Best Practice & Research Clinical Gastroenterology 27 (2013) 59–72

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Best Practice & Research Clinical

Gastroenterology

Nutrition, the gut microbiome and the metabolic

syndrome
Petia Kovatcheva-Datchary, PhD, Postdoctoral Fellow *,
Tulika Arora, PhD, Postdoctoral Fellow 1
Sahlgrenska Center for Cardiovascular and Metabolic Research, Wallenberg Laboratory, Department of
Molecular and Clinical Medicine, University of Gothenburg, Bruna Straket 16, 413 45 Gothenburg, Sweden

a b s t r a c t
Keywords:
Gut microbiota Metabolic syndrome is a lifestyle disease, determined by the inter-
Metabolic syndrome play of genetic and environmental factors. Obesity is a significant risk
Obesity factor for development of the metabolic syndrome, and the preva-
Prebiotic
lence of obesity is increasing due to changes in lifestyle and diet.
Probiotic
Recently, the gut microbiota has emerged as an important contrib-
utor to the development of obesity and metabolic disorders, through
its interactions with environmental (e.g. diet) and genetic factors.
Human and animal studies have shown that alterations in intestinal
microbiota composition and shifts in the gut microbiome towards
increased energy harvest are associated with an obese phenotype.
However, the underlying mechanisms by which gut microbiota af-
fects host metabolism still need to be defined.
In this review we discuss the complexity surrounding the in-
teractions between diet and the gut microbiota, and their connec-
tion to obesity. Furthermore, we review the literature on the effects
of probiotics and prebiotics on the gut microbiota and host meta-
bolism, focussing primarily on their anti-obesity potential.
Ó 2013 Elsevier Ltd. All rights reserved.

Introduction

Diet and lifestyle are crucial factors that influence the susceptibility of humans to metabolic dis-
eases. Metabolic syndrome is a modern concept and is defined as a combination of metabolic and
medical disorders such as obesity, elevated fasting glucose, high blood pressure and dyslipidemia [1,2].

* Corresponding author. Tel.: þ46 31 3428672; fax: þ46 31 82 3762.

E-mail addresses: Petia.Kovatcheva@wlab.gu.se (P. Kovatcheva-Datchary), Tulika.Arora@wlab.gu.se (T. Arora).
1
Tel.: þ46 31 3428672; fax: þ46 31 82 3762.

1521-6918/$ – see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bpg.2013.03.017
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The rates of occurrence of these conditions and interactions with each other differ between sex, age
and ethnicities. However, diagnosis with any component of the metabolic syndrome increases the risk
of developing cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM) [3].
The recent rise in obesity is regarded as the triggering factor for expansion of the metabolic syn-
drome. Although genetics play a role in the development of obesity, environmental factors are thought
to be responsible for the recent dramatic increase in the prevalence of obesity. Obesity results from an
imbalance between energy intake and expenditure. Growing evidence reveals the importance of the
gut microbiota in the development of obesity (obesity pathogenesis). Thus dietary strategies to
manipulate the gut microbiota, particularly the use of probiotics and prebiotics as therapeutics, are
proposed for obesity and metabolic syndrome management (Fig. 1) [4].
The human gut harbours an immense assemblage of microorganisms, the gut microbiota, which
comprise a population of 1014 cells. Their collective genome, termed the metagenome or microbiome,
outnumbers the human genome by 150-fold [5]. Interestingly, this metabolic repertoire delicately
affects our physiology with functions that we have not to evolve on our own. Gut microbiota possess an
array of activities associated with utilization of non-digestible dietary carbohydrates and host-derived
glycoconjugates (e.g. mucin), deconjugation and dehydroxylation of bile acids, biosynthesis of vitamins
(K and B group) and isoprenoids, and metabolism of amino acids and xenobiotics. Based on this col-
lective metabolic potential, the gut microbiota can be viewed as a separate ‘microbial organ’ [6].
In this review, recent advances in understanding the role of the gut microbiota in the development
of obesity and potential therapeutic applications will be explored.

