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Gut-central nervous system axis is a target for nutritional therapies
© Pimentel et al; licensee BioMed Central Ltd. 2012
Received: 19 August 2011
Accepted: 10 April 2012
Published: 10 April 2012
Historically, in the 1950s, the chemist Linus Pauling established a relationship between decreased longevity and obesity. At this time, with the advent of studies involving the mechanisms that modulate appetite control, some researchers observed that the hypothalamus is the "appetite centre" and that peripheral tissues have important roles in the modulation of gut inflammatory processes and levels of hormones that control food intake. Likewise, the advances of physiological and molecular mechanisms for patients with obesity, type 2 diabetes mellitus, inflammatory bowel diseases, bariatric surgery and anorexia-associated diseases has been greatly appreciated by nutritionists. Therefore, this review highlights the relationship between the gut-central nervous system axis and targets for nutritional therapies.
KeywordsGut Central nervous system Nutrition Diet Appetite Inflammatory disease
The energy balance is determined by the relationship between the acquisition and expenditure of energy. This perfect interaction occurs among physiological signals in peripheral organs and the central nervous system (CNS). Apart from the obvious digestive and absorptive functions of the gastrointestinal tract, gut and adipose tissue hormones play an important role in controlling the energy balance, particularly via the regulation of food intake in both the short- and long-term, respectively. Therefore, the enteric nervous system (ENS), gut hormones, and nutrients act in the control process at the beginning and termination of meals [1, 2].
The CNS-gut axis is controlled by the ENS and its importance in the health and disease has been recognised by several studies [3, 4]. According to health professionals, advances in the physiological and molecular mechanisms involving the ENS are responsible for the control of the energy balance, and for the nutritional therapies used in patients with obesity, type 2 diabetes mellitus, inflammatory bowel diseases (IBDs), bariatric surgery and cancer-associated anorexia [5–9].
In the 1950s, the chemist Linus Pauling established a relationship between decreased longevity and obesity . At this time, with the advent of studies involving the mechanisms that modulate appetite control, it was recognised that the hypothalamus is the "appetite centre". In rats, some researchers observed that lesions in the lateral hypothalamus produced anorexia (hunger centre) and lesions in the ventromedial nuclei of the hypothalamus produced obesity (satiety centre) [11–14].
More recently, the discovery of cloned leptin in 1994, which is produced and secreted by adipose tissue, provided some evidence that appetite control could also be modulated by peripheral tissues .
Summary of the main gut hormones that influence the energy homeostasis
Gut hormones (receptor)
PYY (G protein-coupled receptors)
L cells of gut
↓ food intake and delays gastric emptying
L cells of gut
↓ food intake, releases insulin, hand out as incretin, ↓ glucose levels and delays gastric emptying
L cells of gut
↓ food intake
CCK (CCK1 and CCK2)
I cell of small intestine
↓ food intake
Uroguanylin and Guanylin (GUCY2CR)
Intestinal epithelial cells
↓ food intake
K cells of gut
↓ food intake and glucose levels
PP (Y4 and Y5)
PP cells of pancreas
↓ food intake
Amylin (AMY 1-3)
β cells of pancreas
↓ glucose levels
β cells of pancreas
↓ food intake and glucose levels
α cells of pancreas
↑ glucose levels and insulin secretion
↑ food intake
For nutrition professionals, the gut-CNS axis is considered an attractive opportunity, because foods may help to treat and prevent diseases. In this review, we discuss the fact that nutritional therapies could modify the gut flora and may reach the CNS in order to modulate the food intake and inflammatory processes. Some nutritional therapies that are known to modulate the gut-CNS axis via physiological and molecular mechanisms are also discussed.
The main underlying mechanisms behind the connection between microbiota and the central nervous system
The components that interact to form this complex brain-gut communication is bidirectional, with stimuli from gastrointestinal tract (GIT) that influences the brain functions and messages from the brain that may alter some GIT activities, such as motor, sensory and secretory . It was demonstrated that this link occurs via the vagus nerve to the brainstem, and via spinal afferents to the spinal cord . Recently, Bravo et al.  showed that vagotomized mice did not exhibit behavioral and neurochemical effects that L.rhamnosus exerts in CNS, evidencing the correlation of the vagus nerve in the direct communication between the bacteria and the brain.
Moreover, the serotonin (5-HT) levels and hypothalamic-pituitary-adrenal (HPA) axis may also participate in this connection. All connections are involved with modulation of infections and inflammatory diseases, such as obesity, type 2 diabetes mellitus, ulcerative colitis, Crohn's disease, as well as with behavioural problems and psychiatric disorders, such as cognition, mood, emotion, stress and anxiety [21, 22].
Diets and microbiota: A general overview
The microbes that reside in the gut favors the harvest of energy from food, influence the metabolic profiling of organs and exerts nutritional and protective effects on the intestinal epithelium and immune system [23–25]. Moreover, the microbiota consists mainly of bacteria that are divided in two main phylotypes: Bacteroidetes and Firmicutes [26, 27].
Supporting normal digestion and host metabolism, gut microbiota is able to expand nutrient availability, releasing energy through fermentation of otherwise non-digestible oligosaccharides or by modulating absorption. The short chain fatty acids (SCFA), which are the major metabolic products of anaerobic bacteria fermentation, are an important energy source for humans, being used by colonocytes, liver and muscle. It has been reported that 5 to 10% of human basal energy requirements are provided by SCFA [28–31].
Since the interactions of microbes with host leads to a complex balance of host genes, alteration of microbiota population can cause several metabolic disorders.
Obesity and type 2 diabetes mellitus
Since it is known that the microbiota is related to energy homeostasis, digestion of nutrients and metabolism, some low-grade inflammation-related diseases have emerged as an attractive opportunity for researchers.
Cani et al.  proposed that both obesity and type 2 diabetes mellitus can be characterised by increased lipopolysaccharide (LPS) levels. For instance, in the presence of diet induced obesity (DIO), the LPS concentrations are higher than in the fasting state. In addition, either DIO animals or those submitted to subcutaneous injections of LPS represent enhanced LPS-containing microbiota, as well as glucose and body weight gain. Likewise, these authors were the first to demonstrate that "metabolic endotoxaemia" initiates obesity .
