Accepted Manuscript Gut microbiota and obesity: role in aetiology and potential therapeutic target Carthage P. Moran, MB, MRCP Fergus Shanahan, MD, DSc, Professor and Chair

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S1521-6918(14)00083-3

DOI:

10.1016/j.bpg.2014.07.005

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To appear in:

Best Practice & Research Clinical Gastroenterology

Received Date: 6 April 2014 Revised Date:

20 June 2014

Accepted Date: 5 July 2014

Please cite this article as: Moran CP, Shanahan F, Gut microbiota and obesity: role in aetiology and potential therapeutic target, Best Practice & Research Clinical Gastroenterology (2014), doi: 10.1016/ j.bpg.2014.07.005. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT Gut microbiota and obesity: role in aetiology and potential therapeutic target

Carthage P. Moran, MB, MRCP and Fergus Shanahan, MD, DSc

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Dept. Medicine and Alimentary Pharmabiotic Centre, University College Cork National University of Ireland, Cork, Ireland

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Correspondence to: Fergus Shanahan Professor and Chair, Department of Medicine and Alimentary Pharmabiotic Centre Clinical Sciences Building, Cork University Hospital, Wilton, Cork. Ireland Telephone: +353-21-490-1226 FAX +353-21-4345300 Email: [email protected]

Abstract

Obesity is epidemic; chronic energy surplus is clearly important in obesity development but other factors are at play. Indigenous gut microbiota are

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implicated in the aetiopathogenesis of obesity and obesity-related disorders. Evidence from murine models initially suggested a role for the gut microbiota in weight regulation and the microbiota has been shown to contribute to the low grade inflammation that characterises obesity. The microbiota and its

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metabolites mediate some of the alterations of the microbiota-gut-brain axis, the endocannabinoid system, and bile acid metabolism, found in obesity-related

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disorders. Modulation of the gut microbiota is an attractive proposition for prevention or treatment of obesity, particularly as traditional measures have been sub-optimal.

Keywords: Microbiota; Obesity; Endocannabinoids; Bile acids

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ACCEPTED MANUSCRIPT 1. Introduction: microbiota and obesity

The striking increase in incidence of obesity in recent decades has several adverse health implications. While weight gain and obesity are usually considered as an

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imbalance in energy consumption vs expenditure [1], this is too simplistic and belies more complex underlying events (Figures 1 and 2). Obesity is a consequence of

complex interactions among genetic, environmental, socio-economic and dietary

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factors. The rapidity at which obesity is increasing in westernized or socio-

economically developed countries is not fully explained by traditional theories of

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weight gain. Lifestyle factors particularly in early life, such as exposure to antibiotics [2], and other early life environmental modifiers which may be linked with epigenetic changes, are coming under scrutiny as risk factors for obesity later in life.

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Characteristics of obesity include low-grade inflammation, altered microbiota, and increased tone of the endocannabinoid system[3],(Figure 1). Several inter-dependent pathways by which the microbiota may influence adiposity and weight gain by the

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host have been identified. These include extraction of calories from nutrients and the

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generation of specific metabolites, such as Short Chain Fatty Acids (SCFA), modulation of host behavior and satiety through the brain-gut axis and a conditioning influence on inflammatory responses.

The healthy human microbiota is comprised of 1014 microorganisms, which exceeds the number of human cells in the body by ten-fold. Most indigenous microbes reside in the colon[4]. Collectively, the human microbiota encodes 150 times more genes than the human genome (3-4 million)[5]. This enables the microbiota to perform

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ACCEPTED MANUSCRIPT diverse metabolic activities not encoded in the human genome[6]. Approximately 500-1000 different bacterial species comprise this busy ecosystem. The development of the gut microbiota is a dynamic process, as reviewed elsewhere [7]. Factors influencing the microbiota composition include age, diet, antibiotics and most of the

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elements of a modern lifestyle in addition to certain disease states. A high degree of

functional redundancy and resilience is required for a healthy human microbiota [8].

