Obesity and the Gut Microbiota
Involvement of the Endocannabinoid System
Lawrence Aalders (S2609266) July 7, 2016
Bachelor Thesis University of Groningen Behavioural Neurosciences Supervision: prof. dr. G. van Dijk
July 7, 2016
Lawrence Aalders (s2609266) University of Groningen Behavioural Neurosciences
E-mail: L.Aalders.1@student.rug.nl Supervision: prof. dr. Gertjan van Dijk
Abstract
Obesity is becoming one of the most prevalent health problems in today’s society and could be seen as a pandemic. This is concerning, as obesity is associated to be the cause of many diseases. Therefore, in order to design treatments for obesity, the need to unravel the mechanisms underlying the disease is urgent. Obesity is often the cause of imbalances in mechanisms controlling the energy balance. There are multiple systems in the human body that regulate the energy balance, of which the gut microbiota has been given a lot of attention recently. Additionally, the endocannabinoid system also seems an interesting regulator of the energy balance. Given that both systems are in close contact, it could be that there is an interaction.
Therefore, the aim of this paper is to investigate the interaction between the gut microbiota and the endocannabinoid system in causing obesity. It is shown how the Western diet influences the regulatory role of both systems.
Furthermore, it is shown how both systems interact at the level of the gut barrier and how both influence each other’s functions. Although there seems to be a vicious cycle in this interaction, there are more studies needed to confirm this finding.
Contents
1. Obesity Pandemic and Possible Underlying Mechanisms
2. Understanding the Gut Microbiota
2.1 Establishment and development of the gut microbiota 2.2 Composition and functions of the gut microbiota
2.3 Dietary modulation of the gut microbiota and its functions
3. The Endocannabinoid System
3.1 Signallers and mechanisms of the endocannabinoid system 3.2 The endocannabinoid system regulates the energy balance 3.3 Obesity and the endocannabinoid system
4. Interactions between the Gut Microbiota and the Endocannabinoid System Associated With Obesity
4.1 The gut microbiota and the endocannabinoid system interact at the level of the gut barrier
4.2 Persistent hunger through interaction between the gut microbiota and the endocannabinoid system
5. Concluding Remarks 6. References
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1. Obesity Pandemic and Possible Underlying Mechanisms In today’s society, obesity is one of the major concerns for our health. It is not only a problem of the developed countries, as obesity is also becoming more prevalent in developing countries (Ng et al., 2014). Therefore, obesity could be viewed as a modern day pandemic. Since 1980, the number of overweight and obese people in the world increased from 857 million to 2.1 billion in 2013 (Ng et al., 2014). In developed countries, the increase of obesity has reduced slightly in the past eight years, but in developing countries, the number is still increasing (Ng et al., 2014).
Obesity has been long known to be a cause of many different chronic diseases, including type II diabetes, cardiovascular disease, and certain types of cancer (Wyatt et al., 2006). Therefore, obesity substantially impacts health, which gives rise to an increasing economical burden for national healthcare institutions (Lehnert et al., 2013). Several studies have shown that obesity is a very complex disease, which is caused by multiple different factors. Research has shown that there is a strong genetic component (Albuquerque et al., 2015), but most often our modern lifestyle is attributed to a leading cause of obesity (Egger and Dixon, 2014).
One of the most obvious factors of our lifestyle that underlie obesity is nutrition. For the past decades, our society has changed the way we think about and deal with nutrition. The upcoming industrial production after WWII has led to an increase in overall food availability at an even lower cost than before. Current working conditions have forced people to outsource food production and preparation, which have made cooking less energy and time consuming (Daniels et al., 2015). Choosing for these so-called convenience foods comes with a cost, because these are typically associated with a low nutritional value, as they are high in energy, and low in nutrients (Poti et al., 2015).
