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Clin Investig Arterioscler. 2018;xxx(xx):xxx---xxx

www.elsevier.es/arterio

REVIEW ARTICLE

Influence of the microbiota and probiotics in obesity�

Laia Fontanéa, David Benaigesa,b,c, Albert Godaya,b,c,∗, Gemma Llauradóa,b,c,Juan Pedro-Boteta,b,c

a Endocrinology and Nutrition Department, Hospital del Mar, Barcelona, Spainb Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spainc Institut Hospital del Mar d’Investigacions Mèdiques [Hospital del Mar Medical Research Institute] (IMIM), Barcelona, Spain

Received 25 January 2018; accepted 28 March 2018

KEYWORDSObesity;Gut microbiota;Probiotic;Metabolic syndrome

Abstract Gut microbiota plays a key role in the control of body weight. In the present reviewthe different ways in which it can modify the energy homeostasis of the host are exposed,based on its capacity to modify the metabolism of the individual and its contribution in theenergy consumption regulation. With the current evidence, it is not clear what microbiotaprofile is associated with the presence of obesity, although in animal models it seems to berelated to a higher proportion of bacteria of the Firmicutes phylum, to the detriment of thoseof the Bacteroidetes phylum. Other factors clearly involved would be the diversity in the gutmicrobiota or its possible functional changes. More studies in humans are needed to clarify howdysbiosis can influence weight control. On the other hand, probiotics directly affect the gutmicrobiota, modulating its composition and, possibly, its functionality. A large number of studiesin humans have evaluated the impact of probiotics on obesity. Although this intervention mayhave a potentially beneficial effect, more effort is needed to clarify which strains of probioticsshould be recommended, at what dose and for how long.© 2018 Sociedad Espanola de Arteriosclerosis. Published by Elsevier Espana, S.L.U. All rightsreserved.

PALABRAS CLAVE Influencia de la microbiota y de los probióticos en la obesidad

Obesidad;Microbiota intestinal;Probiótico;Síndrome metabólico

Resumen La microbiota intestinal tiene un papel determinante en el control del peso corporal.En la presente revisión se exponen las diferentes vías por las que puede modular la homeostasisenergética del huésped, en base a su capacidad modificadora del metabolismo del individuo ysu contribución en la regulación del aprovechamiento energético. Con las evidencias actuales,

DOI of original article: https://doi.org/10.1016/j.arteri.2018.03.004

� Please cite this article as: Fontané L, Benaiges D, Goday A, Llauradó G, Pedro-Botet J. Influencia de la microbiota y de los probióticos

en la obesidad. Clín Investig Arterioscler. 2018. https://doi.org/10.1016/j.arteri.2018.03.004∗ Corresponding author.

E-mail address: 96002@parcdesalutmar.cat (A. Goday).

2529-9123/© 2018 Sociedad Espanola de Arteriosclerosis. Published by Elsevier Espana, S.L.U. All rights reserved.

ARTERE-442; No. of Pages 9

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2 L. Fontané et al.

no está claro cuál es el perfil de microbiota que se atribuye a la presencia de obesidad, aunqueen modelos animales parece relacionarse con una mayor proporción de bacterias del filo Firmi-cutes, en detrimento de las del filo Bacteroidetes. Otros factores claramente implicados seríanla diversidad en la microbiota intestinal o sus posibles cambios funcionales. Son necesarios másestudios en humanos para poder esclarecer cómo la disbiosis puede influir en el control pon-deral. Por otra parte, los probióticos afectan directamente la microbiota intestinal, modulandosu composición y, posiblemente, su funcionalidad. Un gran número de estudios en humanos hanevaluado el impacto de los probióticos en la obesidad. A pesar de que esta intervención puedetener un potencial efecto beneficioso, es preciso esclarecer qué cepas de probióticos debenrecomendarse, en qué dosis y durante cuánto tiempo.© 2018 Sociedad Espanola de Arteriosclerosis. Publicado por Elsevier Espana, S.L.U. Todos losderechos reservados.

