Nutritional Targets for Modulation ofthe Microbiota in Obesity
Gustavo D. Pimentel,* Thayana O. Micheletti and Fernanda PaceDepartment of Internal Medicine, Faculty of Medical Sciences, State University of Campinas
Key words: obesity; microbiota; nutrition; diet; inflammation; insulin; gut hormones
INTRODUCTION
The human microbiome is a topic of considerableinterest to researchers and health professionals. The gutis now known to be an important metabolic organ con-taining a diversity of bacterial species that influence themaintenance of health or development of diseases [Leyet al., 2006a; Pimentel et al., 2012], e.g., obesity, type 2diabetes (T2D), hepatic steatosis, and hypertension[Caricilli et al., 2011; Kau et al., 2011; Henao-Mejiaet al., 2012; Pluznick et al., 2013].
In humans, obesity is defined with the body massindex (BMI) greater than 30 kg/m2 and has recentlybeen recognized as a disease by the American MedicalAssociation [Pollack, 2013] nearly 60 years after theNobel laureate, Linus Pauling, noted the relationshipbetween obesity and reduced longevity [Pauling, 1958].
Antibiotics have been used as anti-obesity media-tors to improve insulin resistance, reduce inflammation,increase adiponectin levels, and modulate both the bac-terial profile and the gut permeability [Cani et al., 2008;Membrez et al., 2008; Caricilli et al., 2011; Esteveet al., 2011; Carvalho et al., 2012; Murphy et al., 2013].Human and animal studies have shown that exposure to
antibiotics in early life can influence weight gain andincrease food intake in later childhood and adulthood[Kalliomaki et al., 2008; Ajslev et al., 2011; Cho et al.,2012; Morel et al., 2013; Trasande et al., 2013]. Life-style change programs have also been recommendedfor the prevention and treatment of risk factors formetabolic syndrome-linked diseases [Lira et al., 2010,2012; Pimentel et al., 2010a, 2010b].
Nutrients, including Probiotics, dietary fiber,green tea, coffee, and berberine, may represent thera-peutic modulators of the gut microbiota [Delzenneet al., 2011, 2013; Everard et al., 2011; Axling et al.,2012; Jin et al., 2012; Neyrinck et al., 2012a, 2012b;Tremaroli and Backhed, 2012; Zhang et al., 2012; Hsiehet al., 2013; Nakayama and Oishi, 2013; Yan et al.,2013]. This review discusses how obesity can affect the
*Correspondence to: Gustavo Duarte Pimentel, Departmentof Internal Medicine, FCM-State University of Campinas(UNICAMP), 13083-970 Campinas, SP, Brazil.E-mail: [email protected]; [email protected]
Published online in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/ddr.21092
gut microbiota in the context of dietary nutrients knownto be modulators of the intestine, with a special focus onphysiological, metabolic, and molecular aspects.
MICROBIOTA AND OBESITY-RELATED DISEASES
Microorganisms, including the bacterial commu-nity inhabiting the human gastrointestinal (GI) tract, arecollectively called microbiota. Metagenomics studieshave revealed that the human body harbors 10 timesmore bacterial than human cells, reflecting that humansare 90% microbial and 10% human [Cani and Delzenne,2011]. The composition of the gut microbiota isestablished during the first year of life and is stronglyinfluenced by external factors, including the mode ofbirth (natural or Caesarian), early postnatal nutrition(breastfeeding or nutritional formulas), GI infections(bacteria and parasites), the use of antibiotics, and diet.
The human GI tract contains at least 1012
microorganisms/ml of luminal content and approxi-mately 15 000 bacterial species [Ley et al., 2006b]. Thebacterial component of the microbiota has been char-acterized in recent years by sequencing the 16S rRNAgene of the microbiota in fecal samples and hasdetected three dominant bacterial phyla: Firmicutes,Actinobacteria, and Bacteroidetes. Firmicutes is thelargest bacterial phylum, most of which have a Gram-positive cell wall structure. The minority, however, havea porous pseudo-outer-membrane that confers Gram-negative status. This phylum includes 200 genera, e.g.,Lactobacillus, Mycoplasma, Bacillus, and Clostridium[Zoetendal et al., 2006]. Actinobacteria is a group ofGram-positive bacteria that plays important roles in thedigestion of undigested polysaccharides, like cellulose[Ventura et al., 2007]. Although also numerous, it isusually missed by RNA gene sequencing being detectedby in situ hybridization [Shendure and Ji, 2008]. Thephylum Bacteroidetes is composed of three large classesof anaerobic Gram-negative bacteria [Garrity, 2010].