Therefore, we can conclude that there is an increase in the consumption of food and more specifically of high-energy, low-nutrient foods, which is partially the result of outsourcing our food production and preparation. This change in nutritional intake has detrimental effects for our health, also contributing to today’s obesity pandemic. It is of great importance to understand the underlying causes of obesity and to design treatments in preventing the disease. Although it is clear that several factors in our environment may contribute to obesity, the diverse mechanisms that eventually lead to obesity and the retention of the obese phenotype are not fully understood. Following up on this, it is also known that the composition of our diet influences multiple systems involved with the energy balance, and quite recently, there is accumulating evidence that the gut microbiota seems to be one of these systems.
The gut microbiota contains trillions of bacteria, of which there are different types that can be distinguished (Human Microbiome Project Consortium, 2012). It is also known that the gut microbiota provides major functions to
the human body that are very essential (Jandhyala et al., 2015). One of these functions is to metabolize the nutrients in our food. Furthermore, there are specific types of bacteria that mainly process carbohydrates or fats.
Our diet could therefore directly influence the activity of the gut microbiota, and it has been shown that changing a diet, specifically its macronutrient composition, can alter the bacterial structure and activity of the gut microbiota (David et al., 2014).
It is also known that the gut microbiota can influence the energy balance of the host, and specifically the harvest and storage of energy (Bäckhed et al., 2004; Bäckhed et al., 2007; Turnbaugh and Gordon, 2009). The gut microbiota accomplishes this through multiple underlying mechanisms, and it is hypothesized that changes in these mechanisms may lead to obesity (Kobyliak et al., 2016). Thus, it has been shown that changes in diet can alter the mechanisms of the gut microbiota, which in turn can lead to a shift in energy balance of the host.
Another pathway that is associated with the energy balance is the endo- cannabinoid system. It has been shown that the endocannabinoid system regulates both the homeostatic and hedonic control of nutritional intake (Broberger, 2005; Di Marzo et al., 2009). Furthermore, imbalances in the this control of nutritional intake can lead to obesity (Silvestri and Di Marzo, 2013; Monteleone et al., 2016). Additionally, it has been shown that imbalances of the endocannabinoid system tone can also be the result of hyperglycemia or obesity (Matias et al., 2008). Thus, such an imbalance could be either the cause or the consequence of obesity and it seems plausible that the change in endocannabinoid system tone could be due to influences of other mechanisms that regulate metabolism.
Judging on the findings described above, the endocannabinoid system and the gut microbiota may interact with one another, as they are both involved in the regulation of food intake and metabolism. Furthermore, it has been shown that the endocannabinoid system stands in close contact with the gut microbiota, because of the expression of the cannabinoid CB1 and CB2 receptors in the gastrointestinal tract (Maccarrone et al., 2015). Thus, it is likely that an imbalance in the interaction between the two systems may cause obesity. Therefore, in this paper, the relationship between the gut microbiota and obesity will be investigated, as is the interaction between the gut microbiota and the endocannabinoid system in the cause of obesity and its persistence.
2. Understanding the Gut Microbiota
As mentioned in the introduction, the gut microbiota provides the human body with essential functions that the human body does not have itself.
Therefore, the human host and the gut microbiota are in symbiosis: the host taking advantage of the functions of the microbiota and the microbiota living on the nutrients the host provides them with. Thus, the gut microbiota is very important and could be considered as one of the essential organs of our body. To determine the contribution of the gut microbiota in obesity, we first have to gain insight into the development of the gut microbiota, its composition and its functions in controlling the energy balance. Additionally, this chapter explains what happens when there is a persistent change in diet, and what the resulting consequences are for the gut microbiota and its functions.
2.1 Establishment and development of the gut microbiota
The establishment of the microbiota occurs very early on in life. After birth, newborns receive a part of the microbes of their mother, which then settle and are exposed to different types of bacterial species already residing in the gut of the newborn (Backhed et al., 2015). There are many different factors that further contribute to the establishment of the gut microbiota. However, it is suggested that there are two key factors, which are the mode of delivery of the infant and breastfeeding (Backhed et al., 2015; Dominguez-Bello et al., 2010; Bergström et al., 2014).