Recently, it has been shown that food rich in saturated or trans-fatty acids stimulates inflammatory markers [9, 36–40]. Raybould  suggests that intestinal inflammation is associated with obesity due to high LPS levels. In 2011, it was shown that the ingestion of trans fatty acids during gestation and lactation led to an increase in blood LPS levels, the activation of inflammatory signalling in the hypothalamus and an increased food intake in adult offspring rats . Moreover, the same studies [27, 42] observed the presence of intestinal inflammation in different models of obesity, such as eating a high-fat diet, rich in saturated fatty acids and genetic obesity.
When evaluating inflammatory markers in CONV mice fed with a high-fat diet, Ding et al.  observed increased body weights and activation of gut TNF-α mRNA expression. Likewise, Caricilli et al.  showed increased blood LPS levels in toll-like receptor 2 (TLR2)-deficient mice when compared to wild-type mice. TLR2 deficient mice showed activated phosphorylation of janus kinase (JNK), TLR4 and phosphorylation in serine of the insulin receptor substrate-1 of several tissues . In this work, the authors suggest that an increase in LPS levels together with TLR4, in the absence of changes of TLR2, result in a compensatory action that may lead to increased activation of TLR4. Together, this would contribute to insulin resistance in TLR2-deficient mice . Likewise, in a previous study  performed with adult offspring rats from mothers fed trans fatty acids during gestation and lactation, increased blood LPS levels and hypothalamic TLR4 expression were seen with no change to hypothalamic TLR2 expression. Moreover, the increase of blood LPS provoked by a high-fat diet has also been shown by other recent studies [44, 45]. It has also been shown that the actions of fatty acids are aggravated by physiological ligands of G-protein-coupled receptors, such as GPR40, 41, 43, 84 and 119, and, therefore, it may be involved in the progression of several inflammatory diseases .
Another TLR described to influence microbiota is TLR5. Vijay-Kumar et al.  demonstrated that mice deficient in TLR5 exhibit obesity, hyperphagia, dyslipidaemia, hypertension and insulin resistance, and that they also show an altered composition of gut microbiota, such as increased Firmicutes (54%) and lower Bacteroidetes (39.8%).
In addition to inflammatory processes, non-alcoholic fatty liver disease (NAFLD) is a typical hepatic manifestation that has been found to be obesity-related. Recently, inflammasome-deficient mice were shown to have modifications of gut microbes population through the influx of TLR4 and TLR9 agonists into the portal circulation. Therefore, increased hepatic inflammation levels can lead to the development of NAFLD and obesity .
An important study that demonstrated the relationship between intestinal bacterial and obesity in humans was published by Wu et al. in 2011 . In this study, it was found that an increased fat intake and low dietary fibre are associated with the modulation of intestinal microbiota. The authors of this study showed that animal proteins and saturated fatty acids are associated with increased Bacteroidetes levels, and that diets containing carbohydrates but lacking meat and dairy products increased Prevotella levels. Together, these facts create a profile of weight gain and gut inflammation-related bacteria.
DIO experimental models also indicate low expression of tight junction proteins in the gut, and the increasing in intestinal permeability . Brun et al.  found in either ob/ob and db/db mice, an alteration in the intestinal permeability same when mice were submitted to standard chow consumption. In rats fed with hyper-lipidic diet also was observed an increase of intestinal permeability through the reduction of tight junction proteins, such as claudin 1, claudin 3 and junctional adhesion molecule-1 .
Collectively, several obesity models have observed that a major determinant of intestinal permeability is the intercellular tight junction proteins. Tight junctions are organised by the same transmembrane proteins, such as occludin, claudin and junctional adhesion molecule-1 [52–54]. Therefore, these transmembrane proteins interact with Zonula Occludens (ZO-1-3), which anchors the transmembrane proteins  provoking an increase of intestinal permeability. The increased intestinal permeability is thought to be associated with a higher activity of pathogenic bacteria and inflammatory processes. In summary, some studies have described that the main tight junction proteins responsible for this intestinal permeability are ZO-1, myosin light chain, occludin, claudin and junctional adhesion molecule 1 [44, 50, 52–54, 56, 57].
Several papers suggest that saturated fatty acids might enhance the blood LPS levels through GPRs, possibly secreted by gut cells, may affect the CNS and alter numerous central inflammatory markers. In addition, the increased intestinal permeability aggravated by a high-fat diet and LPS may also be responsible for altered epithelial barrier function, and it is therefore possible that the high prevalence of obesity and type 2 diabetes mellitus is connected with an altered gut microbiota-CNS axis.
In the middle of the 1950s, Kremen et al.  postulated that bypass surgery in dogs reduced food absorption. Recently, in humans, bariatric surgery has been found to be a procedure which results in patients rapidly losing weight, accompanied by the resolution of type 2 diabetes mellitus and a reduction of cardiovascular deaths [45, 59]. However, the mechanisms underlying the improvement of metabolic parameters have not been fully elucidated. Likewise, Evans et al.  have shown that obese patients had an increase of blood PYY levels and GLP-1 was restored to normality after gastric bypass surgery compared to patients with normal weights. Short-term Rouxen-Y gastric bypass (six months) was able to activate PYY and GLP-1 secretion, and stimulated the satiety in response to a liquid-meal intake in normal, glucose-tolerant obese patients . Falkén et al.  reported that patients had a progressive rise of the GLP-1 and OXM concentrations after gastric bypass and that this procedure favours weight loss and improved insulin sensitivity.
Inflammatory bowel diseases (IBDs)
The IBDs, that affect the health of humans, include ulcerative colitis, Crohn's disease and irritable bowel syndrome (IBS) [64–66]. Macfarlane et al.  have suggested that the appearance of these diseases may be due to modified gut microbiota, or as a consequence of local inflammation. However, a recent study has shown that the intestinal wall of either inflamed or non-inflamed guts  may be associated with severe disease. Likewise, human studies of patients diagnosed with IBDs have observed increased TLR2, TLR4 and TLR5 expression in the gut wall [69, 70], and other studies have reported an increase of the IL-6, IL-8, TNF-α and interferon-gamma levels [71–73]. Therefore, it is possible to observe that in IBDs that have an inflammatory status higher than that of obesity, more severe disease symptoms are seen. In order to investigate the effects of neuro-inflammation in animals submitted to experimental IBD, Wang K, et al.  observed increased IL-6 mRNA expression in both the colon and brain of these animals when compared to control animals.
