Rev Endocr Metab Disord DOI 10.1007/s11154-014-9288-6

Gut microbiota and GLP-1 Amandine Everard & Patrice D. Cani

# Springer Science+Business Media New York 2014

Abstract A large body of evidence suggests that the regulation of energy balance and glucose homeostasis by fermentable carbohydrates induces specific changes in the gut microbiota. Among the mechanisms, our research group and others have demonstrated that the gut microbiota fermentation (i.e., bacterial digestion of specific compounds) of specific prebiotics or other non-digestible carbohydrates is associated with the secretion of enteroendocrine peptides, such as the glucagon-like peptide-1 (GLP-1) and peptide YY (PYY), produced by L-cells. In this review, we highlight past and recent results describing how dietary manipulation of the gut microbiota, using nutrients or specific microbes, can stimulate GLP-1 secretion in rodents and humans. Furthermore, the purpose of this review is to discuss the putative mechanisms by which specific bacterial metabolites, such as short chain fatty acids, trigger GLP-1 secretion through GPR41/43dependent mechanisms. Moreover, we conclude by discussing the molecular advance showing that the endocannabinoid system or related bioactive lipids modulated by the gut microbiota may contribute to the regulation of glucose, lipid and energy homeostasis. Keywords Gut microbiota . GLP-1 . L-cells . Endocannabinoids . Prebiotics

1 Introduction Throughout the history of evolution, multicellular organisms, including humans, have constantly interacted and co-evolved A. Everard : P. D. Cani (*) WELBIO (Walloon Excellence in Life sciences and BIOtechnology), Metabolism and Nutrition research group, Université catholique de Louvain, Louvain Drug Research Institute, Av. E. Mounier, 73, Box B1.73.11, 1200 Brussels, Belgium e-mail: [email protected]

with microorganisms, thereby exploring the advantages of a symbiotic life [1]. Humans are colonised by a diverse collection of microbes, which are collectively known as the microbiota and consist of bacteria, fungi, and archaea. Microbes colonise several parts of the human body, and the microbiota vary systematically across body habitats [2]. The largest numbers of microbes reside in our distal gut. At birth, the human gut is rapidly colonised by a vast number of gut microbes so that after weaning our gut microbiota is composed of approximately 100 trillion microorganisms [3]. Thus, in reality, we are not entirely human. Rather, we are supraorganisms composed of 10-fold more microorganism cells than human cells [4]. The intestinal gut microbiota consists of approximately 1,000 to 1,150 different bacterial species classified in a rankbased classification system, the bacterial taxonomy [5]. Adult gut microbiota is specific to the individual but remains relatively constant over time [5, 6]. However, age-related changes of the gut microbiota also occur during aging, for example, studies suggest that during aging specific changes in the microbiota occur, with a reduced microbial diversity accompanied by increased inflammation [7, 8]. Certain bacterial species are found in the majority of people, but the relative abundance of shared species can vary greatly, and each person has specific bacterial lineages present in their gut microbial community [9]. Even if these inter-individual variations exist, functions encoded by microbial genes exhibit great similarity between individuals [10]. Due to the high diversity of microbes present in our gut, the total gut bacterial gene set, namely the collective genome of the gut microbiome, contains at least 100-fold more genes than the genome encoded by the human genome [5]. The interactions between humans and microbes have achieved a symbiotic relationship resulting in physiological homeostasis, because the microbiota provides crucial functions to the human body that the body cannot perform for itself, whereas the

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human host provides a nutrient-rich environment to the residing microbes [11]. Importantly, functions encoded by these microbial genes are relevant to their survival, but our gut microbial gene set also assumes metabolic and biological host functions including the control of energy homeostasis, immune system regulation, vitamin synthesis and digestion [12–18]. Therefore, the gut microbiota may be considered as an organ in its own right. This consideration opens up a multitude of unexplored potential pathways involved in human physiology and diseases. Importantly, the gut microbiota affects host metabolism, and gut microbiota alterations have been associated with several diseases including obesity and type 2 diabetes [19, 20, 15, 21]. Moreover, nutritional interventions using non-digestible carbohydrates with prebiotic properties (i.e., causing gut microbiota modulations) have shown promising results in alleviating obesity and associated metabolic disorders [13]. However, the mechanisms involved remain poorly understood. Emerging evidence suggests that enteroendocrine peptides, such as glucagon-like pepetide-1 (GLP-1), produced by L-cells are involved in the regulation of energy balance and glucose homeostasis via the digestion of specific dietary fibres or non-digestible carbohydrates by gut microbiota fermentation (i.e., metabolic process of digestion of specific compounds by the gut microbes) [22]. These functional interactions will essentially be the focus of this review.