When it comes to mode of delivery of the infant, it appears that there is a difference between the microbiota of newborns who are born vaginally or via C-section. The microbiota from vaginally born infants resembled the vaginal microbiota community from their mothers, whereas infants born via C- section lacked this resemblance (Dominguez-Bello et al., 2010). Even more so, the microbiota of infants born via C-section appeared to resemble the microbial community found on the skin of their mothers (Dominguez-Bello et al., 2010). This difference in initial microbial communities directly after birth may explain individual differences of the gut microbiota later on in life.
During the first months of life, infants usually consume breast milk.
Consuming breast milk has been shown to be a major contributor in the development of the gut microbiota. It has been shown that the gut microbiota of infants who have been breast-fed, closer resembled the gut microbiota of adults, in contrast with infants who had been formula-fed (Backhed et al., 2015). After the first period of breastfeeding, the infant is slowly introduced to solid foods, which will eventually help to further develop the microbiota to what it will be when the infant grows to become an adult (Mackie et al., 1999). However, the effects of solid foods only became apparent when breastfeeding was stopped, indicating that cessation of breastfeeding contributes to a further development of the gut microbiota (Backhed et al., 2015).
2.2 Composition and functions of the gut microbiota
The adult gut microbiota consists of an incredible amount of bacteria. The number of bacteria in the human gut is estimated to be around 1014, which is more than ten times the number of cells of the human body (Xu and Gordon, 2010). There are different types of bacteria that can be distinguished. The most abundant types, or more accurately phyla, are Bacteroidetes and Firmicutes, with the phyla Proteobacteria, Verrumicrobia, Actinobacteria, Fusobacteria and Cyanobacteria roughly making up the remainder of the gut microbiota (Qin et al., 2010; Human Microbiome Project Consortium, 2012).
The gut microbiota has multiple essential functions in the human body. The system is associated with the development and modulation of both the innate and adaptive immune system, regulation of the gut barrier and structure, antimicrobial protection and drug metabolism (Jandhyala et al., 2015). However, the most important function of the gut microbiota that is relevant to the context of this paper is the metabolism of nutrients, and specifically the nutrients from indigestible dietary carbohydrates. Some smaller size carbohydrates are already digested in the small intestine, but most of the indigestible carbohydrates are large and have many branches, meaning that these can only be digested further down the gastrointestinal tract in the large intestine (El Kaoutari et al., 2013).
These larger carbohydrates are oligosaccharides and polysaccharides, which are digested through fermentation in the large intestine, because most of the bacteria that are able to ferment the indigestible carbohydrates reside in this part of the gastrointestinal tract (El Kaoutari et al., 2013). It has been estimated that this fermentation process provides around 10% of the total amount of energy the body uses, although this number depends on individual differences in diet (McNeil, 1984). Furthermore, the major products resulting from this fermentation process are short-chain fatty acids (SCFAs), most of which are butyrate, acetate and propionate (Morrison and Preston, 2016). Besides providing energy to the host, it has been shown that there are multiple important functions associated with the SCFAs (Flint et al., 2012).
SCFAs also have important functions when it comes to regulation of the energy balance. SCFAs signal to two gut receptors, both of which are the free fatty-acid receptors FFAR2 and FFAR3 (Morrison and Preston, 2016). Both receptors are associated with appetite control, as they regulate the release of anorexic gut hormones, which include glucagon-like peptide 1 (GLP-1) and peptide YY (PYY) (Sleeth et al., 2010; Lin et al., 2012). This indicates that there is indeed a link between the function of the gut microbiota and appetite control, depending on the formation and signalling of SCFAs to release anorexic gut hormones. Therefore, it seems that the gut microbiota can directly influence energy intake.
