gut microbiota, enteroendocrine functions and metabolism

COPHAR-1227; NO. OF PAGES 6

Gut microbiota, enteroendocrine functions and metabolismPatrice D Cani, Amandine Everard and Thibaut Duparc

Available online at www.sciencedirect.com

ScienceDirect

The gut microbiota affects host metabolism through a number

of physiological processes. Emerging evidence suggests that

gut microbes interact with the host through several pathways

involving enteroendocrine cells (e.g. L cells). The activation of

specific G protein coupled receptors expressed on L cells (e.g.

GPR41, GPR43, GPR119 and TGR5) triggers the secretion of

glucagon-like peptides (GLP-1 and GLP-2) and PYY. These gut

peptides are known to control energy homeostasis, glucose

metabolism, gut barrier function and metabolic inflammation.

Here, we explore how crosstalk between the ligands produced

by the gut microbiota (short chain fatty acids, or SCFAs), or

produced by the host but influenced by gut microbes

(endocannabinoids and bile acids), impact host physiology.

Addresses

Universite catholique de Louvain, Louvain Drug Research Institute,

WELBIO (Walloon Excellence in Life sciences and BIOtechnology),

Metabolism and Nutrition Research Group, Av. E. Mounier, 73 Box

B1.73.11, B-1200 Brussels, Belgium

Corresponding author: Cani, Patrice D ([email protected])

Current Opinion in Pharmacology 2013, 13:xx–yy

This review comes from a themed issue on Endocrine and metabolic

diseases

Edited by Frank Reimann and Fiona M Gribble

S1471-4892/$ – see front matter, # 2013 Elsevier Ltd. All rights

reserved.

http://dx.doi.org/10.1016/j.coph.2013.09.008

IntroductionObesity is associated with numerous metabolic comor-

bidities, such as insulin resistance, diabetes, cardiovas-

cular disease and non-alcoholic fatty liver disease. The

reduction of excessive body weight is effective for alle-

viating many of these metabolic abnormalities; however,

the prevention of positive energy balance remains a

widely practised cornerstone of obesity-prevention strat-

egies [1]. Therefore, more effective weight loss induction

strategies are needed to decrease the incidence and

severity of metabolic abnormalities. Alternatively,

approaches that can treat obesity-related metabolic

abnormalities independent of weight loss are extremely

attractive. Recent data indicate that certain microbes may

provide templates for the development of such strategies

(reviewed in [2,3]). Over the years, the understanding of

the role of these cells (i.e. gut bacteria) has changed,

leading to novel and interesting findings. The gut micro-

biota has profound impacts on host physiology, including

Please cite this article in press as: Cani PD, et al.: Gut microbiota, enteroendocrine functions an

www.sciencedirect.com

in the control of energy homeostasis, the immune system,

vitamin synthesis and digestion [4,5,6�].

Owing to its huge surface area and multiple functions, the

intestine represents one of the most important organs, and

it permits vital interactions with the external world, in-

cluding the gut microbiota. The intestinal epithelium

allows the absorption of nutrients and fluids while acting

as an efficient barrier against toxins and microorganisms.

The gut epithelium is comprised of different cell types,

including epithelial absorptive cells, Goblet cells, Paneth

cells and enteroendocrine cells. Enteroendocrine cells

represent approximately 1% of all epithelial cells in the

intestine and are subdivided into more than 10 different

cell types based on their major secretory products and their

localisation along the gastrointestinal tract. Given that

multiple biological functions are physiologically regulated

by the gut hormones produced by enteroendocrine cells

(e.g. food intake, gastric emptying, gut motility, gut barrier

formation, glucose metabolism) (Figure 1), these cells have

been positioned at the forefront of research to find novel

therapies. The enteroendocrine cells play key roles in the

maintenance of gut homeostasis both by enabling nutrient

absorption and by preserving the essential function of the

gut as a barrier between the external environment (gut

lumen) and the host tissues. Because enteroendocrine cells

are distributed all along the gastrointestinal tract and are in

close proximity to gut bacteria and/or metabolites pro-

duced by the metabolic activity of the gut microbiota, it

is of utmost interest to unravel the crosstalk between the

gut microbiota and these cells and the impact of this

crosstalk on host physiology (Figure 1). However, the study

of the gut microbiota and its relationship with the host

represents a real challenge. Among the enteroendocrine

cells, L cells have attracted particular interest because of

the pleiotropic effects of their secreted peptides [7–9].

Although these cells are known to respond to nutrients

present in the intestinal lumen, they are also able to detect

many other luminal compounds. This is especially true in

the colon, where the gut microbiota and most of its metab-

olites are largely present.

In this review, we discuss the body of evidence linking

gut microbes (and specific metabolites produced by these

bacteria) with enteroendocrine function and thereby host

physiology.