Collectively, it can be speculated that higher levels of gut-related inflammation lead to a reduction of food intake and malnutrition due to the activation of cytokines in the CNS. According to Pavlov & Tracey , the autonomic nervous system plays a key role in the control of the brain in moderating the immune system and inflammation.
In summary, several studies have reported that inflammatory bowel problems are linked to a reduction of Lactobacillus spp and Bacteroidetes, and an increase of the Firmicutes-Bacteroidetes ratio [76–79]. These changes in intestinal flora are aggravated through alterations in the immune system that underlie disease pathogenesis.
Nutritional therapies that improve metabolic diseases through the gut-CNS axis
While microbes have been used to study the underlying mechanisms of inflammatory diseases and insulin resistance, numerous researchers have also stated that nutritional components could be used as a strategy to combat the gravity of these abnormalities. Historically, the Greek physician Hippocrates, "The father of medicine", reportedly said "Let your food be your medicine, and your medicine be your food".
Among the nutritional components that support a healthy intestinal microbiota, we highlight the dietary fibres, probiotics and prebiotics [80–84]. The improvements include a reduction of systemic and local inflammation, as well as less intestinal pain and discomfort, when both probiotics and prebiotics are used [80, 85, 86]. In addition, other studies have shown an inhibition of bacterial translocation and a reduction of intestinal permeability with the use of these nutrients [87, 88].
One study demonstrated that the use of oligofructose, a prebiotic, enhanced the levels of Bifidobacterium spp., and improved insulin sensitivity, as well as restoring inflammatory status through decreased endotoxaemia metabolism .
Oligofructose and resistant starches have been demonstrated to increase short-chain fatty acid-induced GLP-1 expression , and to reduce ghrelin expression . Moreover, in a recent review the nutrients and diets that stimulate the anorexigenic gut peptides, reduce the food intake and break off the obesity were summarised. The main nutrients and diets that can increase the GLP-1, CCK, GIP, OXM and PYY secretion are dietary fibre, dairy products, unsaturated fatty acids and a normal calorie diet .
Recently, it was observed that a prebiotic-enriched diet reduced Firmicutes and increased Bacteroidetes levels, as well as improving glucose sensitivity, body fat, inflammation and oxidative stress . Furthermore, a recent review suggested that SCFA providers provided of dietary fibers, such as propionate and butyrate, induce the reduction of food intake by increasing leptin secretion and reducing pro-inflammatory cytokine expression . These dietary fibres are fermented by microbiota, and higher butyric acid levels were found in animals fed with diets containing a mixture of oligofructose and raffinose .
Necrotising pancreatitis patients with diarrhoea received semi-elemental nutrients via jejunal feeding, and an increase in faecal short-chain fatty acids, such as acetate, propionate and butyrate were found when compared to pre-treatment levels. In addition, a resolution of diarrhoea episodes was seen in approximately 66% of patients. Therefore, this study suggests that dietary fibre supplementation is an excellent method for the improvement of healthy intestinal microbiota, and results in reduced symptoms of dysbiosis .
Concomitant to numerous "healthy" nutrients, it is possible that unsaturated fatty acids, such as omega-3, are an attractive option for the improvement of inflammatory processes, and that this can be modulated by the physiological ligand of these fatty acids, GPR120 [94, 95].
In relation to high-grade inflammatory diseases, such as a provoked by Human Immunodeficiency Virus type1 (HIV-1), patients were shown to have infections in lymphoid tissue, alterations of intestinal microbiota and impaired symptoms of Acquired Immunodeficiency Syndrome (AIDS). Therefore, the use of probiotic diets is suggested for the prevention of progression of HIV-linked infections .
It has been recognised that obese, insulin-resistant and IBD subjects represent a group requiring moderation of intestinal microbiota due to a higher risk of the development of cancer. This is because the mechanisms by which intestinal bacteria induce carcinogenesis are thought to be via chronic inflammation, immune system evasion and immunosuppression. Conversely, the probiotics used have also emerged as an possible mechanism for the reduction of the pro-inflammatory status seen in cancer patients .
Although nutritional compounds are important for the improvement of health, changes to diets, such as an increase of either fruit or vegetable consumption, as well as a reduction of refined carbohydrates and saturated and trans-fatty acids [98, 99], are required, as food restriction can prevent obesity in humans [98, 99] and mice deficient in the TLR5 . Furthermore, micronutrients and macronutrients from existing diets are targets for gut health and strengthening of the immune system .
In summary, the discoveries in understanding these foods and nutrients could help to regulate the gut-CNS axis, but remain a challenge for nutritionists and scientific investigators. Therefore, future research must be focused on looking to improve the effectiveness of diets for the prevention of inflammation between the gut-CNS axis, as well as for the maintenance of microbial homeostasis of the gut.
This work was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP), Brazil and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Brazil.