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he prevalence of obesity is increasing worldwide, espe-ially in industrialised countries, and is a major global healthssue, linked to the onset of multiple comorbidities such asypertension, type 2 diabetes mellitus, non-alcoholic fattyiver disease and cardiovascular disease. According to datarom the Nutrition and Cardiovascular Risk Study in Spain,he most recent population study of cardiovascular risk fac-ors in the country, 16.5% of the population is overweightbody mass index [BMI] 25---30 kg/m2), 21.7% is mildly oroderately obese (BMI 30---40 kg/m2), and 1.2% are severely

r morbidly obese (BMI >40 kg/m2).1

From a simplistic point of view, the pathophysiology ofbesity can be explained by a positive energy balance, withore energy consumed or eaten than expended, which,hen continued for a long period of time, leads to build-p of fat in the adipocytes and, consequently, weight gain.owever, the pathophysiology of this disease is much moreomplex than this, with additional factors playing a role,uch as basal metabolic rate, genetic and environmentalactors. These factors have an even greater impact onndividuals’ weight gain.2 Of the different environmentalactors, eating habits and physical activity play a significantole, although there are other environment-related aspectsnvolved in the onset of obesity.

These include the composition of the individual’s micro-iota and dysbiosis or imbalance processes that may causehanges in the microbiota composition and/or function.ver the last decade, a very close link has been estab-

ished between composition and changes in gut microbiotand obesity, both in experimental and human models.3,4 Pro-iotic microorganisms have also become more popular dueo the increasing number of studies demonstrating that cer-ain strains have health-promoting properties.5 The role oficrobiota in the pathophysiology of obesity and the impact

f probiotic treatment is reviewed below.

ut microbiota

ut microbiota can be defined as the community of microor-anisms that live in the intestines. Prior to birth, the

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ut is sterile and it becomes fully colonised during therst year of life. Mode of delivery and breastfeeding playn important role in the stabilisation of the microbiota.6

he microbiota then changes with age, dietary habitsnd environmental factors, including antibiotic treatment.7

n line with the above, recent investigations show that0-90% of the bacterial phylotypes in the human gutre members of two phyla, Bacteroidetes (gram-negative,.g. Bacteroides and Prevotella) and Firmicutes (gram-ositive, e.g. Clostridium, Enterococcus, Lactobacillus,uminococcus), followed by Actinobacteria (gram-negative,.g. Bifidobacterium) and Proteobacteria (gram-negative,.g. Helicobacter, Escherichia).8---10

Gut microbiota makes an important contribution touman metabolism11 since it modulates host nutrition andnergy consumption through the production of vitamins (K,olic acid and B12), absorption of electrolytes and minerals,ermentation of indigestible components of the host’s dietnd production of short-chain fatty acids (SCFA)10; it alsonfluences homeostasis of the intestinal epithelium, devel-pment of the immune system, protection against pathogensnd drug metabolism.11,12

icrobiota and obesity

f all the functions outlined above, there has been increas-ng concern over the last 10 years about the role of the guticrobiota in energy homeostasis and, more specifically, itsehaviour in metabolic diseases such as obesity. There areultiple studies in both animal models and humans linking

lterations in gut microbiota with the presence of obesity.

tudies in animal models

ole of the microbiota in the regulation of metabolismhe microbiota by itself can only cause weight gain. There-ore, the microbiota derived from genetically obese micer mice rendered obese by diet can cause fat accumulation,

nd this is not mediated by increased food consumption. Therst evidence for the role of the gut microbiota in obesityomes from studies conducted in germ-free (GF) mice, theut of which is sterile, compared to conventional mice.13

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Influence of the microbiota and probiotics in obesity 3

Change in energy homeostasis

Increased systemic inflammation

↑ monosaccharide uptake

↑ intestinal villi

↑ SCFA

↓ FIAF

AMPK

Gut microbiota

↑ LPS absorption Metabolicendotoxemia

Adipose tissue

LPLlipogenesis

Source of energy fromColonocytes

Intestinal epithelium

Mitochondrial FA oxidationKetogenesisGlucose uptakeInsulin secretion

Cholesterol synthesis andtriglyceride lipogenesis

ter osacch

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Figure 1 Mechanisms of action of the microbiota as a promoinduced adipocyte factor; LPL: lipoprotein lipase; LPS: lipopoly