The genome of the bacteria that inhabit the intes-tine, the gut microbiome, encodes 3.3 million non-redundant genes, approximately 150 times larger thanthe human genome [Qin et al., 2010], and because itencodes for metabolic functions different from that ofthe human, it is considered an important extra organ[Frank et al., 2007; Costello et al., 2009; Turnbaughet al., 2009]. Among these functions are the biosynthe-sis of K and B group vitamins [LeBlanc et al., 2013],immune system development [Cerf-Bensussan andGaboriau-Routhiau, 2010; Garrett et al., 2010;Maynard et al., 2012], the production of enzymesinvolved in the utilization of non-digestible carbohy-drates, cholesterol reduction [Gill et al., 2006], short-chain fatty acid (SCFA) production [Samuel et al.,
2008], and regulation of host metabolism. Thus, the gutmicrobiota can regulate the metabolism of the host,leading to obesity [Backhed et al., 2004; Ley et al.,2006b; Turnbaugh et al., 2006; Raoult, 2008], a chronicdisease that has reached epidemic levels and has morethan doubled since 1980. It is expected that, in less than20 years, one-third of the population of the Westernworld will be obese [WHO, 2011]. Obesity results froman increase in caloric intake and/or reduced expendi-ture, leading to energy storage. Consolidating factorsthat facilitate this imbalance are genetics, high-fat andfructose food, and physical inactivity [Hill and Peters,1998]. Moreover, obesity is related to other metabolicdisorders, such as insulin resistance, T2D, hyperten-sion, dyslipidemia, arrhythmias, cancer, asthma,osteoarthritis, neurodegeneration, thromboembolicevents, atherosclerosis, and non-alcoholic fatty liverdisease (NAFLD) [Hotamisligil, 2006].
Alterations in gut microbiota composition areassociated with increased energy storage and anincreased capacity of fermenting and absorbing other-wise undigested carbohydrates [Gill et al., 2006; Leyet al., 2006b; Turnbaugh et al., 2006]. Obesity is alsoassociated with reduced bacterial diversity, along withaltered expression of bacterial genes and metabolicpathways. In addition, studies have demonstrated thatobese humans and mice present a lower percentage ofBacteroidetes and relatively more bacteria from thephylum Firmicutes in their gut microbiota [Ley et al.,2005], and when obese individuals become lean, theproportion of microbes from the Bacteroidetes phylumincreases, a change associated with an increased abilityto extract energy from nutrients. This ability to betterextract energy from food was noted in mice with ahigher proportion of Firmicutes, probably due to thepresence of genes encoding enzymes that break downpolysaccharides otherwise undigested by the host,leading to increased production of more fermentationend-products, e.g., SCFAs, and their hepatic conver-sion to triglycerides.
Alterations in microbiota composition are alsorelated to an increase in low-grade inflammation.Since obesity is a metabolic disease that is associatedwith low-grade systemic inflammation [Wellen andHotamisligil, 2005; Hotamisligil, 2006], the gutmicrobiota may regulate innate immunity (and viceversa) and thereby exert an influence on metabolismand the development of obesity. In this case, inflamma-tion is provoked against Gram-negative bacterial cellwall fragments, i.e., lipopolysaccharide (LPS), and isdirected toward the plasma of the host. Thus, LPS is amarker of chronic inflammation associated with thedevelopment of obesity and its comorbidities in miceand humans [Moreno-Navarrete et al., 2012].