2.3 Dietary modulation of the gut microbiota and its functions
It seems clear that obesity is most often the cause of poor nutritional choices, which is partially due to living in the modern day society. Most of the modern diets include products with high energy and low nutritional value, which is usually associated with higher amounts of salt, sugar and fat. Healthier diets on the other hand are more often plant-based, therefore having higher levels of dietary fibres, which are a great source of oligosaccharides and polysaccharides (Blaut, 2002). Therefore, looking at today’s obesity pandemic, we can see that there is a decrease of the amount of dietary fibres in people’s diets, and thus a decrease of oligosaccharide and polysaccharide intake. But how could this change in diet influence the gut microbiota and its regulation of the energy balance?
This has been shown in a study with germ-free mice (Turnbaugh et al., 2009). In this study, transplanting human fecal microbial communities humanized the gut microbiota of the germ-free mice. After accomplishing this, the mice were switched from a plant-based diet to a modern Western diet. This resulted in a complete change of the gut microbiota structure, with the Western diet inducing an overall increase of Firmicutes bacteria and a decrease of Bacteroidetes. The study also showed that colonizing additional germ-free mice with the changed microbiota increased adiposity relative to germ-free mice that were colonized with the microbiota from a plant-based diet (Turnbaugh et al., 2009). Thus, changing the microbiota by switching to a Western diet is indeed suggested to lead to obesity.
According to the study described above, it seems that the increased ratio of Firmicutes to Bacteroidetes bacteria of the gut microbiota, which is caused by the Western diet, may be the cause of an obese phenotype. This relation between the ratio of Firmicutes and Bacteroidetes and obesity has indeed been shown before (Ley et al., 2006; DiBaise et al., 2008), thus confirming that a Western diet, that has low content of dietary fibres, alters the composition of the gut microbiota and thereby creating an obese phenotype.
However, a study by Schwiertz et al. (2010) found other results in the change of microbial composition, which is reason to doubt previous findings.
But even tough there are conflicting results, most studies did find the same increase of the Firmicutes to Bacteroidetes ratio. But how is the change of the gut microbiota composition translated into a change in function that ultimately leads to obesity?
It has been shown that the gut microbiota harvest energy from our food. This energy is subsequently stored in the host in fat depots. But with the modern Western diet, the altered ratio of Firmicutes to Bacteroidetes results in an increase of fermentation capacity, which would lead to an increase of SCFAs (Fernandes et al., 2014). These extra SCFAs are then stored in fat depots, which would eventually promote adiposity and thus obesity (Bäckhed et al., 2004). Therefore, increased energy harvest by the altered gut microbiota, seems to be the direct cause of obesity.
In this chapter, it was shown which factors develop and shape the structure of the gut microbiota. The main function of the gut microbiota is to harvest energy from our food, thereby confirming its importance in metabolic regulation. It has been explained how the modern Western diet influences the composition of the gut microbiota, which ultimately results in a change of function. The functional changes of the gut microbiota could result in an increase of energy harvest, which results in obesity. To summarize, this chapter shows the importance of the gut microbiota in studying the cause of obesity.
3. The Endocannabinoid System
Now we understand how the gut microbiota functions, and how diet can modulate its functions, it is time to look into the endocannabinoid system.
As said before, the endocannabinoid system is a key player in metabolic regulation. Furthermore, it stands in close contact with the gut microbiota, as is evident from expression of CB1 and CB2 cannabinoid receptors in the gut, giving rise to the belief that the gut microbiota and the endocannabinoid system may somehow interact with one another. But to get a clear image of the interaction between the gut microbiota and the endocannabinoid system, we first have to look how signalling in the endocannabinoid system works and how exactly the energy balance is regulated.