At baseline, conventional mice had 40% more body fat thanGF mice, regardless of food intake. Also, colonisation of GFmice with gut microbiota from conventional mice produceda significant increase in body weight and a 60% increasein body fat, a significant increase in triglyceride synthesisin the liver, leptin secretion and insulin resistance, regard-less of food intake and total energy expenditure. Likewise,the transfer of gut microbiota from conventional mice toGF mice caused a significant increase in body weight andbody fat compared to transplantation of microbiota fromlean mice.14

There are two main mechanisms that may explain whymicrobiota composition promotes obesity: altered hostenergy homeostasis and increased systemic inflammation(Fig. 1). The first mechanism would affect the hosts’ pre-disposition to extract more calories from their food and,consequently, to develop obesity and increased adiposity.13

This can occur by various pathways: (a) enhanced uptakeof monosaccharides that would normally not be digestible,secondary to development of gut epithelium by the micro-biota, increasing the density of intestinal villi capillaries15;(b) increased production of SCFA, which are used as asource of energy by the colonocytes16; (c) increased depo-sition of triglycerides in adipocytes. This mechanism maybe caused by reduced intestinal expression of fasting-induced adipocyte factor by the microbiota. This hormoneinhibits lipoprotein lipase, which is responsible for cellularuptake of fatty acids from lipoproteins and accumulationof triglycerides in adipocytes13; and (d) suppression by thegut microbiota of the release of AMP-activated proteinkinase, which leads to reductions in mitochondrial FA oxida-tion, ketogenesis, glucose uptake and insulin secretion andpotentiation of lipogenesis and cholesterol and triglyceride

17---19

synthesis.The second mechanism, which is related to a systemic

inflammation process, was described by Cani et al.20,who observed, after administering a fat-enriched diet to

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f obesity. AMPK: AMP-activated protein kinase; FIAF: fasting-arides; SCFA: short-chain fatty acids.

group of mice, an increase in the gram-negative-to-ram-positive ratio in the gut microbiota and, therefore,ncreased intestinal absorption of bacterial fragments, suchs lipopolysaccharides, causing the so-called ‘‘metabolicndotoxemia’’, which is classically associated with chronicnflammation and other metabolic diseases related to obe-ity.

ype of microbiota and its influence on obesitynce it had been established that gut microbiota hasn impact on the host metabolism, research focused onlarifying which type of microbiota was associated moreirectly with weight gain. First, the presence of certaintrains of microorganisms has been associated with the pres-nce of obesity. In animal models, it has been concluded,ore or less unanimously, that an increase in the ratio of

ram-positive bacteria (Firmicutes) to gram-negative bac-eria (Bacteroidetes, actinobacteria and proteobacteria) iselated to the presence of obesity.4,8,21

Other authors seem to suggest that the gut microbiotaan be modified through diet. Turnbaugh et al.22 colonisedF mice with human faeces and fed them a Western-styleiet versus a low-fat, plant polysaccharide-rich diet for 2eeks and then transplanted their microbiota into GF mice.he GF mice that received the microbiota of those miceed the Western-style diet gained more weight than thosehich received transplants from those fed a low-fat diet.

n another study, an increase in Firmicutes and a loweratio of Proteobacteria and Actinobacteria (i.e. Bifidobac-erium spp.) was observed in mice fed a high-fat diet.23

n increased ratio of Firmicutes to Bacteroidetes was alsobserved both in mice with obese and lean phenotypes whened a high-fat diet.24

tudies in humans few years after the initial animal model studies, the firstapers focusing on the determination of gut microbiota inumans and its link to obesity began to emerge.

