storage proteins in the aleurone layer and the pericarp . The main hydroxycinnamic acids present in oats include ferulic acid, caffeic, p-coumaric (Fig. 2), o-coumaric and sinapic acids. Hydroxybenzoic acid derivatives are protocatechuic, syringic, vanillic, p-hydroxybenzoic and gallic acids (Kern et al. 2003;El-Seedi et al. 2012;Kumar & Pruthi 2014;Yang et al. 2014). Hydroxycinnamic acids all have a C 6 C 3 carbon skeleton with a double bond in the side chain that may have a cis or trans configuration. By far the most abundant hydroxycinnamic in oats is the trans-ferulic acid, with contents ranging from 95 to 386 lg/g . Analytical data indicate that, on average, 19% of these phenolic acids (range: 50-110 lg/g) are present in the soluble state, 34% as conjugates (range: 111-314 lg/g) and 47% bound (range: 131-640 lg/g) . Another phenolic group specific to oats are the avenanthramides (AVA) (Fig. 3), consisting of an amide conjugate of anthranilic acid and hydroxycinnamic acids. The three major subgroups are avenanthramide-A (AVA-A), avenanthramide-B (AVA-B) and avenanthramide-C (AVA-C), which occur in the bran or outer layers of the kernel (Manach et al. 2004). Total contents of avenanthramides in oats range from 42 to 91 lg/g (Emmons & Peterson 1999;Liu et al. 2004;Manach et al. 2004;Chen et al. 2007).

Bioavailability of phytochemicals and physiological effects of b-glucans
It has been estimated that only 5%-10% of dietary polyphenols are absorbed in the small intestine, with the remaining fraction reaching the large intestine where they are metabolised by the gut microbial community (Manach et al. 2005;Cardona et al. 2013). The absorption and metabolism of ferulic acid can be affected by the form of food matrix ingested (Kern et al. 2003;Rein et al. 2013). Counterintuitively, fibre-bound ferulic acid in wheat bran has been observed to be more bioavailable than free ferulic acid (Rondini et al. 2004). The differences observed in their absorption may relate to the rapid cleavage of the fibre-phenolic ester bond by the intestinal microbiota, which generates a higher amount of free phenolic acids in the large gut, increases their time in the plasma and decreases the level of urinary excretion (Chesson et al. 1999;Rondini et al. 2004). Our group reported intake of 60 g oat bran (2.5 mg avenanthramides, 28.6 mg phenolic acids) resulted in elevated urinary excretion of 30 phenolic acids metabolites, amounting to total recovery of 22.9% AE 5.0%, mainly between 0-2 and 4-8 hours (Schar et al. 2017). The predominant metabolites included vanillic acid, 4-and 3-hydroxyhippuric acids and sulphate conjugates of benzoic and ferulic acid (accounting for two-thirds of total phenolic excretion). The results suggest that bound phenolic acids present in oats are rapidly released by the microbiota. Similarly, another human study  showed peak plasma concentrations of avenanthramides between 2 and 3 hours after high (229.6 mg/kg) AVA intake and 1 and 2 hours for low AVA intake (32.7 mg kg). AVA-B demonstrated a longer half-life and a slower elimination rate than AVA-A and AVA-C. The bioactive properties of polyphenols are greatly dependent on their bioavailability (Chen et al. 2004;Kroon et al. 2004;Manach et al. 2004;Chen et al. 2007). These polyphenols have been observed to inhibit vascular smooth muscle cell proliferation and enhance nitric oxide production (Nie et al. 2006). The physiological activity of b-glucans is in part related to their effects on bile reabsorption and through their ability to increase intestinal chyme viscosity, effects that are dependent on both the concentration and molecular weight of the b-glucans consumed Menon et al. 2016). The molecular weight of b-glucans varies between 100 000 and 1 200 000 g/mol, and those of a small molecular size (370 000 g/mol) have been reported to be less effective at reducing cholesterol levels (Kim et al. 2006) compared with those of high molecular weight   (Braaten et al. 1994). The solubility of b-glucans is another important factor influencing their physiological activity (El Khoury et al. 2012). Their ability to form highly viscous small intestinal chyme likely contributes to the health benefits of b-glucans, as it has been reported that there is an inverse linear relationship between measures of postprandial blood glucose and insulin responses (to an oral glucose load) and the viscosity of the chyme (Wood et al. 2000;Chen & Raymond 2008;Wolever et al. 2018).