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Large inter-individual microbial diversity and abundance is coupled with small

phylogenetic overlap between individuals [9]. Mode of delivery at birth affects the

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composition of the microbiota colonising a newborn; skin-associated microbiota in Caesarian section compared to vaginal tract microbiota in vaginal delivery. Differing data exists on whether caesarian section compared to vaginal delivery increases the risk of obesity on early childhood[10,11]. From birth, the microbiome and host

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immune system co-develop and are mutually inter-dependent [12]. Thus, the microbiota shapes the development of the immune system, and in turn the immune system shapes the composition of the microbiota. Communication between microbes

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and the host occurs via transmission of an array of signaling pathways involving

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different classes of effector ligands and extending beyond the immune system to include metabolic cascades. Disruption or sustained changes to the gut microbiota may be associated with obesity[13], insulin resistance[14] in addition to inflammatory bowel disease (IBD)[15]. Microbial compositional profiles variously termed coabundance groups[16] or enterotypes[17] have been linked with functional implications for the host.

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ACCEPTED MANUSCRIPT 1.1.Composition

The phylum Firmicutes (including Clostridium, Enterococcus, Lactobacillus and Ruminococcus) and Bacteroidetes (including Prevotella and Bacteroides genera)

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constitute over 90% of known phylogenetic categories and dominate the distal gut

microbiota[18]. Obesity is associated with differences in gut microbiota at the phylum level, with less overall diversity[19] and greater proportion of Firmicutes than

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Bacteroidetes in obese individuals compared with normal weigh individuals[19,20]. However these findings are not universal, a number of other studies have shown

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variable patterns in phylum level changes measured in the composition of the microbiota of obese subjects[21,22]. Recent work using data from the Human Microbiome Project, found no association between the Firmicutes:Bacteroidetes (F/B) ratio and obesity or Body Mass Index (BMI)[23]. The usefulness of F/B ratio as a

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biomarker for obesity remains uncertain[24]. Key studies summarizing the levels of evidence for a relationship between obesity and the microbiota are shown in Table 1.

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1.2.Energy Harvest

The gut microbiota significantly affects energy yield from diet, in both mice and humans. Hydrolysis and fermentation of otherwise indigestible dietary polysaccharides by the gut microbiota enhances host energy harvest.

The proximal small intestine and stomach are responsible for most nutrient digestion and absorption. Normally almost all fats, ~ 85% of carbohydrates and 65-95% of proteins are absorbed prior to entering the colon[25]. The remaining indigestible

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ACCEPTED MANUSCRIPT nutrients would be generally excreted in stool without absorption if not for colonic microbiota, which enhances energy uptake or harvest from ingested food. An estimated 20-60g of dietary carbohydrates (resistant starches, plant cell wall polysaccharides and non digestible oligosaccharides), avoiding digestion by host

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enzymes, reach the colon each day. An intact colon in patient’s with short bowel syndrome increases the ability to salvage energy not least because of improved

carbohydrate digestion, compared to patients without an intact colon[26]. Colonic

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microbiota is essential for digestion of a wide variety of dietary polysaccharides, the human genome lacks the required glycoside hydrolases[27,28]. Bacteroidetes are

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reported to encode higher levels of carbohydrate active enzymes than Firmicutes[29]. Glycans are processed by the distal gut microbiota generating biologically significant Short Chain Fatty Acids (SCFA; acetate, butyrate and propionate predominantly), which serve as the principal energy source of colonocytes[30]. SCFA are utilized by

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the liver and peripheral tissues, potentially contributing 10% of basal energy requirements of people living in the western world[31].

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Germ Free (GF) mice develop less body fat than conventionally raised mice (and

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conventionalised GF mice, i.e. mice colonised with the gut microbiota of conventionally raised mice), despite increased intake of food, in addition to having a decreased metabolic rate[32]. The presence of gut microbiota increases monosaccharide uptake, liver triglyceride content, leptin levels (proportional to the increase in body fat) and insulin resistance. GF mice are protected from diet-induced obesity (DIO) secondary to a high fat, sugar- rich western diet in contrast to mice conventionalised with microbiota[33]. GF mice conventionalised with microbiota from ob/ob mice had greater percentage increase in body fat over two weeks, than GF

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ACCEPTED MANUSCRIPT mice conventionalised with microbiota from lean mice[13]. There was no significiant difference in energy consumption, initial body fat/weight between different groups. Different diets affect fat gain in murine models, GF mice gained 68% more body fat on a high fat diet compared to a ‘western diet’ with higher sugar content. The

to diet induced obesity[34], in addition to genetic factors.