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ype of microbiota and its influence on obesitylthough it was concluded, more or less unanimously, in ani-al models that an increase in the ratio of gram-positiveacteria (Firmicutes) to gram-negative bacteria (Bac-eroidetes, Actinobacteria and Proteobacteria) is related tohe presence of obesity, studies in humans have not been asonclusive. In fact, there is a series of papers defending thisdea. In 2006, one year after their first experimental obser-ation in mice,8 Ley et al.9 confirmed that obese subjects,ompared with lean subjects, had a higher proportion ofirmicutes and a relatively low proportion of Bacteroidetes.his study also showed that the ratio of Firmicutes to Bac-eroidetes was similar to the profile of a thin person afterosing weight by following a low-fat or low-carbohydrate dietor 18 months. Likewise, Santacruz et al.25 observed reducedumbers of Bacteroides and increased numbers of Staphy-ococcus, Enterobacteriaceae and Escherichia coli in obeseompared to normal-weight pregnant women. Other papersupporting this line of research observed a significantlyigher level of Lactobacillus species (genus belonging to thehylum Firmicutes) in obese patients.26 Specifically, a higherevel of Lactobacillus reuteri (L. reuteri) and lower levelsf Lactobacillus casei/paracasei, Lactobacillus plantarumL. plantarum) and Bifidobacterium animalis are associatedith obesity.27 Other studies do not make such a conclu-

ive link between the ratio of such bacteria and obesity. Onnalysing a cohort of twin pairs, Turnbaugh et al. detectedigher levels of Bacteroidetes and Actinobacteria in leanubjects compared with obese subjects, with no significantifferences in the proportion of Firmicutes. It is also impor-ant to note that this study detected that obese subjectsad less diverse microbiota.2

Contrary to the initial hypothesis, multiple studiesppose the idea that Firmicutes are the most abundantroup of bacteria in the gut of overweight individuals. Ducant al.28 reported no differences in phyla between obesend non-obese subjects. Furthermore, no significant changesere observed on examining the proportion of Bacteroidetes

n the faeces of obese patients following a weight mainte-ance diet or a weight loss programme. Likewise, anothertudy29 found somewhat more Bacteroidetes in obese sub-ects than in normal-weight individuals and showed thatne genus of Bacteroides (i.e. Prevotella) was particularlyigh in obese subjects. However, it was also observed that,ollowing weight loss secondary to a gastric bypass, thesendividuals had a higher proportion of Gammaproteobacteriaphylum Proteobacteria) and proportionally fewer Firmi-utes. Similarly, Schwiertz et al.30 and Collado et al.31

emonstrated that the ratio of Firmicutes to Bacteroideteshifted in favour of Bacteroidetes in overweight or obeseatients. The reason why these studies do not always agrees the fact that they use less standardised methodologies,ess homogeneous populations and more divergent lifestylesnd diets in comparison with animal models.

As a whole, all these data support the fact that the linketween obesity and microbiota is not due to the proportionf the major groups of bacteria, but to small changes or morepecific variations in each species.32,33 As a result, there are

tudies that support the idea that low levels of Bifidobac-erium (belonging to the phylum Actinobacteria)25,30,31,34 andigh levels of Staphylococcus aureus (S. aureus) (belongingo the phylum Firmicutes)31,34 are related to obesity. One

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xample of this is the paper by Kalliomäki et al.34, whichbserved higher levels of Bifidobacterium spp. in childrenf normal weight at the age of 7 compared to those begin-ing to show signs of being overweight. The relevance of thistudy is due to the fact that its results support the idea thathanges in microbiota composition may precede the statusf being overweight.34 The authors also observed that theevels of S. aureus were lower in children of normal weighthan in those becoming overweight years later. The authorspeculated that S. aureus may act as a trigger of low-gradenflammation. Likewise, Collado et al.31 observed higher lev-ls of Bacteroides spp. and S. aureus in stool samples fromverweight women than in normal-weight women. They alsoound a positive correlation between total Bacteroides spp.evels and BMI, both before and during pregnancy. It shoulde noted that higher levels of bifidobacteria were observedot only in normal-weight women compared to overweightomen, but also in women who gained less weight duringregnancy.