Gut microbiota and enteroendocrinefunctions: effects on glucose and energyhomeostasisWe have previously shown that the modulation of the

gut microbiota using prebiotics in mice and humans

d metabolism, Curr Opin Pharmacol (2013), http://dx.doi.org/10.1016/j.coph.2013.09.008

Current Opinion in Pharmacology 2013, 13:1–6


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2 Endocrine and metabolic diseases


Figure 1

OEA

2-OG

GLP-1

PYY

GLP-2

SCFA Bile acids

Brain Gl tract

LiverPancreas

Adiposetissue

Muscles

GPR43 GPR119

L-cell

TGR5GPR41

Current Opinion in Pharmacology

Schematic overview of the interactions between the gut microbiota, specific metabolites, enteroendocrine L cell functions and targeted organs.

Enteroendocrine L cells express several G protein coupled receptors (GPCRs) (e.g. GPR43, GPR41, GPR119 and TGR5). The endogenous and

physiological ligands of the different receptors are indicated above each receptor and connected with an arrow. The gut microbiota produces several

metabolites, including short-chain fatty acids (SCFAs) that are able to trigger gut peptide secretion by acting directly on specific receptors such as

GPR41 and 43. Specific changes in the gut microbiota have also been associated with changes in N-oleoylethanolamide (OEA) and 2-oleoylglycerol (2-

OG). These bioactive lipids belong to the endocannabinoid family and serve as ligands of the GPR119 receptor. TGR5 (also known as M-BAR, GPBAR-

1 or GPR131) is targeted by bile acids. The stimulation of these receptors by their putative ligands promotes the secretion of gut peptides (GLP-1,

GLP-2 and PYY) by the L cells. These peptides target several organs, including the gastrointestinal tract, brain, adipose tissue and liver, thereby

contributing to improvements in gut barrier function and glucose and energy homeostasis.

significantly affects energy and glucose homeostasis (for

review [10]). In rodents, we found that this was consist-

ently associated with and improved insulin sensitivity

[11] and leptin sensitivity [12], two major features of

obesity and type 2 diabetes. The fermentation of non-

digestible carbohydrates not only changes gut microbiota

composition and activity but also contributes to the

modulation of bioactive metabolites that can reach the

circulation [13��,14]. Among these metabolites, the short-

chain fatty acids (SCFAs, butyrate, propionate and

acetate) are the best studied (Figure 1). Given that

prebiotic fermentation promotes SCFA production, it is

likely that some of the physiological effects associated

with prebiotics use are directly mediated by such metab-

olites [15,16,17�]. In addition to their production by the

fermentation of prebiotics, SCFAs can also be formed

from other dietary sources of complex carbohydrates

[17�,18]. These metabolites have been shown to influ-

ence insulin sensitivity and energy metabolism through

various physiological pathways, including components of

the central nervous system [19–21]. Indeed, these metab-

olites can modify the levels of several gut hormones



involved in glucose and energy homeostasis [22��,23–25]. For example, butyrate and acetate were shown to

suppress weight gain in mice with high-fat diet-induced

obesity, and propionate was shown to reduce food intake

[26]. Lin et al. observed that the oral administration of

butyrate and propionate in mice significantly increased

their plasma levels of glucagon-like peptide-1 (GLP-1)

and glucose-dependent insulinotropic polypeptide (GIP),

accompanied by a moderate increase in peptide YY (PYY)

levels, leading to improved oral glucose tolerance and

reduced fasting insulin and leptin levels; these phenom-

ena are consistent with the observed improvements in

insulin sensitivity [26]. Moreover, butyrate was also

shown to improve insulin sensitivity and increase energy

expenditure in obese mice [27]. Unfortunately, the mol-

ecular pathways underlying these beneficial effects of

SCFAs remain largely unknown. However, the recent

identification of a family of G protein coupled receptors

(GPCRs) that bind these gut microbiome products has

highlighted new potential mechanisms of action for

SCFAs in glucose homeostasis [28]. Interestingly, the

expression of these receptors seems to be regulated by




Gut microbiota and endocrine cells Cani, Everard and Duparc 3


the gut microbiota itself [16,29,30]. Moreover, several

studies have reported that SCFA receptors colocalise in

the epithelium with the enteroendocrine cells that

secrete key modulators of glucose homeostasis such as

PYY, GLP-1 and GIP [31]. Among these receptors,

GPR41 is expressed in the intestinal mucosa and is

particularly abundant in an immortalised murine L cell

line [32], which is consistent with a potential role in

peptide secretion from L, K, and other enteroendocrine

cells, but the role of GPR41 in the regulation of energy

balance and glucose metabolism is poorly understood

(Figure 1). To address this question, a GPR41-deficient

mouse line was generated. These mice have body weights

similar to those of control mice on both normal and high-fat

diets and exhibit normal fasting GLP-1 levels but attenu-

ated GLP-1 secretion in response to butyrate. The GIP and

PYY levels of GPR41-deficient mice were similar to those

of their littermates. These data suggest that only butyrate

stimulation of GLP-1 secretion from L cells is partially

mediated by GPR41 [26]. Tolhurst et al. generated knock-

out mice deficient in GPR43 [25], another SCFA receptor

that is normally expressed in the rat and human colon wall,

mucosa and PYY-expressing enteroendocrine cells [33].