(e.g., hydrogen and carbon dioxide). The proportion of SCFA differs according to the type and amount of compounds fermented in the cecum and colon. The link between fermentable carbohydrates and the modulation of gut peptides involved in energy and glucose homeostasis was first described in 1987 by Goodlad et al. [32]. In this pioneering study, the authors demonstrated that inert bulk fibre could not stimulate colonic epithelial cell proliferation, but that the fermentation processes involving the nondigested carbohydrates were required to stimulate cell proliferation in the colon. At that time, the effects were linked with increased “enteroglucagon” plasma levels. In fact, enteroglucagon is the former name of a peptide containing oxyntomodulin, glicentin and glucagon moieties [33]. In 1991, Longo et al. showed that SCFA were able to stimulate gut peptide production (i.e., PYY) in isolated rabbit colon and, thereby, linked microbial activity with enteroendocrine L-cells [34]. Over the next two decades following this discovery, several reports have described the mechanism of action and the putative specificity of effects according to the different types of dietary fibres appeared in the literature. In the present review, we present a brief overview of the history of those distinct dietary fibres, their impact on the gut microbiota and the link with whole body homeostasis with a specific focus on enteroendocrine peptides. 2.1 Animal studies

2 An old story for a new concept: elucidating the paradigm Unequivocal evidence corroborates the link between dietary fibre intake and the management of the metabolic syndrome [23, 24]. A better knowledge of the biochemical mechanisms allowing dietary fibres to modulate different hallmarks of obesity and associated disorders (e.g., satiety, glucose or lipid metabolism) is critical. In this context, our research group and others have demonstrated that modulation of gastrointestinal peptides by fermentable carbohydrates (i.e., prebiotics, or starches resistant to host digestion, namely, resistant starches) is an important area of research allowing us to delineate the gut-to-brain and the gut-to-peripheral organs axis [24, 22, 25–27]. Several non-digestible carbohydrates are fermented by the gut microbiota, including inulintype fructans, glucans, galactans, arabinoxylans, resistant starches, pectins and their oligosaccharides, all of which have been shown to modulate the gut microbiota composition with distinct profiles according to the source and type of non-digestible carbohydrates (for review [28–31]). The major products of non-digestible carbohydrate metabolism by the gut microbiota are short chain fatty acids (SCFA; e.g., acetate, propionate, butyrate, lactate, succinate) and gases

In the 1990s, various reports have confirmed that microbial fermentation of specific types of non-digestible carbohydrates increased gastrointestinal tract production of enteroglucagon. For instance, Gee et al. demonstrated that lactitol feeding was associated with sustained enteroglucagon release over 8 h after the ingestion of the compound. Importantly, this peptide does not contain GLP-1 but is encoded by the same proglucagon gene [35]. Another study, performed in the same year, shows that rats fed with a very high amount of fibre (300 g/kg of diet) had higher levels of plasma GLP-1, insulin and C-peptide after an oral glucose load. The authors observed that the increased plasma GLP-1 was associated with an increased proglucagon mRNA expression in the intestine [36]. Then, our group demonstrated that rats fed with prebiotics (i.e., oligofructose and inulin-type fructans) [37, 38] exhibited increased plasma GLP-1 levels and increased intestinal GLP-1 peptide content (Fig. 1) [39]. In 2004, we reported that the three different inulin-type fructans, which varied according to their degree of polymerisation (i.e., number of fructose moieties), differentially affected gut peptides secretion. We discovered that the three types of prebiotics used were able to change the gut microbiota in favour of the genus Bifidobacterium spp. and reduced food intake and fat mass proportionally. However, in addition to the correlative impact on food intake, we found

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Fig. 1 Mechanisms linking gut microbiota and GLP-1 secretion. The ingestion of inulin-type fructans and resistant starches reduce food intake, glycaemia and endogenous glucose (EGP), conversely their fermentation by the gut microbiota is associated with an increase in energy expenditure and insulin sensitivity. These effects are associated with an increased GLP-1 secretion and L-cell number. SCFAs produced by the fermentation of dietary fibres bind to the G-protein-coupled receptors (GPCRs) GPR41 and GPR43, thereby triggering GLP-1 secretion by the L-cells. GPR119 ligands such as oleoylethanolamide (OEA) and 2-oleoylglycerol (2-OG) trigger GLP-1 secretion. Specific microbes such as Akkermansia muciniphila are able to regulate intestine endocannabinoid-like compounds such as 2-OG.