Nutrition and gut microbiota maturation

The interactions between diet and the gut microbiota in mammals are extremely complex, and any
major change in lifestyle or diet is likely to affect microbial stability. Diet is a primary determinant in
the development of the microbiota colonization pattern from the first stages of life. Exclusive
breastfeeding results in an infant gut microbiota composition that is enriched in bifidobacteria and
lactic acid bacteria, while formula feeding results in a more diverse community that is dominated by

Fig. 1. Interaction between diet and gut microbiota affects host metabolism. Dietary manipulation with probiotics and prebiotics
alters the composition and metabolic capacity of gut microbiota. Dietary manipulation in obesity with prebiotics and probiotics
changes gut microbiota by favouring bacteria beneficial to the host and enhances the production of short chain fatty acids (SCFAs) –
acetate, propionate and butyrate. These result in decreased lipogenesis, reduced inflammation and oxidative stress in liver;
decreased adipogenesis, and reduced adipocyte size and number in adipose tissue; increased production of gut hormones and
intestinal transit in the large intestine; reduced appetite in the brain. GLP-1: Glucagon like peptide-1, PYY: Peptide YY.
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bifidobacteria, Bacteroides spp., Clostridium spp., and facultative anaerobes [7,8]. Breast milk is rich in
oligosaccharides, which are known to act as substrates for fermentation in the distal gut and promote
the growth of beneficial microbes as bifidobacteria [7]. The introduction of solid food leads to a large
compositional shift into the intestinal microbiota composition [8,9]. Recently, the impact of diet on the
gut microbiota composition at the stage of infant weaning has been studied. Comparison of the fecal
microbiota by 16S rDNA sequencing of children from Burkina Faso (BF) consuming a rural African diet
with children from Italy consuming a modern Western diet showed no significant differences in the
microbiota composition between the two cohorts during the breastfeeding period [10]. However,
weaning resulted in significant changes in the gut microbiota in both groups. In the BF children,
enrichment in Bacteroidetes, with a significant abundance of bacteria from the genera Prevotella and
Xylanibacter, was observed. These functional groups encode enzymes for hydrolysis of cellulose and
xylan, thus enabling degradation of polysaccharides. In addition, fecal levels of short chain fatty acids
(SCFAs), the main products of polysaccharide fermentation, were higher in BF children. A relative
depletion of Firmicutes was also observed in the BF children. In the Italian children, these features were
completely absent.
Parallel ontogenetic changes of the microbiome among Malawian, Venezuelan and American
populations from infants to adults, associated with differences in diet, culture and lifestyle, have been
reported by Gordon’s group [11]. Greatest interpersonal variation, both in species and genes level, has
been recorded in the infant microbiome, but still bifidobacteria was the dominant microbial group. The
functional repertoire of the infant microbiome of the three populations was shaped with genes
necessary for folate biosynthesis with a later shift to folate metabolism. Genes necessary for synthesis
of vitamins, like B1, B7 and especially B12, were more enriched in the adult microbiome, together with
genes involved in fermentation, methanogenesis, and metabolism of certain amino acids. Interestingly,
the authors observed that the gut microbiomes of the Malawian and Venezuelan populations, which
consume a ‘rural’ diet, were enriched in Prevotella spp., similar to the observation of De Filipo et al [10]
in the Burkina Faso cohort. In the American population, since the diet is higher in protein, the
microbiome is enriched with genes necessary for breaking down amino acids. Moreover, the micro-
biome of the American tends to shift to a more Bacteroides-enriched gut community [11]. These results
support previous findings that carnivore microbiomes are enriched in protein degradation genes, while
herbivore microbiomes are enriched in genes necessary to break down starch [12].
Together, these data confirm that nutrition is a driving factor in shaping gut microbiota composition
and its functional maturation, from birth to adulthood. Nevertheless, more studies are needed to
determine what factors or events during gut microbiota maturation might contribute to the devel-
opment of metabolic disorders.