They found that GPR43-deficient mice have reduced

colonic GLP-1 protein content, reduced basal and glu-

cose-stimulated levels of GLP-1 and impaired glucose

tolerance (Figure 1). Other receptors can also stimulate

GLP-1 secretion by L cells. For instance, bile acids can

bind to both nuclear and cell surface receptors. Yet, the gut

microbiota regulates both bile acid synthesis and the

production of secondary bile acids [34]. Two bile acid

receptors are involved in glucose homeostasis. TGR5 is

a GPCR, and its activation improves liver function and

glucose tolerance in obese mice by regulating intestinal

GLP-1 production (Figure 1) [35]. FXR is a nuclear re-

ceptor that is essential for maintaining glucose tolerance

and insulin sensitivity but acts via mechanisms other than

enteroendocrine regulation [36].

Although convincing studies have supported a link be-

tween GPR43/41, enteroendocrine functions and gut

microbiota metabolites (i.e. SCFAs), compelling evi-

dence suggests that other bioactive compounds and

receptors contribute to the secretion of GLP-1/2 and

PYY by the L cells [7]. For instance, bioactive lipids

belonging to the N-acylethanolamine and acylglycerol

families are also able to activate the L cell-specific re-

ceptor GPR119 (Figure 1) [37,38,39��].

To date, few studies have characterised the roles of

specific bacterial species that are able to produce metab-

olites with bioactive effects on these gut hormones.

Interestingly, Akkermansia muciniphila, a mucin-degrading

bacterium that resides in the mucus layer, is able to

produce acetate and propionate [40], which can act on

GPR43. We recently showed that this bacterium was

present at lower levels in obese and type 2 diabetic mice



than in healthy mice [41�] and that the daily adminis-

tration of A. muciniphila for 4 weeks reversed high-fat diet-

induced obesity and type 2 diabetes [41�]. Strikingly, we

also showed that the abundance of A. muciniphila was

associated with L cell number and secretory capacity [12].

Therefore, it appears clear that the gut microbiota and

specific associated metabolites are key partners in the

control of glucose and energy homeostasis. Although the

mechanisms underlying this regulation are still unclear,

the gut microbiota constitutes an important potential

target for treatment of metabolic disorders such as obesity

and type 2 diabetes.

Gut microbiota and enteroendocrinefunctions: effects on gut barrier functionGut barrier disruption has been observed in several

pathological situations and is involved in the pathophy-

siologic process of multiple diseases. Obesity is associated

with an increase in gut permeability that leads to the

abnormal translocation of gut bacteria or gut bacteria

components from the intestinal lumen through the host

blood circulation and tissues [42–45]. We have shown that

these changes in gut barrier activity are associated with

increased plasma levels of gram-negative bacterial cell

wall components, namely lipopolysaccharides (LPS).

Importantly, the increase in plasma LPS levels, which

is defined as metabolic endotoxemia, has been shown to

trigger low grade inflammation and metabolic disorders

associated with obesity and type 2 diabetes [42]. Given

the implications of gut barrier alterations on the onset of

metabolic endotoxemia, inflammation and metabolic dis-

orders associated with obesity and type 2 diabetes, it is of

the utmost importance to determine the underlying

mechanisms and the potential opportunities to reverse

the increase in gut permeability related to this pathology.

One of the principal players involved in the changes in

gut barrier function in obesity and type 2 diabetes is the

gut microbiota. Indeed, it is now well established that

obesity is associated with changes in the diversity and

composition of the gut microbiome [46–49]. Moreover,

we have demonstrated that this link is causal because

modulations of the gut microbiota using prebiotics can

improve gut barrier function and ameliorate metabolic

endotoxemia and inflammation in obesity and type 2

diabetes through mechanisms associated with enteroen-

docrine cell function [12,41�,50,51]. To date, the main

enteroendocrine peptide known to be involved in gut

barrier functions and produced by enteroendocrine cells

is the glucagon-like peptide-2 (GLP-2) (Figure 1). This

peptide is produced by L cells; its production is regulated

by the nutritional status of the host, and it increases the

nutrient absorption capacity of the host. Importantly,

GLP-2 maintains gut barrier functions through different

mechanisms. First, GLP-2 has been demonstrated to

induce intestinal epithelial cell proliferation and thereby






gut trophic effects [52]. Second, GLP-2 increases the

expression of proteins that link epithelial cells together,

that is, intestinal tight junction proteins [53,54]. Third,

GLP-2 has recently been identified to be involved in

regulating the innate immune system by controlling the

expression of antimicrobial peptides produced by Paneth

cells. Antimicrobial peptides are implicated in host–microbiota segregation and consequently the mainten-

ance of gut barrier functions [55].