that the short-chain fructans (present in oligofructose and consisting of a mix of inulin and oligofructose) only, were able to increase proglucagon mRNA expression and to increase intestinal GLP-1 (7–36) amide synthesis with consequences on the portal concentration of GLP-1 (7–36) amide (which was increased). Moreover, our study was the first to link gut microbiota fermentation with decreased levels of plasma ghrelin [40]. Notably, we also linked these effects with increased levels of plasma GLP-2 and PYY [41–45]. It is worth noting that these effects are not exclusively limited to one type of fermentable carbohydrate. For example, resistant starches and arabinoxylans are also fermentable nondigestible carbohydrates that produce effects similar to those observed with inulin-type fructan prebiotics, namely a decrease in food intake, body weight gain and an increase in plasma GLP-1 and PYY [46–52]. 2.2 Human evidence linking gut microbiota fermentation and GLP-1 secretion Although, the link between gut microbiota fermentation of specific non-digestible carbohydrates and the modulation of

gut peptides, such as GLP-1, is becoming widely accepted in rodent studies [53–55], the evidence that similar links exist in humans remains a matter of debate. In 1996, the first evidence that microbial fermentation was linked with the endogenous production of gut peptides was obtained following the ingestion of lactulose or the intracolonic administration of SCFAs in healthy volunteers [56]. In 2003, another study reported that dietary oligofructose (20 g per day) in humans was associated with a significant increase in plasma GLP-1 following a meal [57]. Two other studies reported that gut microbiota fermentation of nondigestible carbohydrates was associated with increased satiety and reduced food intake, which impacted energy intake; however, gut peptides were not measured in these studies [58, 59]. In 2006, we demonstrated that treatment of healthy volunteers with 16 g/d of prebiotics (oligofructose) for 2 weeks promoted satiety and reduced hunger and prospective food consumption [60]. In a follow up study published in 2009 and using a similar protocol, we first confirmed the impact of gut microbiota fermentation of inulin-type fructans on appetite sensations and have correlated these results with higher plasma GLP-1 and PYY levels [61]. In the same year, Parnell and Reimer demonstrated that obese subjects treated with oligofructose for 12 weeks exhibited a modest decrease in visceral fat mass, a decrease in circulating ghrelin and an increase in PYY, but they did not find any modification of plasma GLP-1 [62]. Another study reported also that the acute treatment with prebiotics affected appetite sensations [63] while an additional recent study demonstrated that a single dose of inulin-type fructans increases postprandial plasma GLP-1 and decreases plasma ghrelin, but the appetite sensation was not investigated [64]. More recently, Pedersen et al. found that oligofructose significantly and dose-dependently increased PYY and reduced plasma ghrelin levels. Strikingly, in their clinical settings, the authors did not find any significant effects on subjective appetite scores in acute studies; however, under free-living conditions, hunger scores were suppressed during oligofructose supplementation. A similar observation is true for the resistant starches, because there is no clear consensus at present regarding their ability to change food intake and gut peptides in humans [65–68]. In 2013, Nilsson et al. demonstrated in healthy subjects that microbial digestion of brown beans increased GLP-2 and PYY levels and tends to increase oxyntomodulin, whereas plasma ghrelin was reduced. Importantly, they found that these data were accompanied by a decreased sensation of hunger. Moreover, they found that propionate, butyrate, and isobutyrate were significantly increased after microbial fermentation of brown beans, indicating a link between microbial activities, gut peptide secretion and appetite sensations [69]. Thus, although some studies reliably found links between gut microbiota fermentation, SCFAs, gut peptides and appetite regulation, further studies are needed to delineate whether

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specific adaptations of the gut microbiota and/or of the endogenous gut peptide production are required to observe theses effects. To conclude, additional putative mechanisms by which gut microbes dialogue with the host will be further discussed in this review.