3.1 Signallers and mechanisms of the endocannabinoid system
The endocannabinoid system has been long known to have significant physiological effects in the human body. The very first endocannabinoid that was found is Δ9-tetrahydrocannabinol (THC), which is a well-known component of cannabis. Furthermore, there are two G-protein coupled receptors associated with the endocannabinoid system, which are the CB1 and CB2 cannabinoid receptors. The CB1 receptor was first found in the brain and peripheral nerve endings and was associated with sensory perception, memory processing, appetite regulation, and motor activity (Pertwee et al., 2015). The CB2 receptor was first found in tissues involved in the immune system (Pertwee et al., 2015). However, current understanding indicates that both receptors are expressed throughout the entire human body (Maccarrone et al., 2015).
Besides THC, other ligands that stimulate the CB1 and CB2 receptors have since been identified. The major ones that have been studied are N- arachidonoylethanol-amine (AEA), also known as anandamide, and 2- arachidonoylglycerol (2-AG) (Luchicchi and Pistis, 2012). Other endo- cannabinoids that have been found are analogues of these two ligands.
Important analogues include N-oleoyl-ethanolamine (OEA), which is comparable with AEA, and oleoylglycerol (2-OG), which is comparable with 2-AG (Cani et al., 2016). However, activation of the cannabinoid receptors by these analogues does not directly lead to effects, but they rather mediate the effect of the total endocannabinoid response.
To achieve this, these analogues might stimulate or inhibit the enzymes that synthesize or degrade other endocannabinoids, thereby enhancing the effects of the total endocannabinoid response (Cani et al., 2016). Nevertheless, it has also been shown that they have physiological effects of themselves, which can be achieved by stimulating receptors other than the ‘traditional’
cannabinoid receptors (De Petrocellis and Di Marzo, 2010). This shows that the endocannabinoid system is an intricate signalling system, and that understanding its effects and functions is crucial in developing therapies for diseases (Bosier, 2010).
3.2 The endocannabinoid system regulates the energy balance
As explained, signalling of the endocannabinoid system is very intricate.
Furthermore, the expression of the cannabinoid receptors is widespread throughout the human body (Maccarrone et al., 2015). Therefore, there are also many functions that are associated with the endocannabinoid system.
Many of these functions have been revealed in experimental studies, which have tried to find therapies for several diseases. Evidence suggests that the endocannabinoid system is, amongst others, involved in neurodegenerative, cardiovascular and inflammatory disorders, and obesity or metabolic syndrome (Pacher and Kunos, 2013; Pertwee et al., 2015). But above all, and similarly to the gut microbiota, the endocannabinoid system is a key regulator of the energy balance, and it has been found that it regulates both the hedonic and homeostatic control of nutritional intake (Broberger, 2005;
Di Marzo et al., 2009).
Hedonic control refers to control of nutritional intake, taking in mind its reward and palatability. It is often the case that people consume food because it is attractive and pleasurable, even when people are not hungry at all (Cooper, 2004). In the endocannabinoid system, the hedonic control is accomplished by effects of the CB1 receptor mainly in the brain, which is mediated by the agonists THC, AEA and 2-AG (Jager and Witkamp, 2014). It has been shown in mice that stimulation of the CB1 receptor by these agonists increases nutritional intake, specifically of foods that are more palatable than standard foods (Jager and Witkamp, 2014). Moreover, selective blockade of the CB1 receptor with CB1 antagonists resulted in the opposite effect (Friemel et al., 2014). Thus, elevated levels of endocanna- binoids could increase intake of highly palatable foods.
Earlier, it was shown that the cannabinoid receptors are expressed throughout the entire human body. To ensure a relatively stable energy balance, it is important for the brain to monitor energy levels in the body, which can be achieved by communicating with peripheral organs that monitor energy levels and subsequently control aspects of the energy balance. Therefore, when it comes to homeostatic control, the endo- cannabinoid system is involved with these peripheral organs, which has indeed been shown (Gatta-Cherifi and Cota, 2016). Increasing or decreasing levels of endocannabinoids can modulate the effects of the peripheral organs on energy balance and nutritional intake, which has been shown in multiple articles (Watkins and Kim, 2015). Thus, the endocannabinoid system is important in regulating the energy balance and it is very likely that metabolic disease is a result of imbalances in the endocannabinoid system, a relationship that will be explored in the next paragraph.