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differing dietary components determine the extent of protection conferred on GF mice

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The relationship between dietary energy harvest and microbiota was investigated in lean and obese patients placed on alternating experimental diets[35]. Within three

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days bacterial composition of the gut was altered by dietary calorie load. Over nutrition was associated with raised F/B ratio. Interestingly in lean subjects, phylum level changes in the faecal microbiota from weight maintaining pre diet, to either experimental diet, were significantlty associated with stool energy loss (positively

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associated with proportional increase in Bacteroidetes, the converse for Firmicutes). Nutrient absorption was increased by roughly 150kcal with a 20% increase in the proportional representation of Firmicutes, and nutrient absorption was decreased by

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similar level with 20% proportional increase in Bacteroidetes. However these findings

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of association between changes in gut microbial community structure and nutrient absorption were not observed in the obese cohort, suggesting that lean and obese may respond differently.

2. Short Chain Fatty Acids (SCFA)

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ACCEPTED MANUSCRIPT SCFA are produced by gut microbiota and play an integral role in communication between microbiota and host, in addition to being an energy source for host. The gut microbiota catabolizes dietary fibres not completely hydrolysed by host enzymes, in addition to utilizing polysaccharides as an energy source[36]. Overweight individuals

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have more faecal SCFA than lean individuals, with significantly elevated levels of

propionate[21]. Higher faecal SCFA in overweight individuals are not secondary to differences in diet or SCFA absorption[37]. SCFA, especially butyrate, have well

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known anti-proliferative effects against colon cancer. Propionate reduces cancer cell proliferation in the liver[38], however its role in the protection against colorectal

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cancer is not clear[39]. Further research is needed to elucidate the role SCFA play in the development of colorectal cancer in obese populations. Production of propionate is largely attributed to Bacteroidetes, and butyrate to Firmicutes. SCFAs influence intestinal barrier function through mucus production[40] and stimulation of tight

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junctions[41]. SCFAs are also key signaling molecules, they are endogenous ligands for the G protein couple receptors free fatty acid receptor 2 (FFAR2) and free fatty acid receptor 3 (FFAR3) expressed in intestinal mucosa, immune cells, liver and

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adipose tissue[42], in addition to being modulators of the epigenome through altering

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histone acetylation. FFAR2 and FFAR3 activation results in the production and release of the gut hormones Glucagon-like peptide-1 and Peptide YY, which stimulate satiety[43]. SCFAs produced by the gut microbiota, are involved in the recognition of post-prandial nutrient excess and utilization of energy expenditure to maintain energy homeostasis[44]. FFAR2 is activated by SCFAs to regulate energy uptake in white adipose tissue, subsequently influencing energy expenditure in systemic tissues including muscle and liver. SCFAs activate the sympathetic nervous system via FFAR3 at ganglionic level, regulating energy expenditure[45]. Acetate, butyrate and

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ACCEPTED MANUSCRIPT propionate protect against DIO; butyrate and propionate induce gut hormones and reduce food intake[46]. The ability to influence satiety and modulate low grade inflammation suggest that SCFA may link diet, obesity and related disorders and gut

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3. Microbiota-associated Inflammation

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microbiota[47].

Microbiota-driven inflammation exacerbates metabolic and end organ complications

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of obesity, and obesity per se is an inflammatory state. In health, the intestinal epithelium is integral to mucosal homeostasis and barrier function, permeable to nutrients and essential macromolecules but a restraint on translocation of toxic macromolecules, bacteria, and luminal antigens, including lipopolycacharride (LPS).

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LPS is a pro-inflammatory component of the cell wall of gram-negative bacteria. Systemic levels of LPS levels are elevated in obesity. Obesity is linked with increased intestinal permeability in both animal and human studies. Other events that promote

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increased translocation with subsequent elevation of LPS are alcohol

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consumption[48], radiation[49] and stress[50]. Metabolic endotoxemia (increased levels of LPS) has been documented in the development of obesity and related disease states[51].