Cardiovascular benefits of the oat intake
Atherosclerosis is one of the main underlying pathophysiological processes in CVD development (Stamler et al. 1986;Shepherd et al. 1995), with several different actions, such as oxidation of LDL cholesterol, adhesion of monocytes across the endothelial surface, development of monocytes to macrophages and the formation foam cells (Andersson & Hellstrand 2012). The potential modulation of atherogenic pathways following oat intake has been suggested and may involve anti-inflammatory activity, the maintenance of endothelial function and the reduction in plasma cholesterol (Fig. 4) (Ryan et al. 2007(Ryan et al. , 2011Jonnalagadda et al. 2011;Thies et al. 2014;Whitehead et al. 2014;Shen et al. 2016). Additionally, oat fibre and phenolics are capable of interacting directly with the gut microbiota, leading to a shift in their profile and composition, secondary changes in cholesterol and bile metabolism, and the production of key metabolites such as SCFAs and phenolic acids metabolites (Fig. 4).
Effects of oat intake on microbiome compositionin vitro and animal data Several in vitro fermentation (Table 2) and animal studies (Table 3) suggest that increased oat intake leads to gut microbiota alterations. In vitro fermentation of oat grains has been shown to increase Bifidobacterium and Lactobacillus populations (Connolly et al. 2010) and Bacteroides and Prevotella groups (Chappell et al. 2015), whilst decreasing clostridia levels (Kedia et al. 2009). However, although oatderived b-glucans extracts increased Lactobacillus-Enterococcus after 5 hours and Bacteroides after 24 hours in one in vitro study, they were found to not influence bifidobacterial growth (Hughes et al. 2008). In another in vitro study, it has been reported that the b-glucans are fermented by Bacteroides spp but not by Lactobacillus and Bifidobacterium (Crittenden et al. 2002). The fermentation of oats in anaerobic, pH-controlled, faecal batch cultures has been shown to increase SCFA production, with significant increases in acetate, propionate and butyrate levels (Hughes et al. 2008;Kedia et al. 2009;Kim & White 2009;Connolly et al. 2010Connolly et al. , 2012b. Consumption of oats by rodents has been reported to result in many specific changes in their microbiota, such as increases in the growth of Prevotellaceae, Lactobacillaceae and Alcaligenaceae families 175.5% (P = 0.03), 184.5% (P = 0.01) and 150.0% (P = 0.004). However, these results are not consistent with the findings from other animal studies that indicate oat bran intake increases only Bifidobacterium and Lactobacillus growth (Drzikova et al. 2005;Berger et al. 2014). The range of oat products used in these studies, including oat flour and bran (Drzikova et al. 2005), or insoluble fibre and soluble fibre combinations (Zhou et al. 2015), might explain the reported variability in microbiota growth in rodents. Hence, further well-designed in vitro and human studies are required to examine which oat components may result in beneficial changes to the microbiota.