3 Potential mechanisms linking gut microbiota metabolic activities with host metabolism Because the gut microbiota metabolic activities have been implicated in the regulation of host metabolism, nutritional interventions that promote modulation of the gut microbiota and fermentation are currently proposed as interesting therapeutic approaches to alleviate obesity and associated metabolic disorders [13]. Understanding the mechanisms involved in these beneficial effects is critical. We have previously shown that the beneficial effects of prebiotics on gut barrier function, inflammation and insulin resistance in obesity requires a functional GLP-1 receptor and protects against obesity by increasing the release of gut hormones, such as GLP-1 and GLP-2 [44, 45]. These endocrine peptides represent an interesting pathway involved in the crosstalk between gut microbes and host cells and therefore we will focus the discussion on the potential mechanism involved in the regulation of endocrine peptides through the gut microbiota (Fig. 1). SCFAs are key candidates involved in the crosstalk existing between microbes and host cells. As described earlier, the major SCFAs produced by gut microbiota fermentation are acetate, propionate and butyrate. Butyrate is used as an important energy source for the colonic epithelium, whereas propionate and acetate are used by the liver and other peripheral tissues [70]. In total, SCFAs provide approximately 10 % of human energy requirements [70]. Importantly, an increased capacity to extract energy from the diet and to generate SCFAs is associated with obesity [71]. In addition to their contributions to gut health and energy resources, SCFAs are able to act as host signalling molecules by binding to the G-proteincoupled receptors (GPCRs) GPR41 (also known as FFAR3) and GPR43 (also known as FFAR2) (Fig. 1) [72, 73]. By signalling through these receptors expressed by different cell types (e.g., immune cells, adipocytes, enterocytes, enteric neurons and enteroendocrine cells), SCFAs are able to modulate several different functions, such as inflammation and host metabolism [74]. As discussed earlier in this review, gut microbiota fermentation resulting in SCFA production influences satiety hormones produced by the host. Because of the beneficial systemic effects of PYY and GLP-1 on energy homeostasis and glucose metabolism, understanding the mechanisms involved in enhancing the secretion of these peptides from intestinal L cells may provide beneficial effects in obese and type-2 diabetic patients (Fig. 1) [75]. Interestingly, it has been demonstrated that enteroendocrine peptide

secretion may be regulated through the SCFA activation of GPR41 and 43 expressed on enteroendocrine cells (Fig. 1) [74]. SCFA activation of GPR41 promotes the secretion of peptide YY, which inhibits gastric emptying and food intake [76], whereas SCFA activation of GPR41 and 43 promotes the secretion of GLP-1, which inhibits gastric emptying and food intake but also stimulates insulin secretion [77]. These data suggest that the increase in intestinal GLP-1 and plasma levels observed with short-chain fructans could be explained by the direct influence of SCFAs produced by bacterial fermentation on L-cells to enhance the secretion of GLP-1. Conversely, we recently contributed to the investigation of how gut microbiota affects the production of GLP-1 [78]. By comparing mice that lack a microbiota (germ-free mice) and mice that have a normal microbiota, we found that germ-free mice exhibited higher plasma GLP-1 levels compared to conventionally raised control mice [78]. Together with our colleagues, we proposed that this could be dependent on an adaptive response to insufficient energy availability developed by germ free mice to slow the intestinal transit. Interestingly, the modulation of plasma SCFAs have been related with changes in gut hormones regulating appetite but have also been associated with lower inflammatory markers in insulin-resistant subjects [79, 80]. SCFAs not only regulate enteroendocrine peptides production but also regulate leptin secretion by adipocytes via GPR41 and 43 activation (Fig. 1) [81, 82]. Through the regulation of hormone secretion, SCFAs and GPR41/43 act as key messengers between gut microbiota metabolic activities and host metabolism; however, their effects in metabolic diseases, such as obesity, remain a matter of debate [83–86]. Moreover, different SCFAs may exhibit distinct or even opposite effects; therefore, the fact that the ratio of SCFAs produced is more relevant than the amount of one specific SCFA may also contribute to some discrepancies observed between studies [87]. However, other mechanisms may also be related to the enhanced GLP-1 secretion observed with prebiotics. GLP-1 secretion is also stimulated by the activation of GPR119 [88, 89]. The first identified endogenous ligand of GPR119 was the endogenous lipid signalling agent oleoylethanolamide (OEA) (Fig. 1) [90]. OEA is a bioactive lipid involved in body weight and food intake regulation related to the endocannabinoid system [41, 91, 92]. Endocannabinoid-like compounds are bioactive lipids that share their biosynthetic and degradation pathways with endocannabinoids but which do not bind cannabinoid receptors 1 and 2 [93]. Interestingly, Lauffer et al. recently showed that OEA increases GLP-1 secretion from intestinal L-cells through the activation of the GPR119 fatty acid derivate receptor, located on these enteroendocrine cells [94]. Additional endocannabinoid-like compounds, such as 2-oleoylglycerol (2-OG), are also able to activate GPR119 receptor (Fig. 1) [95]. Importantly, 2-OG activates GPR119 with significantly lower potency than the