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Cani et al. [2007a] showed a relationship betweenobesity, inflammation, and Toll-like receptor 4 (TLR4)expression. Bacterial LPS binds to TLR4 and promotessystemic inflammation in high-fat diet-induced meta-bolic syndrome. Mice that exhibited an obese pheno-type underwent a shift in the gut microbiota to lowerlevels of Bifidobacteria with an increase in circulatingLPS levels, termed metabolic endotoxemia. Moreover,infusion of LPS into mice, to reproduce this condition,leads to the development of the metabolic anomaliesgenerated by a high-fat diet, showing that LPS isresponsible for the systemic inflammation frequentlyobserved in obesity models [Cani et al., 2007a]. Therelationship between LPS and metabolic endotoxemiawas further demonstrated in CD14 knockout mice thatreceived an LPS infusion and were resistant to thedevelopment of low-grade inflammation, a characteris-tic of obesity (CD14 acts as a co-receptor for TLR4 inthe detection of bacterial LPS).
Vijay-Kumar et al. [2010] elegantly demonstrateda relationship between metabolic syndrome and TLR5(Toll-like receptor 5) that recognizes bacterial flagellin.TLR5 knockout mice presented a shift in gutmicrobiota composition, leading to low-grade inflam-matory signaling, increased weight, insulin resistance,and metabolic syndrome. When fed a high-fat diet, theTLR5 knockout mice showed a more exaggerated obesephenotype.
Recently, a relationship between TLR2 (Toll-likereceptor 2) and microbiota composition was demon-strated with TLR2 knockout mice showing a higherproportion of Firmicutes, an increase in LPS absorp-tion, subclinical inflammation, insulin resistance,glucose intolerance, and, finally, the development ofobesity reinforcing the idea that a change in the pro-portions of bacterial phyla promotes metabolic altera-tions that culminate in obesity [Caricilli et al., 2011].Mice fed a high-fat diet have also shown gut micro-biota alterations, e.g., an increase in Gram-negativelevels. However, mice exposed to a high-fat diet adlibitum in the context of treatment with specific anti-biotics showed a decline in plasma LPS levels, adiposetissue inflammation, oxidative stress, and macrophagemarkers; thus, the antibiotics treatment preventedadipocyte hypertrophy and improved metabolicparameters including diabetes and obesity [Cani et al.,2008].
A number of other obesity-associated diseaseshave been linked to changes in microbiota composition.For instance, NAFLD has a close relationship withobesity, metabolic syndrome, and insulin resistance[Baffy, 2009], and can evolve into chronic liver diseaseor progress to liver cirrhosis, liver failure, andhepatocellular carcinoma [Bugianesi et al., 2002]. A
relationship also exists between the small intestinemicrobiota and NAFLD [Spencer et al., 2011;Henao-Mejia et al., 2012]. Exogenous stimuli, likedietary choline, can promote changes in gut microbiotacomposition and drive NAFLD and the consequentmetabolic alterations [Szabo et al., 2010; Spencer et al.,2011]. NAFLD is mediated by bacterial LPS derivedfrom bacteria mostly found in the intestine of obeseindividuals [Cani and Delzenne, 2009]. Recent studieshave also demonstrated that the metabolites from thegut microbiota can reverse the cholesterol transportpathway by affecting ABCA1/ABCG1 cholesterol-mediated efflux [Wang et al., 2012]. A relationship wasobserved between gut Actinobacteria and decreasedlipoprotein cholesterol, while a negative correlationwas observed for a group of Proteobacteria andphosphatidylcholine [Jalanka-Tuovinen et al., 2011].
An association between the gut microbiota andT2D, the most prevalent endocrine disease worldwide,has also been established. A metagenome study charac-terized patients with T2D with moderate gut microbialdysbiosis and showed a lower number of butyrate-producing bacteria and a greater diversity of opportu-nistic pathogens present in the human gut microbiota.In these patients, an increase in microbial functionsconferring sulfate reduction and oxidative stress resis-tance was also observed [Qin et al., 2012].