Importantly, we have shown that the beneficial effects of

gut microbiota modulation on gut barrier function are

associated with an increase in GLP-2 production related

to an increase in the number of L cells in the intestine

[12,53]. It is worth noting that treatment with a GLP-2

antagonist completely abolished the improvements in gut

barrier function following prebiotic-induced changes in

the gut microbiota. These data suggest that specific

interactions between the gut microbiota and enteroendo-

crine L cells control gut permeability and inflammation in

obesity and type 2 diabetes.

As discussed above, we have recently identified A. muci-niphila as one species that is involved in the crosstalk

between the gut microbiota and intestinal epithelium in

the context of obesity and type 2 diabetes. Compelling

evidence suggests that A. muciniphila seems to play a

special role in gut barrier function. Indeed, several path-

ologies associated with increased gut permeability are

also associated with a decrease in the abundance of A.muciniphila in the gut [56,57]. Importantly, the abundance

of this bacterium negatively correlates with the levels of

gut permeability markers and inflammatory markers

[41�]. In a recent study, we found that A. muciniphilatreatment decreases metabolic endotoxemia and inflam-

mation by improving intestinal mucosal barrier function

in high-fat fed mice [41�]. Our data suggest that the

effects of A. muciniphila on gut barrier function could

be mediated through enteroendocrine L cells.

Indeed, we demonstrated that A. muciniphila adminis-

tration significantly increases the intestinal levels of 2-

oleoylglycerol (2-OG), a bioactive lipid belonging to the

endocannabinoid system [41�]. Interestingly, 2-OG

stimulates the secretion of glucagon-like peptides

through the activation of GPR119 localised on intestinal

L cells (Figure 1) [39��].

It is worth noting that L cells and their secretory products

are not the only enteroendocrine peptides and cells

involved in the relationship between the gut microbiota

and gut barrier function. For instance, intestinal signalling

by serotonin (another enteroendocrine product) is involved

in gut barrier function during obesity. Levels of serotonin

and the type 3 serotonin receptor (5-HT3R) are increased

in mice with genetic or high-fat diet-induced obesity, and

5-HT3R antagonists increase the expression of intestinal



tight junction proteins such as occludin and claudin-1, an

effect that is associated with decreases in metabolic endo-

toxemia and fatty acid liver diseases associated with obesity

[58,59]. A link between specific gut microbes and the

modulation of serotonin production has been proposed

[60,61]; however, the connections between serotonin,

the gut microbiota and the secretory capacity of other

enteroendocrine cells remain to be elucidated.

ConclusionsSeveral studies have shown that modification of the gut

microbiota affects various physiological processes. However,

it has so far proven difficult to determine the precise

mechanisms linking gut microbiota composition and/or

activity with specific metabolic pathways involved in energy

and glucose homeostasis. The gut microbiota represents an

extremely diverse group of microbes and is not a static

ecosystem but is subject to rapid modifications that are

directly associated with nutrient intake. Several studies have

suggested that targeting the gut microbiota and thereby the

production of specific metabolites may be one interesting

approach toward improving metabolic features associated

with obesity and type 2 diabetes. However, it remains to be

determined whether these modifications are a cause or a

consequence of the metabolic changes observed.

Emerging evidence suggests that the gut microbiota

interacts with their hosts through several pathways invol-

ving the enteroendocrine cells. Thus, specific GPCRs

expressed on enteroendocrine L cells may constitute a

putative therapeutic target.

To date, it is not known whether the modifications of

enteroendocrine cell activities by the microbiota are strain

or metabolite dependent. The next challenge is to develop

approaches to decipher the mechanisms involved in mol-

ecular signalling modulated by gut microbes to ultimately

identify new therapeutic targets for the management of

various metabolic conditions. Thus, additional research is

needed to further isolate and identify the key mechanisms

involved in gut microbe–host interactions.

AcknowledgementsPDC is a research associate from the FRS-FNRS (Fonds de la RechercheScientifique) Belgium. AE is a doctoral fellow from the FRS-FNRS.TD is postdoctoral fellow from the FRM (Fondation pour la RechercheMedicale, France). PDC is recipients of an ERC Starting Grant 2013(336452-ENIGMO), FSR and FRSM subsidies (Fonds speciaux derecherches, UCL, Belgium; Fonds de la recherche scientifique medicale,Belgium) and ARC (Action de Recherche Concertee).

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� of special interest

�� of outstanding interest

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39.��

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gut microbiota, enteroendocrine functions and metabolism

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