Gut microbiome and obesity

The development of obesity is a multifactorial process involving genetic susceptibility and envi-
ronmental factors, such as lifestyle and inappropriate diet. Still the root of obesity aetiology is an
imbalance between food intake and energy expenditure.
Recently, the gut microbiota has been suggested as a driving force in the pathogenesis of metabolic
disease and particularly obesity. Bäckhed and co-workers showed that mice raised in absence of mi-
croorganisms, termed germ-free (GF), had less total body fat than mice that were colonized with a
normal microbiota at birth, termed conventionally raised (CONV-R), despite the fact that GF animals had
higher caloric intake [13]. Colonization of GF mice with cecal content from CONV-R donors (resulting in
‘conventionalized’ (CONV-D) mice) resulted in increased total body fat without any increase in food
consumption or energy expenditure. The CONV-D animals also displayed impaired glucose metabolism,
increased levels of circulating leptin and glucose, and adipocyte hypertrophy after the two-week
colonization period [13]. In a following study, Bäckhed and co-workers demonstrated that GF mice fed a
high-fat, high-carbohydrate Western diet for eight weeks gained significantly less weight than CONV-R
mice and were protected against diet-induced glucose intolerance and insulin resistance [14]. These
findings suggest a relationship between nutrition, gut microbiota and energy homeostasis.
Furthermore, several studies have suggested that the obese microbiome has an altered composition
and functional repertoire. The development of obesity in genetically obese leptin deficient ob/ob mice
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has been associated with a reduction in the abundance of Bacteroidetes and a proportional increase in
Firmicutes, two of the major bacterial phyla in the gut microbiota [15]. Similar changes in microbiota
composition have been observed in wild-type mice fed a high-fat/high-sugar Western diet [16].
However, comparisons of the abundance of the two major bacterial phyla in obese vs. lean microbiome
in animals and humans, have produced conflicting results. While several studies have reported similar
increases in the ratio between Firmicutes and Bacteroidetes in obese individuals [17–19], other studies
have not observed a change in the Firmicutes/Bacteroidetes ratio [20–22]. For example, one study
reported reductions in Bifidobacterium spp. and Bacteroidetes and increases in specific members of
Firmicutes (e.g. Staphylococcus) and Proteobacteria (e.g. Enterobacteriaceae) in overweight pregnant
women [19], while another study found enrichment in Prevotellaceae, a group within the Bacteroidetes
phylum, in obese individuals [20]. These disparities highlight the importance of considering factors
such as diet, age, degree of obesity, demographic geography and population size, as well as technique
and methodology used to profile the gut microbiota, when comparing studies.
Nevertheless, an altered functional repertoire has been associated with the obese microbiome.
Turnbaugh and co-workers identified a ‘core microbiome’ of microbial genes shared among individuals
and found that variations from that core are associated with obesity [23]. Further metagenomic and
systems biology-based approaches reached a similar conclusion, indicating that obese microbiomes
have reduced taxonomic richness and a less modular metabolic network in comparison with lean
microbiomes [5,24,25]. Comparable observations have been reported in a study comparing the
microbiomes of pregnant women in the first and third trimester. The microbiomes from women in the
third trimester were characterized by reduced microbial diversity and enrichment in Proteobacteria
and Actinobacteria. Moreover, the transfer of fecal microbiota from women in the third trimester to
germ-free mice induced symptoms of metabolic syndrome in the mice [26]. We might need more
studies focused on identifying important microbial genes instead of on characterizing gut microbiota
composition in order to describe the obese microbiome and further predict its response after thera-
peutics treatment. More mechanistic studies in animals are needed in order to elucidate functions of
specific gut microbes on the host and to better understand their interactions with environmental
factors (e.g. diet).

Dietary manipulation in obesity

As discussed earlier, it is possible to manipulate the gut microbiota composition with diet. The
major dietary ingredients studied in recent years include prebiotics, probiotics and synbiotics. The
interaction of these dietary ingredients with the microbiota is accompanied by physiological changes
in the host. We will focus on the metabolic interaction of probiotics and prebiotics with the host and
their anti-obesity potential (Fig. 1).

Probiotics

Metabolic interactions of probiotics with gut microbiota

Probiotics are dietary supplements consumed in the form of fermented milk products, fermented
foods or as drugs. Probiotics are defined as the live microorganisms that, when administered in
adequate amounts, confer health benefits to the host [27]. Probiotic supplementation results in
enrichment of the probiotic species in intestinal contents. It also results in alterations in the compo-
sition of gut microbiota and microbial metabolites, like SCFAs, in both murine models [28] and humans
[29]. Recent applications of metagenomic and associated techniques have provided insight into the
interaction of probiotics with the host gut microbiome. To reduce the complexity of studying crosstalk
between probiotic species and millions of resident bacteria, GF mice were colonized with a simplified
microbiota or mono- or bi-associated with representative bacterial species. Their interaction with
probiotic bacteria was determined in this simplified setting by either global transcriptomics or global
metabolite analysis as discussed in the following section.
With regard to energy homeostasis, probiotics have been reported to expand the carbohydrate
utilization properties of host microbiota members. In GF mice monocolonized with Bacteroides
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thetaiotamicron, co-colonization with Bifidobacterium longum resulted in upregulation of a gene locus