As obesity is involved in several othercomorbidities and has a direct correlation with shifts ingut microbiota composition, it is not surprising thatdiseases associated with obesity are related to modifi-cations in intestinal microbiota composition. While it iseasy to conclude that the commensal bacteria thatinhabit the human body definitely control host metabo-lism, different diets and nutrients may be able to modu-late the gut microbiota, thereby affecting the physiologyand metabolism of obese patients. Thus, the relation-ships between nutrients and the gut microbiota areequally important to the mechanisms underlying modi-fication of the host intestine.
DIET AND MICROBIOTA
Probiotics
Probiotics are microorganisms that confer healthyeffects on the host [FAO/WHO, 2002]. In mice fed ahigh-fat diet, an improvement in several metabolic indi-cators was noted after 8 weeks of treatment withprobiotics (Lactobacillus curvatus and Lactobacillusplantarum) [Park et al., 2013]. These included a reduc-tion in body weight and mass fat, blood insulin, leptin,and total cholesterol levels, in the adipose tissue levelsof tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), interleukin 1β (IL-1β), and monocyte
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chemotactic protein-1 (MCP-1), and increased hepa-tic expression of peroxisome proliferator-activatedreceptor (PPAR)-γ coactivator 1-α, carnitine palmi-toyltransferase I (CPT1), CPT2, and acyl-coenzymeA oxidase 1 (ACOX1). A higher fecal content ofBacteroidetes was also found when compared toplacebo. Mice treated with Lactobacillus rhamnosusand Lactobacillus sakei had reduced mass fat, acetyl-CoA carboxylase (ACC), fatty acid synthase (FAS), andstearoyl-CoA desaturase-1 (SCD-1) in the liver, as wellas in the Firmicutes : Bacteroidetes ratio, favoringimproved adipogenesis and bacterial profile [Ji et al.,2012].
In women during the first trimester of pregnancyreceiving L. rhamnosus and Bifidobacterium lactis, therisk of developing gestational diabetes mellitus isreduced [Luoto et al., 2010], and in obese adults,L. gasseri (200 g/day for 3 months) reduced visceral andsubcutaneous fat and BMI, with an increase inadiponectin levels [Kadooka et al., 2010]. Other studiesevaluating short-term probiotic intake (less than 3months) failed to show positive results in gut microbiotaindicators in either adults or adolescents [Gobel et al.,2012; Leber et al., 2012]. Similarly, in patients withmetabolic syndrome treated for 3 months with L. caseiShirota, no effect was seen in gut permeability,C-reactive protein, CD14, neutrophil function, andTLR expression [Leber et al., 2012], while a studyon obese adolescents, short-term consumption ofL. salivarius increased the fecal content of this pro-biotic, but pro-inflammatory cytokine, insulin, andglucose levels were not modified [Gobel et al., 2012].
Collectively, studies have shown that the anti-obesity effects of probiotics appear to be mediatedby attenuated fatty acid absorption, a reduction inproinflammatory cytokine levels, altered adipogenesis-related gene expression, a lower Firmicutes : Bacteroi-detes ratio, and an increase in adiponectin levels.Nevertheless, these findings remain exclusive torodents or pigs as few obese human studies have beenpublished.
Prebiotics and Dietary Fiber
Prebiotics are nondigestible or fermentable foodcomponents that lead to the stimulation of several bac-teria species contributing to gut health [Roberfroidet al., 2010; Delzenne et al., 2013]. In humans, resis-tance to digestion in the small intestine results fromthe absence of enzymes hydrolyzing polymer bonds,so prebiotics reach the colon intact, provoking localfermentation, and affecting the beneficial flora.Among the commonly consumed prebiotics are inulin,oligofructose, fructooligosaccharides and raffinose. In
ob/ob mice, oligofructose enhanced the presence ofLactobacillus, Bifidobacterium, and C. coccoides-E. rectal, reduced gut permeability and inflammation,and re-established tight junction integrity. Dietaryoligofructose also improved insulin sensitivity [Caniet al., 2007b], while its consumption in diet-inducedobese mice led to a higher content of Bifidobacteriumand a reduction in endotoxemia [Martin et al., 2009].