Increased energy intake especially from a high fat diet increases LPS and gut permeability. Modulation of gut microbiota of mice fed a high fat diet increases intestinal permeability and reduced expression of genes encoding for proteins of the tight junctions (occludin and ZO-1[52]). Bifidobacteria, which have been shown to

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ACCEPTED MANUSCRIPT reduce LPS levels and improve mucosal barrier function, attenuates the impact of high fat diet induced endotoxaemia and inflammatory tone[53]. Intestinal alkaline phosphatase (IAP) is regulated by the gut microbiota[54] and involved in LPS detoxification. Decreased activity of IAP is associated with obesity[55] and increased

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activity is associated with reduced metabolic endotoxemia[56]. Other immune

pathways involved in mediating inflammatory response involved in microbe induced obesity and related metabolic diseases include Toll-like Receptor 5[57],

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lymphotoxin[58] and inflammasomes[59] in addition to the endocannabinoid system

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(eCB).

4. The Endocannabinoid System

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The endocannabionoid (eCB) system refers to endocannabinoids (bioactive lipids, namely N-arachidonoylethanolamine (AEA) or anandamide, and 2-AG or 2arachidonoylglycerol) and the proteins that regulate their production and degradation,

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in addition to the receptors through which they signal. Endocannabinoids are

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synthesized locally in the gastrointestinal tract. The main endocannabinoid receptors, CB1 and CB2, are G-coupled receptors that present a distinct expression pattern[60], endocannabinoids also affect other receptors through modulation and activation. CB1 is expressed by the liver, pancreas, adipose tissue in addition to the peripheral and central nervous systems[61]. CB2 is mainly expressed by immune cells, being found in the brain, pancreas and adipose tissue[62]. The eCB regulates diverse physiological processes including gut motility[63] and appetite[64]. The eCB plays a major role in energy homeostasis through the regulation of appetite and metabolism via the

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ACCEPTED MANUSCRIPT microbiota-gut-brain axis, reviewed previously[65]. Obesity is associated with increased eCB tone[66]; altered expression of the cannabinoid receptor 1 (CB1), and increased eCB levels in plasma and adipose tissues. Studies of receptor gene-deficient mice[67] and using pharmacological blockade of receptors[68] provides evidence of

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the role upregulated eCB signaling plays in the development of obesity. Inverse CB1 receptor agonists Rimonabant and Taranabant induce significant weight loss in obese individuals. Unfortunately they are associated with psychiatric side-effects including

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depression, which has resulted in their withdrawal from the market[69,70].

It is hypothesised that the eCB is a mediator involved in communication between the gut microbiota and adipose tissue. It has been shown using multiple mice models that the gut microbiota regulates the activity of the peripheral eCB system in intestinal and

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adipose tissue, which in turn controls gut barrier function and adipogenesis[71]. Studying obese mice (ob/ob), those fed oligofructose prebiotics (resulting in selective increase of bifidobacteria) had decreases in colonic CB1 mRNA expression and AEA

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(endogenous CB1 ligand) levels, and increases in fatty acid amide hydrolase (FAAH;

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the main enzyme in degradation of AEA) mRNA expression. These markers were not affected in the jejenum however, suggesting that colonic CB1 receptors may be selectively modulated by the gut microbiota. The mice fed prebiotics had reduced plasma LPS levels correlating with reductions in both AEA levels and CB1 mRNA expression.

5. Bile acid dysmetabolism and obesity

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ACCEPTED MANUSCRIPT Bile Acids (BAs) are well known to play a key role in the emulsification of fats, regulation of cholesterol metabolism and release of fat-soluble vitamins in the intestine[72]. More recently, BAs have been shown to be key pleiotropic signaling mediators in inflammation[73], intestinal barrier function and metabolism, with

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ability to differentially activate BA receptors, including Vitamin D receptor (VDR),

Farnesoid X receptor (FXR), Pregnane X receptor (PXR) and the G-coupled protein

receptor TGR5[74]. These receptors are not just expressed locally in the intestine but

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systemically[75], including adipose tissue, and can act as systemic signaling

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molecules[76]. This systemic signaling can alter host gene expression[77].

The gut microbiota transforms BAs, initially mediated by the enzyme Bile Salt Hydrolase (BSH), resulting in the deconjugation of conjugated BAs[78]. Analysis of the bile metabolic capacity of the normal human gut microbiota indicates a

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widespread ability to metabolise BAs by individual members of the gut microbiota[79]. Further bacterial transformations also occur in the gastrointestinal tract include dehydrogenation, dehydroxylation and desulfication, producing a variety

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of secondary and tertiary BAs[78]. Therefore the gut microbiota plays a key role in

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determining BA composition and subsequent effects on host metabolism. Germ-free rodents have limited BA receptor activation[77].