3.3 Obesity and the endocannabinoid system
As we have seen in the first chapter, obesity is mostly caused by poor nutritional choices, with people choosing more frequently for foods with a
high energy, but low nutrient content. More specifically, these modern Western diets are usually associated with increased levels of omega-6 polyunsaturated fatty acids (Ailhaud et al., 2006). Furthermore, it is known that the endocannabinoids AEA, 2-AG and their analogues are synthesized from omega-6 polyunsaturated fatty acids (Kim et al., 2011). Therefore, the increase of omega-6 polyunsaturated fatty acids in diets is associated with higher levels of endocannabinoids, which has indeed been shown in studies with piglets (Berger et al., 2001) and mice (Watanabe et al., 2003). Therefore, obesity is, in this case, the cause of increased levels of endocannabinoids, which in turn is the result of increased levels of omega-6 polyunsaturated fatty acids in diets.
The increased levels of endocannabinoids in obesity have indeed been shown in multiple different studies (Engeli et al., 2005; Côté et al., 2007; Matias et al., 2008). Increased levels of endocannabinoids do not only contribute to the establishment of obesity. It has been shown that when the endocannabinoid system tone was chronically increased, the energy balance is continuously shifted to the side of nutritional intake, and less so to the side of energy expenditure (Matias and Di Marzo, 2006). In the brain, the elevated tone of the endocannabinoid system increased nutritional intake, which could be seen as an increase of meal size and frequency. In peripheral organs, the elevated tone of the endocannabinoid increased body weight, white adipose tissue, and triglycerides, while brown adipose tissue thermogenesis and muscle activity decreased. Thus, the endocannabinoid system tone can be continuously elevated as a cause of increased levels of omega-6 polyunsatured fatty acids in modern Western diets, which would be the ultimate cause of the establishment of obesity and its persistence.
4. Interactions between the Gut Microbiota and the Endo- cannabinoid System Associated With Obesity
In the previous chapters we have seen how the gut microbiota and the endocannabinoid system both work in controlling the energy balance.
Furthermore, it was shown how alteration of the gut microbiota composition and a continuously elevated endocannabinoid tone both contribute to obesity. Expression of the CB1 and CB2 cannabinoid receptors in the gut is evidence for a possible interaction between both systems, and therefore an interaction in controlling the energy balance. This final chapter shows how both systems are interrelated and how both could contribute to obesity.
4.1 The gut microbiota and the endocannabinoid system interact at the level of the gut barrier
We have seen that our diet can alter the composition of the gut microbiota, which resulted in increased adiposity and ultimately obesity. It has been shown that these changes of the gut microbiota cause a dysfunction of the gut barrier, which can be seen in an increase of gut permeability (Cani et al., 2008). The increased permeability leads to transport of gut components over the gut barrier. These gut components also consists of lipopolysaccharides (LPS), which are cell components of gram-negative bacteria. This ‘leakage’
causes an increase of plasma LPS levels, which has been associated with metabolic endotoxemia and the initiation of obesity (Cani et al., 2007).
Furthermore, the increase of LPS plasma levels has also been associated with an increase of endocannabinoids (Maccarrone et al., 2001; Liu et al., 2003).
It has been shown that obesity is associated with an elevated tone of the endocannabinoid system. Similarly to the gut microbiota, the endo- cannabinoid system can increase adiposity, which might indicate a possible link between both systems. Following up on this, it has been shown that the gut microbiota controls levels of intestinal endocannabinoids (Muccioli et al., 2010). Furthermore, elevated endocannabinoid tone has been shown to increase gut barrier permeability, showing the control of the gut barrier by the endocannabinoid system (Muccioli et al., 2010). Therefore, there seems to be a vicious cycle, which has been proposed by Cani et al. (2012). They showed that the gut microbiota increases intestinal endocannabinoid levels, which leads to an increase of gut permeability. This leads to an increase of plasma LPS levels, which in turn increases the level of endocannabinoids.