- Pimentel GD MJ, Mota JF, Oyama LM: Oxintomodulina e obesidade. Rev Nutr. 2009, 22: 727-737. 10.1590/S1415-52732009000500013.View ArticleGoogle Scholar
- Pimentel GD, Zemdegs JC: [Foods and nutrients modulates the release of anorexigenic gastrointestinal hormones]. Acta Med Port. 2010, 23: 891-900.PubMedGoogle Scholar
- Mayer EA: Gut feelings: the emerging biology of gut-brain communication. Nat Rev Neurosci. 2011, 12: 453-466.View ArticlePubMedGoogle Scholar
- Washington MC, Raboin SJ, Thompson W, Larsen CJ, Sayegh AI: Exenatide reduces food intake and activates the enteric nervous system of the gastrointestinal tract and the dorsal vagal complex of the hindbrain in the rat by a GLP-1 receptor. Brain Res. 2010, 1344: 124-133.View ArticlePubMedGoogle Scholar
- Inui A, Asakawa A, Bowers CY, Mantovani G, Laviano A, Meguid MM, Fujimiya M: Ghrelin, appetite, and gastric motility: the emerging role of the stomach as an endocrine organ. FASEB J. 2004, 18: 439-456. 10.1096/fj.03-0641rev.View ArticlePubMedGoogle Scholar
- Hobson KG, Havel PJ, McMurtry AL, Lawless MB, Palmieri TL, Greenhalgh DD: Circulating leptin and cortisol after burn injury: loss of diurnal pattern. J Burn Care Rehabil. 2004, 25: 491-499. 10.1097/01.BCR.0000144532.02792.6E.View ArticlePubMedGoogle Scholar
- Laviano A, Meguid MM, Rossi-Fanelli F: Improving food intake in anorectic cancer patients. Curr Opin Clin Nutr Metab Care. 2003, 6: 421-426.PubMedGoogle Scholar
- Thaler JP, Choi SJ, Schwartz MW, Wisse BE: Hypothalamic inflammation and energy homeostasis: resolving the paradox. Front Neuroendocrinol. 2010, 31: 79-84. 10.1016/j.yfrne.2009.10.002.View ArticlePubMedGoogle Scholar
- Pimentel GD, Lira FS, Rosa JC, Oliveira JL, Losinskas-Hachul AC, Souza GI, das Gracas TdCM, Santos RV, de Mello MT, Tufik S, et al: Intake of trans fatty acids during gestation and lactation leads to hypothalamic inflammation via TLR4/NFkappaBp65 signaling in adult offspring. J Nutr Biochem. 2012, 23: 265-271. 10.1016/j.jnutbio.2010.12.003.View ArticlePubMedGoogle Scholar
- Pauling L: The Relation between Longevity and Obesity in Human Beings. Proc Natl Acad Sci USA. 1958, 44: 619-622. 10.1073/pnas.44.6.619.View ArticlePubMedPubMed CentralGoogle Scholar
- Hetherington AW RS: Hypothalamic lesions and adiposity in the rat. Anat Rec. 1940, 78: 149-172. 10.1002/ar.1090780203.View ArticleGoogle Scholar
- Anand BK, Brobeck JR: Hypothalamic control of food intake in rats and cats. Yale J Biol Med. 1951, 24: 123-140.PubMedPubMed CentralGoogle Scholar
- Teitelbaum P, Stellar E: Recovery from the failure to eat produced by hypothalamic lesions. Science. 1954, 120: 894-895. 10.1126/science.120.3126.894.View ArticlePubMedGoogle Scholar
- Miller NE: Experiments on motivation. Studies combining psychological, physiological, and pharmacological techniques. Science. 1957, 126: 1271-1278. 10.1126/science.126.3286.1271.View ArticlePubMedGoogle Scholar
- Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM: Positional cloning of the mouse obese gene and its human homologue. Nature. 1994, 372: 425-432. 10.1038/372425a0.View ArticlePubMedGoogle Scholar
- Leibowitz SF, Wortley KE: Hypothalamic control of energy balance: different peptides, different functions. Peptides. 2004, 25: 473-504. 10.1016/j.peptides.2004.02.006.View ArticlePubMedGoogle Scholar
- Schwartz MW, Woods SC, Porte D, Seeley RJ, Baskin DG: Central nervous system control of food intake. Nature. 2000, 404: 661-671.PubMedGoogle Scholar
- Valentino MA, Lin JE, Snook AE, Li P, Kim GW, Marszalowicz G, Magee MS, Hyslop T, Schulz S, Waldman SA: A uroguanylin-GUCY2C endocrine axis regulates feeding in mice. J Clin Invest. 2011, 121: 3578-3588. 10.1172/JCI57925.View ArticlePubMedPubMed CentralGoogle Scholar
- Cryan JF, O'Mahony SM: The microbiome-gut-brain axis: from bowel to behavior. Neurogastroenterol Motil. 2011, 23: 187-192. 10.1111/j.1365-2982.2010.01664.x.View ArticlePubMedGoogle Scholar
- Mayer EA: Gut feelings: the emerging biology of gut-brain communication. Nat Rev Neurosci. 2011, 12: 453-466.View ArticlePubMedGoogle Scholar
- Bravo JA, Forsythe P, Chew MV, Escaravage E, Savignac HM, Dinan TG, Bienenstock J, Cryan JF: Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. Proc Natl Acad Sci USA. 2011, 108: 16050-16055. 10.1073/pnas.1102999108.View ArticlePubMedPubMed CentralGoogle Scholar
- Grenham S, Clarke G, Cryan JF, Dinan TG: Brain-gut-microbe communication in health and disease. Front Physiol. 2011, 2: 94-View ArticlePubMedPubMed CentralGoogle Scholar
- Backhed F, Ley RE, Sonnenburg JL, Peterson DA, Gordon JI: Host-bacterial mutualism in the human intestine. Science. 2005, 307: 1915-1920. 10.1126/science.1104816.View ArticlePubMedGoogle Scholar
- Ley RE, Turnbaugh PJ, Klein S, Gordon JI: Microbial ecology: human gut microbes associated with obesity. Nature. 2006, 444: 1022-1023. 10.1038/4441022a.View ArticlePubMedGoogle Scholar