s weight control only affected by the type of microbiota?n extensive assessment of the relationship between BMInd the taxonomic composition of the gut microbiome inhe ‘Human Microbiome Project’ dataset has recently beenonducted. The results were compared to those obtainedn another large metagenomic study of the gut microbiota,he MetaHIT study, as well as to two smaller studies thatpecifically sampled lean and obese individuals. There waso association between BMI and the taxonomic compositionr diversity of the microbiome in the ‘Human Microbiomeroject’ cohort.35 Furthermore, inter-study variability wasound to far exceed differences in composition between leannd obese individuals within each study and the authors con-luded that this suggests that there is no simple taxonomicignature of obesity in the gut microbiota. An identicalonclusion was reached in a meta-analysis of indicator taxan the microbiome and general features of the microbiotassociated with obesity.36

Another important point to highlight is that certain stud-es, instead of correlating the type of microbiota observedith the risk of developing obesity, defend the idea that

t is the limited diversity of the gut microbiota that mayredispose individuals to weight gain.37---39 This fact may belosely linked to evidence that a lack of diversity in theut microbiota of the Western population40---42 may influencehe increase in overweight and obesity rates in the samenvironment.

Finally, as in animal models, it can also be concludedhat, in the case of humans, a low-calorie diet modifies theicrobiota composition, generally increasing the proportion

f Bacteroidetes and reducing the proportion of Firmicutes,nd is also accompanied by weight loss.9,43,44 One study con-ucted in overweight adolescents even shows that a certainut microbiota composition may potentiate the efficacy ofietary interventions in weight loss.45

robiotics and obesity

he classic approach to obesity involves making lifestylehanges and restricting bariatric surgery to the most severeases. The main limitation of the conventional treatment

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Influence of the microbiota and probiotics in obesity 5

Table 1 Use of probiotics for weight control: animal model studies.

Reference Animals Strain (dose) Duration of treatment Main outcome

Miyoshi et al., 201555 29 mice withdiet-induced obesity

Lactobacillus gasseriSBT2055 (5 × 108 CFU)

24 weeks ↓ Weight and body fat↓ Leptin

Park et al., 201456 40 mice withdiet-induced obesity

Lactobacillusplantarum LG42(107 CFU and 109 CFU)

12 weeks ↓ Weight and body fat

Park et al., 201357 36 mice withdiet-induced obesity

Lactobacilluscurvatus HY7601(5 × 109 CFU) andLactobacillusplantarum KY1032(5 × 109 CFU)

18 weeks ↓ Weight and body fatModulation ofpro-inflammatorygenes or fatty acidoxidation-relatedgenes in the liver andadipose tissue

Fåk et al., 201258 39 mice withmetabolic syndrome

Lactobacillus reuteriATCC PTA 4659, DSM17938 and L6798(109 CFU)

12 weeks ↓ Weight and bodyfat (for ATTC PTA4659 only)↓ Insulin resistance(fasting insulinaemia)

Kondo et al., 201059 18 mice withdiet-induced obesity

Bifidobacteriumbreve B-3 (108 or109 CFU)

8 weeks Suppression of weightgainImprovedcholesterolaemia,insulinaemia andbasal glycaemia

An et al., 201160 36 male rats BifidobacteriumpseudocatenulatumSPM 1204,Bifidobacteiumlongum SPM 1205 and1207 (108---109 CFU)

7 weeks ↓ Weight and body fat↓ Blood pressure

Yin et al., 201032 48 male rats Bifidobacteria L66-5,L75-4, M13-4 andFS31-12 (108 CFU)

6 weeks ↓ Weight in L66-5 andimproved weight gainin M13-4↓ Triglyceridaemiaand cholesterolaemia

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CFU: colony-forming unit; ↓: decrease.

of diet and physical activity is its limited efficacy, both inthe short and long term.46 Bariatric surgery, however, whichis the most effective treatment for obesity, can achieveremission of comorbidities.47,48 Nevertheless, surgery is notexempt from potential complications and it is therefore nec-essary to find new therapeutic strategies for obesity control,in combination with adjuvant lifestyle changes, such as newdrugs or the use of probiotics as treatment. This was themotive for early studies to analyse the efficacy of probioticsas a possible way of controlling obesity.