This vicious cycle could be the underlying factor that contributes to obesity and its persistence.
4.2 Persistent hunger through interaction between the gut microbiota and the endocannabinoid system
Another possible mechanism that may explain why obesity is persistent is the demobilisation of endocannabinoids in the intestine. We now know that the gut microbiota controls intestinal levels of endocannabinoids, which is an indication that the gastrointestinal tract is a site of endocannabinoid production. Furthermore, it has been shown that endocannabinoids control nutritional intake. Analogues of the endocannabinoids AEA and 2-AG have been shown to have activity of their own, even without stimulating the cannabinoid CB1 and CB2 receptors (De Petrocellis and Di Marzo, 2010). It might be that OEA and 2-OG, the analogues of AEA and 2-AG, are key players in this mechanism.
OEA and 2-OG are regulators of nutritional intake. It has been shown that they both are satiety factors, which decrease nutritional intake (Rodriguez de Fonseca et al., 2001; Piomelli, 2013). This is achieved by stimulation of GPR119-receptors, which reside on the enteroendocrine cells of the gastro- intestinal tract (Lauffer et al., 2009), activation of peroxisome proliferator- activated receptor type-α (PPAR-α) (Fu et al., 2003) or via directly stimulating afferent sensory fibers. Stimulation of each of these targets can induce the anorexic response. Especially the stimulation of GPR199-receptors on the enteroendocrine L-cells seems to be important here, as these cells are essential in secreting GLP-1 upon stimulation of the GPR119-receptors (Lauffer et al., 2009; Syed et al., 2012). Thus, under normal circumstances, the endocannabinoid system also produces anorexic signals to inhibit nutritional intake.
However, we have seen that the composition of the gut microbiota can be altered by our diet. This can result in different levels of intestinal endocannabinoids. It has been shown for example that specifically altering the gut microbiota can increase endocannabinoid levels (Everard et al., 2013). This study showed that the gut microbiota of diet-induced obese mice had decreased levels of Akkermansia muciniphila, and treating these mice with Akkermansia muciniphila resulted in elevated levels of the endocanna- binoids 2-OG and 2-AG. Thus, this study shows that obesity is also associated with decreased levels of specific endocannabinoids that normally control gut barrier and gut peptide secretion. These decreased levels of 2-OG might indicate that the GPR119-receptor is less stimulated, which results in less secretion of GLP-1. Thus, with obesity there seems to be a continuous decrease of GLP-1, which could indicate that the satiety signal from the gut is continuously attenuated. This might be an indicator of the increased meal size and frequency observed during obesity.
A factor that might contribute to the observed decrease of GLP-1 is the decreased mobilization of endocannabinoids during obesity. Igarashi et al.
(2015) found that in diet-induced obese mice the feeding-induced mobili- zation of endocannabinoids is decreased, especially the mobilization of OEA.
This could partially explain the reduced levels of GLP-1, as stimulation of the
GPR119-receptor by OEA would normally result in GLP-1 secretion. Reduced mobilization could be due to the effects of the gut microbiota on endocannabinoid levels. However, this has not been studied as of yet, indicating that this remains questionable. But together, these findings are alarming, because increasing meal size and frequency during obesity is obviously detrimental for the human body. In this situation, it seems like there is also a vicious cycle, because increased intake of more foods that are high in energy and low in nutrients will again lead to an alteration of the gut microbiota composition, which would eventually lead to even more nutri- tional intake.
5. Concluding Remarks
In this paper, it was shown that both the gut microbiota and the endocannabinoid system regulate the energy balance and how alterations to both systems could contribute to obesity. Furthermore, it was shown how the interaction between the gut microbiota and the endocannabinoid system contribute to obesity.