- Zhang H, DiBaise JK, Zuccolo A, Kudrna D, Braidotti M, Yu Y, Parameswaran P, Crowell MD, Wing R, Rittmann BE, Krajmalnik-Brown R: Human gut microbiota in obesity and after gastric bypass. Proc Natl Acad Sci USA. 2009, 106: 2365-2370. 10.1073/pnas.0812600106.View ArticlePubMedPubMed CentralGoogle Scholar
- Eckburg PB, Bik EM, Bernstein CN, Purdom E, Dethlefsen L, Sargent M, Gill SR, Nelson KE, Relman DA: Diversity of the human intestinal microbial flora. Science. 2005, 308: 1635-1638. 10.1126/science.1110591.View ArticlePubMedPubMed CentralGoogle Scholar
- Caricilli AM, Picardi PK, de Abreu LL, Ueno M, Prada PO, Ropelle ER, Hirabara SM, Castoldi A, Vieira P, Camara NO, et al: Gut microbiota is a key modulator of insulin resistance in TLR 2 knockout mice. PLoS Biol. 2011, 9: e1001212-10.1371/journal.pbio.1001212.View ArticlePubMedPubMed CentralGoogle Scholar
- Cummings JH, Pomare EW, Branch WJ, Naylor CP, Macfarlane GT: Short chain fatty acids in human large intestine, portal, hepatic and venous blood. Gut. 1987, 28: 1221-1227. 10.1136/gut.28.10.1221.View ArticlePubMedPubMed CentralGoogle Scholar
- McNeil NI: The contribution of the large intestine to energy supplies in man. Am J Clin Nutr. 1984, 39: 338-342.PubMedGoogle Scholar
- Zaibi MS, Stocker CJ, O'Dowd J, Davies A, Bellahcene M, Cawthorne MA, Brown AJ, Smith DM, Arch JR: Roles of GPR41 and GPR43 in leptin secretory responses of murine adipocytes to short chain fatty acids. FEBS Lett. 2010, 584: 2381-2386. 10.1016/j.febslet.2010.04.027.View ArticlePubMedGoogle Scholar
- Sekirov I, Russell SL, Antunes LC, Finlay BB: Gut microbiota in health and disease. Physiol Rev. 2010, 90: 859-904. 10.1152/physrev.00045.2009.View ArticlePubMedGoogle Scholar
- Forsythe P, Sudo N, Dinan T, Taylor VH, Bienenstock J: Mood and gut feelings. Brain Behav Immun. 2010, 24: 9-16. 10.1016/j.bbi.2009.05.058.View ArticlePubMedGoogle Scholar
- Ley RE, Backhed F, Turnbaugh P, Lozupone CA, Knight RD, Gordon JI: Obesity alters gut microbial ecology. Proc Natl Acad Sci USA. 2005, 102: 11070-11075. 10.1073/pnas.0504978102.View ArticlePubMedPubMed CentralGoogle Scholar
- Turnbaugh PJ, Ley RE, Mahowald MA, Magrini V, Mardis ER, Gordon JI: An obesity-associated gut microbiome with increased capacity for energy harvest. Nature. 2006, 444: 1027-1031. 10.1038/nature05414.View ArticlePubMedGoogle Scholar
- Cani PD, Amar J, Iglesias MA, Poggi M, Knauf C, Bastelica D, Neyrinck AM, Fava F, Tuohy KM, Chabo C, et al: Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes. 2007, 56: 1761-1772. 10.2337/db06-1491.View ArticlePubMedGoogle Scholar
- De Souza CT, Araujo EP, Bordin S, Ashimine R, Zollner RL, Boschero AC, Saad MJ, Velloso LA: Consumption of a fat-rich diet activates a proinflammatory response and induces insulin resistance in the hypothalamus. Endocrinology. 2005, 146: 4192-4199. 10.1210/en.2004-1520.View ArticlePubMedGoogle Scholar
- Zhang X, Zhang G, Zhang H, Karin M, Bai H, Cai D: Hypothalamic IKKbeta/NF-kappaB and ER stress link overnutrition to energy imbalance and obesity. Cell. 2008, 135: 61-73. 10.1016/j.cell.2008.07.043.View ArticlePubMedPubMed CentralGoogle Scholar
- Milanski M, Degasperi G, Coope A, Morari J, Denis R, Cintra DE, Tsukumo DM, Anhe G, Amaral ME, Takahashi HK, et al: Saturated fatty acids produce an inflammatory response predominantly through the activation of TLR4 signaling in hypothalamus: implications for the pathogenesis of obesity. J Neurosci. 2009, 29: 359-370.View ArticlePubMedGoogle Scholar
- Ropelle ER, Flores MB, Cintra DE, Rocha GZ, Pauli JR, Morari J, de Souza CT, Moraes JC, Prada PO, Guadagnini D, et al: IL-6 and IL-10 anti-inflammatory activity links exercise to hypothalamic insulin and leptin sensitivity through IKKbeta and ER stress inhibition. PLoS Biol. 2010, 8: e1000465-10.1371/journal.pbio.1000465.View ArticlePubMedPubMed CentralGoogle Scholar
- Duarte Pimentel G, Rosa JC, Santos de Lira F: Differences in diet between the 19th and 21st centuries: could they lead to insulin and leptin resistance and inflammation?. Endocrinol Nutr. 2011, 58: 252-254. 10.1016/j.endonu.2011.02.007.View ArticlePubMedGoogle Scholar
- Raybould HE: Gut microbiota, epithelial function and derangements in obesity. J Physiol. 2012, 590: 441-446.View ArticlePubMedGoogle Scholar
- Duparc T, Naslain D, Colom A, Muccioli GG, Massaly N, Delzenne NM, Valet P, Cani PD, Knauf C: Jejunum inflammation in obese and diabetic mice impairs enteric glucose detection and modifies nitric oxide release in the hypothalamus. Antioxid Redox Signal. 2011, 14: 415-423. 10.1089/ars.2010.3330.View ArticlePubMedGoogle Scholar
- Ding S, Chi MM, Scull BP, Rigby R, Schwerbrock NM, Magness S, Jobin C, Lund PK: High-fat diet: bacteria interactions promote intestinal inflammation which precedes and correlates with obesity and insulin resistance in mouse. PLoS One. 2010, 5: e12191-10.1371/journal.pone.0012191.View ArticlePubMedPubMed CentralGoogle Scholar
- de La Serre CB, Ellis CL, Lee J, Hartman AL, Rutledge JC, Raybould HE: Propensity to high-fat diet-induced obesity in rats is associated with changes in the gut microbiota and gut inflammation. Am J Physiol Gastrointest Liver Physiol. 2010, 299: G440-G448. 10.1152/ajpgi.00098.2010.View ArticlePubMedPubMed CentralGoogle Scholar