A study of GF mice colonosed with microbiota from twins that were discordant for obesity, suggests that differences in body composition correlate with differences in BA profiles and metabolism[80]. Obese mice housed in isolation had reduced levels of caecal BA compared to lean mice. These obese mice also had increased FXR and fibroblast growth factor 15 (Fgf15) mRNA levels in their ileum and decreased hepatic

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ACCEPTED MANUSCRIPT cholesterol 7-a-hydroxylase (the rate limiting enzyme in BA biosynthesis)[80]. Interestingly co-housing obese and lean mice together ameliorated these changes. FXR activity does not rely on total BA concentrations, rather on individual BA levels[77]. Germ-free and antibiotic treated[81] rodent models show increased ileal

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BAs and significantly reduced BA diversity secondary to reduced metabolism of BA by the gut microbiota. The increase in ileal BAs is associated with a reduction in FXR signaling in these models. Unconjugated BAs were decreased in antibiotic treated

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mice, suggesting that unconjugated BA rather than their conjugates contribute to ileal

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FXR signaling in mice[75].

Antibiotics have been shown to significantly affect human physiology by altering the gut microbiota and BA metabolism. Obese volunteers treated with a week’s course of oral vancomycin had decreased peripheral insulin sensitivity and bile acid dehydoxylation, with marked changes in gut microbiota (amoxicillin treatment did not

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affect these parameters)[82]. Vancomycin treatment resulted in a decrease in the number of gram-positive bacteria, with specific groups affected belonging to the

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Clostridium cluster IV and XIVa, Lactobacillus plantarum and various butyrate producing species including Faecalibacterium prausnitzii. The gut microbiota, in

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particular the Firmicutes contribute to BA metabolism and subsequently glucose metabolism in humans. Gram-negative intestinal bacteria have no capacity to deconjugate BAs, except two strains of Bacteroides[72]. In contrast gram-positive bacteria (targeted by vancomycin) have capacity to transform BAs into secondary BAs via deconjuagtion, oxidization and hydroxylation[83]. The gut microbiota in turn can be influenced by concentrations of particular BAs[84], thus BA are a further mechanism of bidirectional communication and feedback between the gut microbiota and host. 12

ACCEPTED MANUSCRIPT 6. Microbiota-gut-brain axis

The brain-gut axis is the complex bi-directional communication system linking the central nervous system (CNS) and the GI tract. This complex network of

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communication between the GI tract and brain encompasses the CNS, the gut

microbiota, the parasympathetic and sympathetic branches of the autonomic nervous system, the enteric nervous system, as well as the neuroimmune and neuroendocrine

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systems[85]. The microbiota-brain-gut axis communicates via humoral signaling

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molecules, hormonal components in addition to neuronal routes.

Afferent neuronal fibres of the ventral and dorsal vagal trunks in the abdomen are involved in regulating satiety and appetite. Efferent vagal fibres are involved in control of motor and secretory functions of the gastrointestinal tract involved in

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digestion and absorption. Disruption of the vagus nerve through vagotomy or electrical nerve stimulation to inhibit function led to decreased intake of food and early satiety and weight loss[86]. Microbial metabolites participate in the microbiota-

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gut-brain axis, affecting host metabolism. SCFAs (propionate and butyrate) generated

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by fermentation of soluble dietary fibre by the gut microbiota activate intestinal gluconeogenesis (IGN), by complementary mechanisms. Butyrate directly activates IGN gene expression in enterocytes, via an increase in cAMP. Propionate acts as a FFAR3 agonist in the periportal afferent neural system, inducing IGN via the microbiota-gut-brain axis[87]. IGN produced glucose is detected by a portal vein glucose sensor, which communicates to the brain by the peripheral nervous system to promote beneficial effects on food intake and glucose metabolism[88].