We have seen that obesity is becoming an increasing problem in today’s society, which is often the cause of poor nutritional choices. Following up on that, it was shown how this change in our diet could alter the functions of the gut microbiota and the endocannabinoid system. The Western diet contains less oligosaccharides and polysaccharides, which lead to change in the composition of the gut microbiota. The ratio of Firmicutes to Bacteroidetes increased, which is found in many studies to be an indication of the obese phenotype. This change in composition induces increased fermentation capacity, meaning that the gut microbiota becomes more efficient in processing nutrients. We know that the major end products of this fermentation are SCFAs, which are stored in adipose tissue. Therefore, increased fermentation leads to increased storage of SCFAs in adipose tissue, thereby contributing to the increased adiposity seen in obesity.
These Western diets are not only associated with decreased levels of oligosaccharides and polysaccharides, but also with an increase of omega-6 polyunsaturated fatty acids. It was shown that endocannabinoids are synthesized from these fatty acids, meaning that the Western diet is associated with increased endocannabinoid levels. Furthermore, chronically increased endocannabinoid levels have been associated with a continuous shift of the energy balance. This relation was attributed to the central and peripheral actions of the endocannabinoids, which induced an increase of meal size and frequency, body weight, white adipose tissue and triglycerides, and a decrease of thermogenesis activity of brown adipose tissue and muscle activity. Therefore, it was concluded that chronically increased endo- cannabinoid levels are the cause of the establishment of obesity and its persistence.
Furthermore, it has been shown that the changes of the gut microbiota composition cause a dysfunction of the gut barrier, which increases gut permeability and transport of gut components over the gut barrier. It was shown that plasma LPS levels increased as a result, which eventually resulted in increased endocannabinoid levels. Additionally, increased endocannabinoids levels increased gut barrier permeability, showing the control of the gut barrier by the endocannabinoid system. Therefore, it was shown that there is a vicious cycle, a mechanism that has been proposed by the research group of P.D. Cani. This vicious cycle is proposed to be the underlying factor that contributes to obesity and its persistence.
It was shown that the gut microbiota controls intestinal levels of endocannabinoids, thus making it a site of endocannabinoid production.
Additionally, the endocannabinoid analogues OEA and 2-OG were shown to decrease nutritional intake by increasing levels of GLP-1. It has been shown that specifically altering the gut microbiota of obese mice can increase levels of specific endocannabinoids. Thus, obesity is associated with a decrease of specific endocannabinoids, which include OEA and 2-OG. Knowing that these analogues regulate GLP-1 secretion, it seems that obesity is also associated with continuously decreased levels of GLP-1, which is proposed to be the indicator of the increased meal size and frequency observed during obesity. Furthermore, decreased mobilization of endocannabinoids could be the cause this finding. It was shown that OEA mobilization was decreased in obesity, which can partially explain the decreased GLP-1 levels and thus the increased nutritional intake. Although the gut microbiota could be a factor that may contribute to this observation, this has not been studied yet. It was proposed that there is another vicious cycle, with increased nutritional intake leading to a change of the gut microbiota, and thus even more nutritional intake.
Even though these findings seem plausible, there is however a lot of speculation. More studies are needed to confirm these findings. It would be great to see more research that explains the interaction of the gut microbiota and the endocannabinoid system. Cani et al. are one of the leading research groups in this area, as they have many studies dedicated finding out more about this interaction. Even more specific studies trying to find out more about the mobilization of endocannabinoids by the gut microbiota seem to be particularly interesting, as this interaction might explain that, even though there are increased endocannabinoid levels in obesity, some endocannabinoids cannot act on their targets because they are not mobilized. Even more interesting would be studies dedicated to the vicious cycle in the interaction of the gut microbiota and the endocannabinoid system. This positive feedback loop seems to be one of the main reasons why there are chronically increased endocannabinoid levels, which are shown to increase adiposity and thus the obese phenotype.
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