Probiotics were defined by the Food and Agriculture Orga-nization and by the World Health Organization as ‘‘livemicroorganisms which, when administered in adequateamounts, confer a health benefit on the host’’.49 Thesemicroorganisms do not permanently colonise the gut andmust remain alive along the entire length of the digestive

tract. Therefore, to be considered good candidates, bacte-rial strains must have certain features that contribute tohost colonisation: tolerance of low pH in the stomach, resis-tance to bile salts and adherence to the host epithelium.50

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Probiotics interact with the host through pattern recogni-ion receptors in intestinal cells, such as Toll-like receptors,nd these can play multiple roles in the individual’s body.he mechanisms of action of probiotics associated with obe-ity control may be modulation of endogenous microbiotaunctions which affects interaction with the host, compet-tive exclusion of pathogens, improved epithelial barrierunction and other innate immune responses, modulationf fat absorption and excretion, reduced endotoxemia andnflammation, and modulation of numerous genes involvedn hepatic lipogenesis or lipolysis in adipose tissue.51---54

tudies in animal models

here are a large number of studies (Table 1) that have

bserved a decrease in body weight and body fat in obeseice after introducing different strains of Lactobacillus:

actobacillus gasseri SBT2055 for 24 weeks55, L. plantarumG42 for 12 weeks56, Lactobacillus curvatus HY7601 and

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6 L. Fontané et al.

Table 2 Use of probiotics for weight control: human studies.

Reference Design Subjects Strain (dose) Duration oftreatment

Main outcome

Agerholm-Larsenet al., 200068

DBPCR 70 overweight orobese subjects

Enterococcusfaecium (109 CFU),Lactobacillusacidophilus(109 CFU),Lactobacillusrhamnosus(1010 CFU) and twostrains ofStreptococcusthermophilus(109 CFU, 1010 CFUor 1011 CFU)

8 weeks ↓ LDL cholesterol↑ Fibrinogen withE. faecium(109 CFU) + S.thermophilus(1011 CFU)No effects on bodyweight or leanmass

Brahe et al.,201572

SBPCR 50 obesepost-menopausalwomen

Lactobacillusparacasei N19(9.45 × 1010 CFU)

6 weeks No effects

Kadooka et al.,201061

DBPC 87 subjects withhigh BMI

Lactobacillusgasseri SBT2055(5 × 1010 CFU)

12 weeks ↓ Body weight,BMI, visceral andsubcutaneous fat,waist and hipcircumference↑ Plasmaadiponectin

Kadooka et al.,201362

DBPC 210 adults withhigh abdominaladiposity

Lactobacillusgasseri SBT2055(5 × 1010 CFU)

12 weeks ↓ BMI, visceral andsubcutaneous fat,waist and hipcircumference

Gøbel et al.,201273

DBPC 50 obeseadolescents

Lactobacillussalivarius LS-33(1010 CFU)

12 weeks No effects

Jung et al., 201363 DBPCR 62 obese subjects Lactobacillusgasseri BNR17(6 × 1010 CFU)

12 weeks ↓ Body weight andhip circumference

Larsen et al.,201369

DBPCR 50 obeseadolescents

Lactobacillussalivarius LS-33(1010 CFU)

12 weeks ↑ Bacteroides,Prevotella andPorphyromonas

Leber et al.,201274

Open-label trial 28 obese subjectswith metabolicsyndrome and 10healthy controls

Lactobacillus caseiShirota (1010 CFU)

3 months No effects

Luoto et al.,201064

DBPCR 159 pregnantwomen

Lactobacillusrhamnosus ATCC53103 (1010 CFU)

4 weeks beforedelivery+6 months afterdelivery

↓ BMI of childrenin early life (1-10years)

Omar et al.,201370

DBPCR 28 obese subjects Lactobacillusamylovorus andLactobacillusfermentum(1.39 × 109 CFUand1.08 × 109 CFU)

43 days ↓ Body fat, nochanges in bodyweight

Rajkumar et al.,201371

SBPCR 60 overweightsubjects

Bifidobacteria,Lactobacilli andStreptococcusthermophilus(112.5 × 109 CFU)