Overall, these studies indicate inconsistent findings regarding the influence of oats on the growth of the microbiota and their diversity, which might be partly explained by the various different study and experimental designs. It is also important to note that these studies considered only the influence of the b-glucans fraction within oats and not other oat bioactives, such as polyphenols, which have also been observed to Table 2 The impact of oats on the gut microbiota and short-chain fatty acid (SCFA) production based on data from in vitro studies at 24 hours

Reference
Intervention Effects on bacterial composition Effects on SCFA production Hughes et al. (2008) Oat-derived b-glucans Low molecular weight (LMW) 150 kDa High molecular weight (HMW) 230kDa

Effects of oat intake on microbiome compositionhuman trials
Whilst in vitro (Kedia et al. 2009;Connolly et al. 2010Connolly et al. , 2012a and animal studies (Immerstrand et al. 2010;Berger et al. 2014) indicate that oat intake increases the production of SCFAs, these effects are difficult to quantify in humans as SFCAs are rapidly absorbed or utilised in the large intestine. For example, butyrate is almost entirely used by the colonocytes as their preferred energy substrate (Cummings et al. 1987), propionate is primarily absorbed and removed by the liver (Hong et al. 2005), whilst acetate passes into the peripheral circulation (Roediger 1980). The use of in vitro tools can help to investigate whether various substrates lead to increased SCFA generation, as faecal SCFA measurements are an uncertain estimate of colonic SCFA production (Valeur et al. 2016). Findings from human trials on the effects of oats on the microbiota vary, possibly due to differences in study design (i.e. intervention dose, study duration, study population, the method of microbial enumeration) and because these studies assessed the effects of fibre but not the polyphenols in oats (Table 4). Two randomised controlled trials provide evidence that wholegrain wheat may exert effects on gut microbiota (Costabile et al. 2008;Vitaglione et al. 2015). A daily intake of 48 g of wholegrain wheat significantly increased the growth of Bifidobacterium (0.8 log 10 cells per g faeces) and Lactobacillus (0.6 log 10 cells per g faeces) and increased plasma ferulic acid levels (Costabile et al. 2008). In contrast, intake of 70 g per day of wholegrain wheat was found not to increase levels of Bifidobacterium, although faecal ferulic acid levels were found to be associated with an increase in Bacteroides, Firmicutes and a reduction in Clostridium (Vitaglione et al. 2015). To date, no human trials have studied the direct effects of extracted or purified oat phenolic acids on the growth of the microbiota, or whether they contribute to the prebiotic effects of wholegrain intake, although data do exist on the impact of flavanols, which have been found to promote the growth of specific beneficial bacteria (Tzounis et al. 2011). These data suggest that phenolic acids present in wholegrain cereals may potentiate gut microbiota diversity; however, further research is required to distinguish between the effects of fibre and polyphenols on gut health.

Impact of oat intake on cholesterol metabolism and bile acid synthesis
Oat b-glucans have been suggested to lower cholesterol by causing an increased viscosity of the intestinal chime (Ryan et al. 2007). The gel formed is thought to act as a physical barrier to lipid (triglycerides) absorption in the small intestine, in particular that of cholesterol reabsorption (Bae et al. 2010;Andersson & Hellstrand 2012;Bao et al. 2014). b-glucans have also been shown to bind to luminal BAs, which increases the excretion of bile in the faeces and triggers an increase in hepatic conversion of cholesterol into BAs, thereby decreasing blood cholesterol levels (Lia et al. 1995;Bae et al. 2010;Grundy et al. 2017). It has been reported that the intake of 75 g of Table 3 Animal studies examining the effects of oat intake on growth of gut microbiota and short-chain fatty acid (SCFA) production Reference Intervention (duration) Oat effects on bacterial composition and/or SCFA production compared to control Animals Drzikova et al. (2005) Oat flour (F); oat bran ( extruded oat bran (11 g b-glucans) resulted in a near doubling of serum 7 alpha-hydroxy-4-cholesten-3-one concentration within 8 hours, which lead to increased BA synthesis (Andersson et al. 2002). BA excretion is well known to stimulate cholesterol uptake from the circulation, resulting in a decreased serum cholesterol concentration (Grundy et al. 2017).