- Monte SV, Caruana JA, Ghanim H, Sia CL, Korzeniewski K, Schentag JJ, Dandona P: Reduction in endotoxemia, oxidative and inflammatory stress, and insulin resistance after Roux-en-Y gastric bypass surgery in patients with morbid obesity and type 2 diabetes mellitus. Surgery. 2012, 151: 587-593. 10.1016/j.surg.2011.09.038.View ArticlePubMedGoogle Scholar
- Vinolo MA, Hirabara SM, Curi R: G-protein-coupled receptors as fat sensors. Curr Opin Clin Nutr Metab Care. 2012, 15: 112-116. 10.1097/MCO.0b013e32834f4598.View ArticlePubMedGoogle Scholar
- Vijay-Kumar M, Aitken JD, Carvalho FA, Cullender TC, Mwangi S, Srinivasan S, Sitaraman SV, Knight R, Ley RE, Gewirtz AT: Metabolic syndrome and altered gut microbiota in mice lacking Toll-like receptor 5. Science. 2010, 328: 228-231. 10.1126/science.1179721.View ArticlePubMedPubMed CentralGoogle Scholar
- Henao-Mejia J, Elinav E, Jin C, Hao L, Mehal WZ, Strowig T, Thaiss CA, Kau AL, Eisenbarth SC, Jurczak MJ, et al: Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature. 2012, 482: 179-185.PubMedPubMed CentralGoogle Scholar
- Wu GD, Chen J, Hoffmann C, Bittinger K, Chen YY, Keilbaugh SA, Bewtra M, Knights D, Walters WA, Knight R, et al: Linking long-term dietary patterns with gut microbial enterotypes. Science. 2011, 334: 105-108. 10.1126/science.1208344.View ArticlePubMedPubMed CentralGoogle Scholar
- Brun P, Castagliuolo I, Di Leo V, Buda A, Pinzani M, Palu G, Martines D: Increased intestinal permeability in obese mice: new evidence in the pathogenesis of nonalcoholic steatohepatitis. Am J Physiol Gastrointest Liver Physiol. 2007, 292: G518-G525.View ArticlePubMedGoogle Scholar
- Suzuki T, Hara H: Dietary fat and bile juice, but not obesity, are responsible for the increase in small intestinal permeability induced through the suppression of tight junction protein expression in LETO and OLETF rats. Nutr Metab (Lond). 2010, 7: 19-10.1186/1743-7075-7-19.View ArticleGoogle Scholar
- Furuse M, Hirase T, Itoh M, Nagafuchi A, Yonemura S, Tsukita S: Occludin: a novel integral membrane protein localizing at tight junctions. J Cell Biol. 1993, 123: 1777-1788. 10.1083/jcb.123.6.1777.View ArticlePubMedGoogle Scholar
- Furuse M, Fujita K, Hiiragi T, Fujimoto K, Tsukita S: Claudin-1 and -2: novel integral membrane proteins localizing at tight junctions with no sequence similarity to occludin. J Cell Biol. 1998, 141: 1539-1550. 10.1083/jcb.141.7.1539.View ArticlePubMedPubMed CentralGoogle Scholar
- Martin-Padura I, Lostaglio S, Schneemann M, Williams L, Romano M, Fruscella P, Panzeri C, Stoppacciaro A, Ruco L, Villa A, et al: Junctional adhesion molecule, a novel member of the immunoglobulin superfamily that distributes at intercellular junctions and modulates monocyte transmigration. J Cell Biol. 1998, 142: 117-127. 10.1083/jcb.142.1.117.View ArticlePubMedPubMed CentralGoogle Scholar
- Gonzalez-Mariscal L, Betanzos A, Nava P, Jaramillo BE: Tight junction proteins. Prog Biophys Mol Biol. 2003, 81: 1-44. 10.1016/S0079-6107(02)00037-8.View ArticlePubMedGoogle Scholar
- Cani PD, Bibiloni R, Knauf C, Waget A, Neyrinck AM, Delzenne NM, Burcelin R: Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes. 2008, 57: 1470-1481. 10.2337/db07-1403.View ArticlePubMedGoogle Scholar
- Osbak PS, Bindslev N, Hansen MB: Relationships between body mass index and short-circuit current in human duodenal and colonic mucosal biopsies. Acta Physiol (Oxf). 2011, 201: 47-53. 10.1111/j.1748-1716.2010.02202.x.View ArticleGoogle Scholar
- Kremen AJ, Linner JH, Nelson CH: An experimental evaluation of the nutritional importance of proximal and distal small intestine. Ann Surg. 1954, 140: 439-448. 10.1097/00000658-195409000-00018.View ArticlePubMedPubMed CentralGoogle Scholar
- Sjostrom L, Peltonen M, Jacobson P, Sjostrom CD, Karason K, Wedel H, Ahlin S, Anveden A, Bengtsson C, Bergmark G, et al: Bariatric surgery and long-term cardiovascular events. JAMA. 2012, 307: 56-65. 10.1001/jama.2011.1914.View ArticlePubMedGoogle Scholar
- Evans S, Pamuklar Z, Rosko J, Mahaney P, Jiang N, Park C, Torquati A: Gastric bypass surgery restores meal stimulation of the anorexigenic gut hormones glucagon-like peptide-1 and peptide YY independently of caloric restriction. Surg Endosc. 2012, 26: 1086-1094. 10.1007/s00464-011-2004-7.View ArticlePubMedGoogle Scholar
- Morinigo R, Moize V, Musri M, Lacy AM, Navarro S, Marin JL, Delgado S, Casamitjana R, Vidal J: Glucagon-like peptide-1, peptide YY, hunger, and satiety after gastric bypass surgery in morbidly obese subjects. J Clin Endocrinol Metab. 2006, 91: 1735-1740. 10.1210/jc.2005-0904.View ArticlePubMedGoogle Scholar
- Falken Y, Hellstrom PM, Holst JJ, Naslund E: Changes in glucose homeostasis after Roux-en-Y gastric bypass surgery for obesity at day three, two months, and one year after surgery: role of gut peptides. J Clin Endocrinol Metab. 2011, 96: 2227-2235. 10.1210/jc.2010-2876.View ArticlePubMedGoogle Scholar