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ACCEPTED MANUSCRIPT 7. Interventions

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7.1.Bariatric Surgery

Bariatric surgery is the most effective treatment at present for morbidly obese

patients. it is estimated that less than 1% of obese individuals who meet criteria, will

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undergo procedure[89]. A recent review[90] discusses advances and challenges in the

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management of obesity that is beyond the remit of our review.

The beneficial effects of bariatric surgery on glucose homeostasis, energy expenditure, enhanced satiation and satiety, are not fully explained by restriction of food reservoir and malabsorption. Changes in hormone levels and microbiota profile

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also occur. Certain operations such as the Roux-en-Y gastric bypass (RYGB) have been shown to cause alterations in gut microbiota profiles, potentially contributing to some of the favourable effects of these operations. Zhang et al., initially reported

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changes post RYGB[22]. They found a large increase in Gammaproteobacteria, a

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proportional decrease in Firmicutes and a loss of methanogens. More recently a French study investigated changes in gut microbiota and gene expression in white adipose tissue in 30 women post RYGB[91]. They also observed augmentation in Proteobacteria and a decrease in Firmicutes, in addition to increased richness of the gut microbiota post RYGB. The role of microbiota in RYGB induced weight loss was shown in an experiment in which GF mice receiving transfer of microbiota from RGYB treated mice had significant weight loss and decreased fat mass, compared to GF mice receiving microbiota from mice undergoing a sham-operation[92].

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7.2.Antibiotics

Vancomycin has been shown to alter BA and microbiota profiles, subsequently

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reducing peripheral insulin sensitivity in males with metabolic syndrome[82].

However vancomycin-induced alterations of microbiota (significant reductions in the proportions of Firmicutes and Bacteroidetes and a dramatic increase in

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Proteobacteria) in mice resulted in reduced weight gain and improved fasting glucose, plasma TNF-alpha and triglyceride levels [93]. The discrepancies between these

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studies reinforce the need for further research investigating the effects of different antibiotics at varying strengths and length of administration, in diverse populations. Modulation of the microbiota-gut-brain axis with antibiotics is utilised in treatment of hepatic encephalopathy[94], the potential for further manipulation of this axis in the

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7.3.Prebiotics

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prevention and treatment of obesity is intriguing.

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Administration of the prebiotic oligofructose to ob/ob mice and high fat dietary induced obesity (HF DIO) mice restored Akkermansia muciniphilia abundance, in addition to improving gut barrier function and a reduction in body weight and total fat mass significantly[95]. Oligofructose administered to DIO rats, reduced fat mass and weight gain, with a marked increase in bifidobacteria and lactobacilli[96]. Oligofructose supplementation can help promote weight loss in overweight and obese humans[97]. Treatment of HF DIO mice with Flos Lonicera, a traditional herbal medicine, resulted in a decrease in body mass and abdominal adipose tissue weight.

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ACCEPTED MANUSCRIPT These changes were also accompanied by an increase in A. muciniphila, Bacteroidetes and a decrease in the F/B ratio[98].

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7.4.Probiotics

Altering the microbiota of obese individuals with beneficial micro-organisms or

probiotics is an attractive concept in combating obesity and related disorders. It is

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important to understand probiotics effects vary widely depending on the strain

administered, i.e. not all probiotics are the same. Diet induced obesity mice treated

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with L. curvatus HY7601 and L. plantarum KY1032 showed reduced weight gain and down regulation of pro-inflammatory genes in adipose tissue[99]. B. infantis 35624 has been shown to modulate extra-intestinal host inflammatory processes in diverse patient groups[100]. Lactobacillus gasseri administration has been associated with

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reduction in BMI, with continuous consumption required to maintain beneficial effects[101], using this as an example we can see the potential benefits of probiotics

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in obesity prevention.

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7.5.Bile acid derivatives

A recent phase II trial of Obeticholic acid (OCA) administered for 6 weeks, in patients with diabetes and Non Alcoholic Fatty Liver Disease (NAFLD), resulted in a small but meaningful decrease in body weight in addition to improved insulin sensitivity[102]. OCA is a natural agonist of FXR, which has been shown to preserve the integrity of epithelial barrier function[103]. Another proposed mechanism of OCA

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ACCEPTED MANUSCRIPT is that it can modulate gut microbiota, though enhanced expression of cathelicidin, a natural antibiotic.