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OEA, but 2-OG is the most abundant of the GPR119 agonists in intestine (i.e., OEA, linoleylethanolamine (LEA) and 2OG) [96]. In addition to GLP-1, the secretion of other enteroendocrine peptides is also affected by endocannabinoid-like lipids. We have found that plasma ghrelin levels of OEA-treated rats were 35 % lower compared with those of the vehicle-injected rats [41]. Importantly, we also revealed that gut microbiota modulate the intestinal endocannabinoid system tone [97] and that specific microbes (i.e., Akkermansia muciniphila) are able to regulate intestine endocannabinoid-like compounds such as 2-OG (Fig. 1) [98]. These data support a direct link between gut microbiota and intestinal bioactive lipids related to the endocannabinoids and involved in enteroendocrine peptides secretion. We propose that these endocannabinoid-like compounds could constitute an interesting pathway involved in the crosstalk between gut microbes and enteroendocrine host cells. Surprisingly, receptors known to be involved in mediating gustatory signals in the oral cavity have also been located on enteroendocrine cells. These receptors have been proposed to be involved in chemosensing in the gut [99]. Moreover, a recent report suggests the involvement of such receptors in the regulation of GLP-1 secretion [100]. Treatment of colonic mucosa isolated from wild-type mice with acetate, butyrate, oleic acid, oleoylethanolamide, or lithocholic acid stimulates GLP-1 secretion, whereas induction of GLP-1 release was impaired in colonic tissues from α-gustducin knockout mice [100]. Inulin-type fructans not only influence GLP-1 secretion but also increase GLP-1 production by stimulating the expression of the GLP-1 precursor (i.e. proglucagon mRNA) in the colon and in the small intestine of normal and obese rodent [101, 102, 45]. Of the phenomena that contribute to a higher endogenous GLP-1 production, we have found that fermentation of dietary non-digestible carbohydrates in the gut may promote L-cell differentiation in the proximal colon and thereby increase the number of L-cells in rats (Fig. 1) [103]. We recently found that this effect may also occur in the small intestine and in the colon of obese mice treated with prebiotics [104]. Importantly, these effects have been confirmed by Kaji et al. and associated with the density distribution of GPR43expressing and GLP-1-producing enteroendocrine L cells after ingestion of oligofructose [105]. Finally, considering that boosting gut microbiota fermentation with prebiotic treatment increases colon length and weight, the increase in GLP-1 production is also reinforced by a greater pool of L-cells in the colon [104].

4 Future directions Numerous putative associations between gut microbes and host have been discovered. Whether targeting the gut

microbiota by using specific non-digestible carbohydrates such as prebiotics constitute an interesting approach to increase endogenous production of GLP-1 and PYY warrants further investigations. So far, different pilot studies performed in humans have shown that prebiotic treatment increases GLP-1 and PYY, and decreased Ghrelin [61, 62, 64, 106, 107], however, the real impact on glucose homeostasis, appetite and fat mass should be clarified in large scale studies. In addition, the exact mechanisms linking the gut microbiota, the metabolites produced by specific microbes and host metabolism are still under investigation. Thus, the next challenges will be to delineate the different mechanisms involved in such complex crosstalk existing between gut microbes and the host and whether specific microbes or metabolites may be used in future therapeutic strategies or as pharmaceutics to control obesity and type 2 diabetes.

5 Conclusions Past studies have shown that specific non-digestible carbohydrates modulate the gut microbiota and improve glucose and energy homeostasis. Now, the contribution of specific bacterial metabolites, such as SCFA, is becoming clear. Moreover, putative novel targets (e.g., the endocannabinoid system and related bioactive lipids) have been suggested. Nevertheless, whether some specific bacteria (e.g., Bifidobacterium spp., Lactobacillus spp. or A. muciniphila) contribute to this modulation via direct or indirect mechanism merits further investigation [97, 108, 98]. Acknowledgments P. D. Cani is a research associate from the FRSFNRS (Fonds de la Recherche Scientifique) and a recipient of grants from the FNRS and PDR (projet de recherche, Belgium) and ARC (Concerted Research Activities–French Community of Belgium convention: 12/17047). Moreover, P. D. Cani is a recipient of the ERC Starting Grant 2013 (European Research Council, Starting grant 336452-ENIGMO). A.E. is a research fellow from the FRS-FNRS. Conflict of interest None of the authors have conflict of interest to declare in relation with the content of this manuscript.

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Gut microbiota and GLP-1.

A large body of evidence suggests that the regulation of energy balance and glucose homeostasis by fermentable carbohydrates induces specific changes ...
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