- Beckman LM, Beckman TR, Earthman CP: Changes in gastrointestinal hormones and leptin after Roux-en-Y gastric bypass procedure: a review. J Am Diet Assoc. 2010, 110: 571-584. 10.1016/j.jada.2009.12.023.View ArticlePubMedPubMed CentralGoogle Scholar
- Danese S, Fiocchi C: Ulcerative colitis. N Engl J Med. 2011, 365: 1713-1725. 10.1056/NEJMra1102942.View ArticlePubMedGoogle Scholar
- Uchino M, Ikeuchi H, Matsuoka H, Matsumoto T, Takesue Y, Tomita N: Clinical features and management of duodenal fistula in patients with Crohn's disease. Hepatogastroenterology. 2012, 59: 171-174.PubMedGoogle Scholar
- Koloski NA, Jones M, Kalantar J, Weltman M, Zaguirre J, Talley NJ: The brain-gut pathway in functional gastrointestinal disorders is bidirectional: a 12-year prospective population-based study. Gut. 2012,Google Scholar
- Macfarlane S, Macfarlane GT: Regulation of short-chain fatty acid production. Proc Nutr Soc. 2003, 62: 67-72. 10.1079/PNS2002207.View ArticlePubMedGoogle Scholar
- Walker AW, Sanderson JD, Churcher C, Parkes GC, Hudspith BN, Rayment N, Brostoff J, Parkhill J, Dougan G, Petrovska L: High-throughput clone library analysis of the mucosa-associated microbiota reveals dysbiosis and differences between inflamed and non-inflamed regions of the intestine in inflammatory bowel disease. BMC Microbiol. 2011, 11: 7-10.1186/1471-2180-11-7.View ArticlePubMedPubMed CentralGoogle Scholar
- Brint EK, MacSharry J, Fanning A, Shanahan F, Quigley EM: Differential expression of toll-like receptors in patients with irritable bowel syndrome. Am J Gastroenterol. 2011, 106: 329-336. 10.1038/ajg.2010.438.View ArticlePubMedGoogle Scholar
- Cario E, Podolsky DK: Differential alteration in intestinal epithelial cell expression of toll-like receptor 3 (TLR3) and TLR4 in inflammatory bowel disease. Infect Immun. 2000, 68: 7010-7017. 10.1128/IAI.68.12.7010-7017.2000.View ArticlePubMedPubMed CentralGoogle Scholar
- Dinan TG, Quigley EM, Ahmed SM, Scully P, O'Brien S, O'Mahony L, O'Mahony S, Shanahan F, Keeling PW: Hypothalamic-pituitary-gut axis dysregulation in irritable bowel syndrome: plasma cytokines as a potential biomarker?. Gastroenterology. 2006, 130: 304-311. 10.1053/j.gastro.2005.11.033.View ArticlePubMedGoogle Scholar
- Rodriguez-Perlvarez ML, Sanchez VG, Pastor CM, Gonzalez R, Flores EI, Muntane J, Camacho FG: Role of serum cytokine profile in ulcerative colitis assessment. Inflamm Bowel Dis. 2012,Google Scholar
- Grijalva CG, Chen L, Delzell E, Baddley JW, Beukelman T, Winthrop KL, Griffin MR, Herrinton LJ, Liu L, Ouellet-Hellstrom R, et al: Initiation of tumor necrosis factor-alpha antagonists and the risk of hospitalization for infection in patients with autoimmune diseases. JAMA. 2011, 306: 2331-2339. 10.1001/jama.2011.1692.View ArticlePubMedPubMed CentralGoogle Scholar
- Wang K, Yuan CP, Wang W, Yang ZQ, Cui W, Mu LZ, Yue ZP, Yin XL, Hu ZM, Liu JX: Expression of interleukin 6 in brain and colon of rats with TNBS-induced colitis. World J Gastroenterol. 2010, 16: 2252-2259. 10.3748/wjg.v16.i18.2252.View ArticlePubMedPubMed CentralGoogle Scholar
- Pavlov VA, Tracey KJ: Neural regulators of innate immune responses and inflammation. Cell Mol Life Sci. 2004, 61: 2322-2331.View ArticlePubMedGoogle Scholar
- Malinen E, Rinttila T, Kajander K, Matto J, Kassinen A, Krogius L, Saarela M, Korpela R, Palva A: Analysis of the fecal microbiota of irritable bowel syndrome patients and healthy controls with real-time PCR. Am J Gastroenterol. 2005, 100: 373-382. 10.1111/j.1572-0241.2005.40312.x.View ArticlePubMedGoogle Scholar
- Kerckhoffs AP, Samsom M, van der Rest ME, de Vogel J, Knol J, Ben-Amor K, Akkermans LM: Lower Bifidobacteria counts in both duodenal mucosa-associated and fecal microbiota in irritable bowel syndrome patients. World J Gastroenterol. 2009, 15: 2887-2892. 10.3748/wjg.15.2887.View ArticlePubMedPubMed CentralGoogle Scholar
- Frank DN, St Amand AL, Feldman RA, Boedeker EC, Harpaz N, Pace NR: Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases. Proc Natl Acad Sci USA. 2007, 104: 13780-13785. 10.1073/pnas.0706625104.View ArticlePubMedPubMed CentralGoogle Scholar
- Rajilic-Stojanovic M, Biagi E, Heilig HG, Kajander K, Kekkonen RA, Tims S, de Vos WM: Global and deep molecular analysis of microbiota signatures in fecal samples from patients with irritable bowel syndrome. Gastroenterology. 2011, 141: 1792-1801. 10.1053/j.gastro.2011.07.043.View ArticlePubMedGoogle Scholar
- Cani PD, Neyrinck AM, Fava F, Knauf C, Burcelin RG, Tuohy KM, Gibson GR, Delzenne NM: Selective increases of bifidobacteria in gut microflora improve high-fat-diet-induced diabetes in mice through a mechanism associated with endotoxaemia. Diabetologia. 2007, 50: 2374-2383. 10.1007/s00125-007-0791-0.View ArticlePubMedGoogle Scholar
- O'Keefe SJ, Ou J, Delany JP, Curry S, Zoetendal E, Gaskins HR, Gunn S: Effect of fiber supplementation on the microbiota in critically ill patients. World J Gastrointest Pathophysiol. 2011, 2: 138-145. 10.4291/wjgp.v2.i6.138.View ArticlePubMedPubMed CentralGoogle Scholar