Treatment of genetically obese mice with aprebiotic-enriched diet favored a reduction in Firmi-cutes colonization, with an increase in Bacteroidetesleading to an improvement in glucose tolerance and areduction in inflammation, oxidative stress, and body fat[Everard et al., 2011]. In obese mice, a higher contentof Firmicutes and a lower content of Bacteroidetes havebeen reported [Ley et al., 2006a, 2006b; Armougomet al., 2009; Caricilli et al., 2011; Gauffin Cano et al.,2012]. A probiotic/prebiotic mixture diminished circu-lating levels of LPS and proinflammatory cytokines inhealthy subjects [Lecerf et al., 2012]. Prebiotics, bychanging the phyla of the bacteria in the gut microbiota,can ameliorate the consequences of obesity. A reduc-tion in LPS levels after treatment with or consumptionof prebiotics improved gut permeability and reduced itsinflammatory status [Cani et al., 2007b, 2009; Lecerfet al., 2012; Nakamura and Omaye, 2012; Neyrincket al., 2012b].
Long-term consumption of inulin by adolescentswas sufficient for reducing the BMI and body fat[Abrams et al., 2007]. Additionally, short-term con-sumption of oligofructose diminished body fat inobese adults. These findings may be due to decreasedghrelin and increased peptide YY (PYY) levels [Parnelland Reimer, 2009]. Oligofructose and inulin leadto an increase in glucagon-like peptide 1 (GLP-1)and reduced ghrelin concentrations [Reimer andMcBurney, 1996; Tarini and Wolever, 2010], whichmay involve inulin-induced increased SCFA thatincrease anorexigenic and reduce orexigenic hormones[Tarini and Wolever, 2010]. Prebiotics also promotethe secretion of cholecystokinin, gastric inhibitorypolypeptide, and oxyntomodulin [Pimentel andZemdegs, 2010], gut hormones responsible for activat-ing central anorexigenic neurons (POMC/CART),and inhibiting orexigenic neurons (AgRP/NPY), thusreducing food intake and supporting the maintenanceof body weight [Konturek et al., 2004; Parker andBloom, 2012].
Furthermore, SCFAs from dietary fibers, such aspropionate and butyrate, increase leptin secretion andreduce proinflammatory cytokine expression, alongwith reduced food intake [Roelofsen et al., 2010].Dietary fibers are fermented by gut microbiota, andhigher fatty acid levels occur after the consumption of a
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diet high in oligofructose, pectin, resistant starch,raffinose, and cellulose [Haska et al., 2011; Peng et al.,2013; Yan et al., 2013].
Treatment with a fiber-enriched diet in mice fed ahigh-fat diet plus infected with E. coli improved thecolonization of bacteria [Zumbrun et al., 2013]. Pigstreated with inulin had an attenuated high-fat diet-induced body weight gain, fat mass, and expression ofsterol regulatory element binding protein 1c (SREBP-1c) with an associated reduction in cholesterol synthesis[Yan et al., 2013]. In overweight humans, consump-tion of a galactooligosaccharide mixture increased thecontent of fecal bifidobacteria, accompanied by areduction in blood C-reactive protein and insulin levels,improved dyslipidemia status, and a reduction in bothtotal cholesterol and triacylglycerols [Vulevic et al.,2013].
Dietary changes, e.g., an increase in either fruit orvegetable consumption, a reduction in refined carbohy-drates, and saturated and trans-fatty acids [Pimentelet al., 2010a, 2010b; Lira et al., 2012], are required for
maintaining health. Food restriction can also preventobesity in humans [Pimentel et al., 2010a, 2010b] andmice deficient in TLR5 [Vijay-Kumar et al., 2010]. Fur-thermore, dietary micronutrients and macronutrientsare important for maintaining gut health and robustimmune system function [Flint et al., 2012; Calder,2013; Kamada et al., 2013].
Several studies indicate that prebiotics reduce thehepatic accumulation of triacylglycerols and high-fatdiet-induced steatosis [Correia-Sa et al., 2013; Pachikianet al., 2013]. Oligofructose decreased steatosis in theliver of obese rodents [Correia-Sa et al., 2013], whilemice fed a diet free of n-3 fatty acids supplemented withfructooligosaccharides increased Bifidobacterium spp.and reduced Roseburia spp. levels [Pachikian et al.,2013], suggesting that the improvement in hepaticsteatosis and cholesterol synthesis occurred via a reduc-tion in PPAR-α-driven fatty acid oxidation and SREBP2expression [Pachikian et al., 2013].