Oat intake and short-chain fatty acid production SCFA production is highly dependent on the donor and availability of substrates (Cook & Sellin 1998). The ability of oats (and isolated b-glucans) to increase SCFA production is well established (Connolly et al. 2010(Connolly et al. , 2012aBerger et al. 2014). After 12 hours of in vitro fermentation, oat bran (containing 22% oat b-glucan) induced significantly higher concentrations of propionate compared to other prebiotic dietary fibres, such as inulin and xylooligosaccharide (Carlson et al. 2017). The production of SCFAs in the large intestine following oat consumption has been reported and postulated to contribute to reductions in serum lipids and other CVD risk markers (Andersson & Hellstrand 2012). As such, SCFAs may act as mediators of the beneficial effects of wholegrain oat intake of human CVD. These effects might be dependent on SCFAs' ability to: (1) affect liver and muscle cellular metabolism via their potential to increase insulin sensitivity and decrease lipid accumulation in liver (Oda et al. 1994;Ulmius et al. 2011;Zhang et al. 2012;Chang et al. 2013;McNabney & Henagan 2017); (2) suppress cholesterol synthesis, increase fatty acid Table 4 The relationship between oats, the growth of gut microbiota and short-chain fatty acid (SCFA) production based on data from human intervention trials Reference Intervention (duration) Oat effects on bacterial composition and/or SCFA production compared to control Bridges et al. (1992) 20 ( Intestinal gas production SCFAs and no changesfaeces b-galactosidase and urease -↓ Rectal level of PGE 2no significant difference Connolly et al. (2016) 32 mild or hypercholesterolaemia adults (23-64 years, 12 men/20 women) Wholegrain oat granola (WGO) -45 g granola breakfast cereals (6.3 g fibre, 2.9 g glucans) Non-wholegrain (NWG) -45 g non-wholegrain breakfast cereals (control) (3 g fibre, no glucans) (6 weeks) A focus on wholegrain oats oxidation and decrease de novo fatty acid synthesis in the liver (Andersson et al. 2002(Andersson et al. , 2017Cloetens et al. 2012;Han et al. 2015); (3) increase adipogenesis and decrease lipolysis (Gao et al. 2015;Heimann et al. 2016); (4) modulate satiety through their potential to bind to G protein-coupled receptors (GPR41, GPR43), leading to the increased production of the gut hormones glucagon-like peptide-1 and peptide YY (Hooda et al. 2010;Koh et al. 2016;Rebello et al. 2016) and regulate satiety centrally (Bridges et al. 1992;Canfora et al. 2015;Canfora & Blaak 2017); and 5) improve colon and liver glucose homeostasis via their induction of intestinal gluconeogenesis (den Besten et al. 2013;Bourassa et al. 2016;Cheng et al. 2017;Jayachandran et al. 2018) (Fig. 4). In addition, butyric acid has been reported to increase phenolic acid absorption in the colon (Ziegler et al. 2016), which subsequently may induce endothelium-dependent vasodilation (Suzuki et al. 2002(Suzuki et al. , 2007Choi et al. 2012). Recent studies have also indicated that the ratio of acetate and propionate may be important for defining the precise effects of SCFAs on various physiological systems. For example, a high serum acetate:propionate ratio has been associated with reductions in total serum cholesterol in men (Weitkunat et al. 2017;Boets et al. 2017;Wolever et al. 1996).

Conclusions
Evidence suggests that wholegrain oats may reduce CVD risk due to their influence on lipid metabolism and plasma cholesterol levels. Oat b-glucans are likely to be partly responsible for any effects as they can change the gut microbiota composition, increase cholesterol excretion in the gut and increase the levels of SCFAs, which may inhibit hepatic cholesterol synthesis and affect glucose homeostasis in adipose tissues and muscle cells. However, inconsistent findings from in vitro, animal and human studies have been reported regarding the influence of oat intake on these outcomes, possibly due to differences in experimental techniques and the focus on b-glucan rather than other compounds present in oats, such as phenolic acids and avenanthramides, which may also contribute to beneficial changes in the gut microbiota and lipid/cholesterol metabolism. Clinical, observational and experimental studies to date have not explored the extent to which cardiovascular benefits are dependent on oat fibre or phenolic acid levels. Hence, further randomised, controlled trials are required to examine the relative effects of oat phenolics on microbial pathways and cardiovascular risk markers.