- Sanz Y: Gut microbiota and probiotics in maternal and infant health. Am J Clin Nutr. 2011, 94: 2000S-2005S. 10.3945/ajcn.110.001172.View ArticlePubMedGoogle Scholar
- McNulty NP, Yatsunenko T, Hsiao A, Faith JJ, Muegge BD, Goodman AL, Henrissat B, Oozeer R, Cools-Portier S, Gobert G, et al: The impact of a consortium of fermented milk strains on the gut microbiome of gnotobiotic mice and monozygotic twins. Sci Transl Med. 2011, 3: 106ra106-10.1126/scitranslmed.3002701.View ArticlePubMedPubMed CentralGoogle Scholar
- Thomas LV, Ockhuizen T: New insights into the impact of the intestinal microbiota on health and disease: a symposium report. Br J Nutr. 2012, 107 (Suppl 1): S1-S13.View ArticlePubMedGoogle Scholar
- Whorwell PJ: Do probiotics improve symptoms in patients with irritable bowel syndrome?. Therap Adv Gastroenterol. 2009, 2: 37-44. 10.1177/1756283X09335637.View ArticlePubMedPubMed CentralGoogle Scholar
- Hakansson A, Molin G: Gut microbiota and inflammation. Nutrients. 2011, 3: 637-682. 10.3390/nu3060637.View ArticlePubMedPubMed CentralGoogle Scholar
- Zareie M, Johnson-Henry K, Jury J, Yang PC, Ngan BY, McKay DM, Soderholm JD, Perdue MH, Sherman PM: Probiotics prevent bacterial translocation and improve intestinal barrier function in rats following chronic psychological stress. Gut. 2006, 55: 1553-1560. 10.1136/gut.2005.080739.View ArticlePubMedPubMed CentralGoogle Scholar
- Mangell P, Lennernas P, Wang M, Olsson C, Ahrne S, Molin G, Thorlacius H, Jeppsson B: Adhesive capability of Lactobacillus plantarum 299v is important for preventing bacterial translocation in endotoxemic rats. APMIS. 2006, 114: 611-618. 10.1111/j.1600-0463.2006.apm_369.x.View ArticlePubMedGoogle Scholar
- Reimer RA, McBurney MI: Dietary fiber modulates intestinal proglucagon messenger ribonucleic acid and postprandial secretion of glucagon-like peptide-1 and insulin in rats. Endocrinology. 1996, 137: 3948-3956. 10.1210/en.137.9.3948.PubMedGoogle Scholar
- Tarini J, Wolever TM: The fermentable fibre inulin increases postprandial serum short-chain fatty acids and reduces free-fatty acids and ghrelin in healthy subjects. Appl Physiol Nutr Metab. 2010, 35: 9-16. 10.1139/H09-119.View ArticlePubMedGoogle Scholar
- Everard A, Lazarevic V, Derrien M, Girard M, Muccioli GG, Neyrinck AM, Possemiers S, Van Holle A, Francois P, de Vos WM, et al: Responses of gut microbiota and glucose and lipid metabolism to prebiotics in genetic obese and diet-induced leptin-resistant mice. Diabetes. 2011, 60: 2775-2786. 10.2337/db11-0227.View ArticlePubMedPubMed CentralGoogle Scholar
- Roelofsen H, Priebe MG, Vonk RJ: The interaction of short-chain fatty acids with adipose tissue: relevance for prevention of type 2 diabetes. Benef Microbes. 2010, 1: 433-437. 10.3920/BM2010.0028.View ArticlePubMedGoogle Scholar
- Haska L, Andersson R, Nyman M: A water-soluble fraction from a by-product of wheat increases the formation of propionic acid in rats compared with diets based on other by-product fractions and oligofructose. Food Nutr Res. 2011,Google Scholar
- Chawla A, Nguyen KD, Goh YP: Macrophage-mediated inflammation in metabolic disease. Nat Rev Immunol. 2011, 11: 738-749. 10.1038/nri3071.View ArticlePubMedPubMed CentralGoogle Scholar
- Oh DY, Talukdar S, Bae EJ, Imamura T, Morinaga H, Fan W, Li P, Lu WJ, Watkins SM, Olefsky JM: GPR120 is an omega-3 fatty acid receptor mediating potent anti-inflammatory and insulin-sensitizing effects. Cell. 2010, 142: 687-698. 10.1016/j.cell.2010.07.041.View ArticlePubMedPubMed CentralGoogle Scholar
- Cunningham-Rundles S, Ahrne S, Johann-Liang R, Abuav R, Dunn-Navarra AM, Grassey C, Bengmark S, Cervia JS: Effect of probiotic bacteria on microbial host defense, growth, and immune function in human immunodeficiency virus type-1 infection. Nutrients. 2011, 3: 1042-1070. 10.3390/nu3121042.View ArticlePubMedPubMed CentralGoogle Scholar
- Compare D, Nardone G: Contribution of gut microbiota to colonic and extracolonic cancer development. Dig Dis. 2011, 29: 554-561. 10.1159/000332967.View ArticlePubMedGoogle Scholar
- Pimentel GD, Portero-McLellan KC, Oliveira EP, Spada AP, Oshiiwa M, Zemdegs JC, Barbalho SM: Long-term nutrition education reduces several risk factors for type 2 diabetes mellitus in Brazilians with impaired glucose tolerance. Nutr Res. 2010, 30: 186-190. 10.1016/j.nutres.2010.03.003.View ArticlePubMedGoogle Scholar
- Pimentel GD, Arimura ST, de Moura BM, Silva ME, de Sousa MV: Short-term nutritional counseling reduces body mass index, waist circumference, triceps skinfold and triglycerides in women with metabolic syndrome. Diabetol Metab Syndr. 2010, 2: 13-10.1186/1758-5996-2-13.View ArticlePubMedPubMed CentralGoogle Scholar
- Kau AL, Ahern PP, Griffin NW, Goodman AL, Gordon JI: Human nutrition, the gut microbiome and the immune system. Nature. 2011, 474: 327-336. 10.1038/nature10213.View ArticlePubMedPubMed CentralGoogle Scholar
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