The main effect of prebiotics in modulating riskfactors for obesity are likely mediated by increased
Fig. 1. Gut microbiota impairments in individuals susceptible to obesity, insulin resistance, and inflammation.
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GLP-1, PYY, and SCFA concentrations, reduced bloodLPS, triacylglycerols, proinflammatory cytokines andinsulin levels, and diminished hepatic PPAR andSREBP2 expression.
Green Tea
Extracts of green tea have been used to treat orprevent various obesity-related metabolic outcomes. Toour knowledge, only one published study has investi-gated the relationship between green tea and themicrobiota in obese mice [Axling et al., 2012]. Micewere fed a high-fat diet plus 4% green tea powderand/or Lactobacillus plantarum. The green tea grouphad lower fat mass, hepatic triacylglycerols, and choles-terol accumulation when compared to the green teaplus L. plantarum group. However, the Lactobacilluscontent was higher in the group that received green teaplus L. plantarum compared to the control or green teaonly groups [Axling et al., 2012]. Thus, both greentea and Lactobacillus attenuate several high-fat diet-induced risk factors for obesity. In addition, a Japanese
study observed that the intake of green tea by adultindividuals for 10 days may be responsible for anincrease in Bifidobacterium species, leading to ahealthier colon [Jin et al., 2012].
Coffee
Antibiotic-like activity was seen in sevenpathogen-free rodents treated with coffee (500 μL/day), e.g., inhibition of E. coli and Clostridiumspp. growth and an increase in Bifidobacteriumspp. without changing the Bacteroidetes sp. andLactobacillus sp. profile in the colon [Nakayama andOishi, 2013]. In healthy humans consuming three cupsof coffee per day for 21 days, an increase in fecalBifidobacterium spp. was observed [Jaquet et al.,2009]. Limited data exist on the beneficial effect ofcoffee – and by extrapolation caffeine – on the gutmicrobiota. Polyphenols like those present in coffeecan affect the functional ecology of the microbiome[Moco et al., 2012], indicating that this topic is worthyof further study.
Fig. 2. Main nutritional targets for modulating the gut microbiota in obese patients.
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Berberine
Berberine is a herbal compound of the alkaloidfamily derived from Rhizoma coptidis [Zhou et al.,2009] that has been used in China for more than 1400years for protection against metabolic syndrome [Leeet al., 2005; Wang et al., 2005; Brusq et al., 2006; Yinet al., 2008]. In rodents fed a high-fat diet, berberineincreased SCFA-induced bacterial proliferation, e.g.,Blautia and Allobaculum, reduced adiposity, MCP-1,and leptin, and increased insulin sensitivity andadiponectin levels [Zhang et al., 2012]. Further studiesare necessary to clarify the effects of this herbal supple-ment on the human gut microbiota.
Figure 1 summarizes the interactions betweenthe gut microbiota that may impair insulin sensibilityand gut hormones and lead to increased inflammationand obesity. Figure 2 highlights how the probiotics,prebiotics, a diet enriched in dietary fiber (vegetariandiet-like), green tea, coffee, and berberine may improvethe consequences of obesity via the microbiota.
CONCLUSION
In summary, the gut microbiota has a key role inthe development of obesity, with TLR signaling, LPSlevels, gut permeability, the microbiome bacterialprofile and insulin resistance, and gut hormones beingmodulated by a high-fat diet and obesity. Conversely,a healthy diet is linked with a diminution in obesity-related consequences. It remains a challenge for clini-cians to study which nutrients should be prescribed forobese patients.
ACKNOWLEDGMENTS
This work was supported by Fundação de Amparoà Pesquisa do Estado de São Paulo (FAPESP), Brazil.
CONFLICT OF INTEREST
The authors declare that they have no competinginterests.
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