6 weeks Improved lipidprofile and insulinresistance(HOMA-IR)↓ CRP

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Influence of the microbiota and probiotics in obesity 7

Table 2 (Continued)

Reference Design Subjects Strain (dose) Duration oftreatment

Main outcome

Sharafedtinovet al., 201365

DBPCR 40 obese adults Lactobacillusplantarum TENSIA(1.5 × 1011 CFU/g)

3 weeks ↓ Body fat, BMIand blood pressure

Woodard et al.,200966

Open-label trial 40 morbidly obesesubjects aftergastric bypass

Lactobacillus spp.Puritan’s Pride(2.4 × 109 CFU)

6 months ↓ Body weight at 3months

Zarrati et al.,201367

DBCR 75 subjects withhigh BMI

Lactobacillusacidophilus La5,Bifidobacteriumlactis Bb12 andLactobacillus caseiDN001 (108 CFU/g)

8 weeks ↓ Body weight,BMI

BMI: body mass index; CFU: colony-forming unit; CRP: C-reactive protein; DBPC: double-blind, placebo-controlled clinical trial; DBPCR:low d

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double-blind, placebo-controlled, randomised clinical trial; LDL:

domised clinical trial; ↓: decrease; ↑: increase.

L. plantarum KY1032 for 18 weeks57, L. reuteri ATCC PTA465958; among others.11 Other metabolic changes, such asdecreased leptin levels55, reduced resistance to insulin58

or modulation of pro-inflammatory genes or fatty acidoxidation-related genes in the liver and adipose tissue, havealso been noted.57

Similar studies have been conducted in animal modelson Bifidobacterium treatment in obesity, showing weightloss or decreased body fat: Bifidobacterium breve B-3for 8 weeks59, Bifidobacterium pseudocatenulatum SPM1204, Bifidobacterium longum SPM 1205 and 1207 for 7weeks60 or Bifidobacteria L66-5 for 6 weeks.32 Decreasedcholesterolaemia, glycaemia and insulinaemia59 or lowerconcentrations of leptin or lipase60 were also reported,among other beneficial effects.

Studies in humans

Few studies have been conducted in humans to date toexamine the effect of probiotics on body weight. In com-parison with the mainly favourable results of animal modelstudies, there is little evidence from human studies for rec-ommending the use of probiotics in treating obesity.

Based on the long tradition of using lactic acid bacte-ria with no harmful effects on human health, bacteria fromthe genera Lactobacillus and Bifidobacterium have an estab-lished history of safe use and have received GRAS (GenerallyRecognised as Safe) status from the Food and Drug Admin-istration. As a result, these two groups of bacteria havebeen evaluated the most (Table 2). Not all studies show apositive relationship between probiotic use and obesity con-trol. While some have linked the administration of differentstrains of bacteria (L. gasseri SBT2055, L. gasseri BNR17,Lactobacillus rhamnosus ATCC 53103, L. plantarum TENSIA,

Lactobacillus spp. Puritan’s Pride, Lactobacillus acidophilusLa5, Bifidobacterium lactis Bb12 and L. casei DN001) toweight loss61---67, others have observed positive metabolicchanges but with no change in weight parameters.68---71 Other

ensity lipoprotein; SBPCR: single-blind, placebo-controlled, ran-

apers, however, showed no significant changes with probi-tic use as a treatment for obesity.72---74

The different findings may be due to inconsistenttudy methodologies, less homogeneous study populations,ample size, wide variability in study strains and short inter-ention time.

To conclude, the studies conducted have confirmed thenfluence of microbiota on the host metabolism, with a focusn its role in the regulation of energy homeostasis and itsathogenic role. However, more extensive epidemiologicaltudies are required to be able to confirm whether the rela-ionship between microbiota and obesity is due to diversityn bacterial flora, the presence of specific species in the gut,ossible functional changes in gut microbiota or a combina-ion of different factors.

With regard to the role of probiotics as a treatment forbesity, available evidence is controversial and thereforedditional studies are required to assess the therapeutic usef probiotics for treating obesity.

onflicts of interest

he authors declare that there is no conflict of interestegarding the publication of this article.

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