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7.6.Faecal Microbiota Transplant (FMT)

Gut microbiota play an active role in energy homeostasis as gut microbiota transplant studies have demonstrated. The recipient of microbiota in obese to lean, and lean to

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obese transfer takes on some of the metabolic features of the donor. Germ-free mice are resistant to diet-induced obesity, transplantation of microbiota from obese mice

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can confer the metabolic phenotype to germ-free mice[13]. Patients with metabolic syndrome had increased insulin sensitivity six weeks after infusion of microbiota from lean donors[104].

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Summary

The gut microbiota is involved in the development of obesity through energy harvest,

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communication with both inflammatory and metabolic cascades via microbial

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metabolites and by interaction with the brain-gut axis, (figure 2). Understanding of these complex interactions is expanding rapidly.

Combatting obesity will require changes at individual and societal levels. Regression in life expectancy in the 21st century is predicted if the rate of obesity continues uncontrolled[105]. Current treatments available for obesity include intensive lifestyle and dietary modifications, pharmacolological and surgical interventions. Unfortunately lifestyle modifications and pharmacological strategies are generally

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ACCEPTED MANUSCRIPT associated with modest and poorly sustained weight loss (3kg) [106]. Alternative approaches to the treatment and prevention of obesity and related disorders are required. Therapeutic manipulation of the gut microbiota promises much, but will require further understanding of microbiota. Therapeutic manipulation of the

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microbiota has been successful in other settings such as H. pylori eradication in the management of peptic ulcer disease and associated gastric lymphoma, and faecal transplantation to treat recurrent C. difficile infection. However microbial

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manipulation for obesity-related disorders should complement rather than be a

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substitute for addressing lifestyle factors at individual and societal levels.

Practice Points •

Obesity develops from an imbalance between energy intake and expenditure,

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but this is dependent upon complex interactions between the gut microbiota and inflammatory and metabolic cascades in the host. •

Rapid increase in obesity rates in recent decades can be predicted as

Current interventions for morbid obesity are generally poorly effective.

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•

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developing countries undergo socio-economic development.

Research agenda •

Detailed studies to define the causality of microbiota composition and function in obesity pathogenesis.

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To modulate the microbiota-gut-brain axis in the prevention and treatment of obesity.

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Place table 1 before references

Conflict of interest and acknowledgements: Carthage Moran: None

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Fergus Shanahan’s research is supported by Science Foundation Ireland and he has

received research grants from GlaxoSmithKline and Alimentary Health Ltd, none of

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which constrained nor influenced the content of this article.

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Figure captions: Fig. 1. Mechanisms involved in the pathogenesis of obesity include altered gut microbiota, increased gut permeability and LPS levels leading to low grade inflammation, in addition to chronic energy excess.

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Fig. 2. Factors which influence gut microbiota include diet, medications, lifestyle habits such as exercise. Higher function is affected by the microbiota---gut---brain axis. The gut microbiota interacts with metabolic and immune---inflammatory cascades.

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Table 1. Obesity and the microbiota – levels of evidence

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Observation

Comment

Ref

Microbiota important in

GF mice develop less fat despite increased intake and decreased metabolic rate.

energy harvest and obesity

GF mice resistant to obesity from high fat, sugar rich diet.

development

Association between changes in gut microbial community structure and nutrient absorption observed in lean

33,34

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cohort but not obese.

Microbiota transplant studies GF mice conventionalised with microbiota from ob/ob mice had greater percentage increase in body fat than GF mice conventionalised with microbiota from lean mice.

phenotypes

Improved insulin sensitivity in humans with metabolic syndrome post transplant from lean donor.

Human Twin studies reveal

Reduced biodiversity in obesity

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reveal transferrable

compositional and

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Transmissable donor phenotypes of twins discordant for obesity. Changes in body composition correlated with

microbiota in twins

differences in SCFA fermantation and bile acid metabolism.

13

104 19

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functional differences in

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discordant for obesity

GF mice receiving microbiota transplant from post RYGB donors had more weight loss than those receiving

an potential avenue for

transplants from sham donors

obesity treatment

Vancomycin induced reduction in weight gain and improved metabolic markers in mice

93

Vancomycin treatment in humans decreased microbial diversity, bile acid dehydrozylation and peripheral

82

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Modulation of microbiota is

insulin sensitivity

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