in B. thetaiotamicron involved in the hydrolysis of xylose containing glycans. In contrast, co-
colonization with Lactococcus casei upregulated a different set of genes encoding hexosaminidases
and arabinosidases [30]. Enhanced carbohydrate utilization from non-digestible plant polysaccharides
is known to result in higher production of SCFAs that contribute to total energy in the host. In GF mice
monoassociated with the probiotic strains Lactobacillus plantarum WCFS1 [31] and Lacobacillus john-
sonii NCC533 [32], an upregulation of genes involved in carbohydrate transport and metabolism was
observed. While increased efficiency to hydrolyse different complex sugars in L. plantarum WCFS1
resulted in higher production of fumarate and alcohol [31], it led to a longer colonization period of L.
johnsonii NCC533 in the mouse gut [32]. Consumption of fermented milk containing multiple probiotic
strains led to enrichment of enzymes catalysing carbohydrates into propionate in both monozygotic
twins and gnotobiotic mice containing a model human microbiota community [33].
Global metabolite profiling has also demonstrated that probiotics may affect the gut microbiome. L.
paracasei altered levels of lipid species, creatine and glutathione implicating changes in lipid synthesis,
nutrient absorption and oxidative stress in gnotobiotic mice [34]. L. paracasei and L. rhamnosus
administration decreased the acetate:propionate ratio and increased catabolism of amino acids in
humanized gnotobiotic mice. Changes in bile acid metabolism were observed with L. paracasei
exclusively [35]. Thus, probiotics can alter both gene expression and function of the gut microbiota,
thereby altering energy homeostasis and physiological functions in the host.

Anti-obesity potential of probiotics

With advancing knowledge of how probiotics interact with the gut microbiome, there is an
increasing interest in exploring the anti-obesity potential of probiotics. Our main focus is to include the
studies that have reported effects of probiotic supplementation on weight loss, energy intake or
epididymal fat reduction (Table 1).
Conjugated linoleic acid (CLA) is a naturally occurring derivative of linoleic acid found in foods and
dairy products and has been shown to increase metabolic rate in mice [36]. The CLA-producing pro-
biotic strain L. rhamnosus PL60 has been reported to reduce body weight gain and white adipose tissue
mass with no effect on food intake in high-fat diet fed mice. The effect was coupled to higher
expression of uncoupling protein-2 (UCP2), while expression of fatty acid synthase (fas) and serum
leptin and glucose levels were reduced [37]. Another probiotic strain that produces CLA, L. plantarum
PL62, also resulted in reduced body weight gain and glucose levels in diet-induced obese mice [38].
Probiotics have been shown to reduce adipocyte size in different adipose depots [39,40], which is
considered an important parameter in assessing their anti-obesity potential. The putative mechanisms
put forth are increased fecal excretion of neutral sterols and bile acids, decreased lymphatic absorption
of triglycerides, phospholipids and cholesterol [41], or increased lipolysis [42]. In the 3T3-L1 cell line,
incubation with L. plantarum KY1032 cell free extract resulted in reduced adipogenesis [43], and in-
cubation with the insoluble fraction from fermented kefir resulted in reduced adipocyte differentiation
[44]. Administration of L. paracasei NCC2461 to rats increased sympathetic nerve activity in white and
brown adipose tissue, resulting in higher thermogenesis in brown adipose tissue and increased
lipolysis in white adipose tissue [45]. Supplementation with L. paracasei F19 resulted in reduced total
body fat and decreased triglyceride levels in different lipoprotein fractions in mice fed high-fat diet
[46]. In addition, both GF and CONV-R mice supplemented with L. paracasei F19 had increased serum
levels of Angiopoietin-like 4 (ANGPTL4), a microbially regulated lipoprotein lipase inhibitor that reg-
ulates lipid deposition into adipocytes [14,46]. Administration of L. paracasei F19 and L. acidophilus
NCFB1748 to GF mice resulted in enrichment of probiotic strains in the ileum compared to the colon
and upregulation of insulin-sensitizing hormones, adipsin and adiponectin. Decreased expression of
resistin-like b, known to induce insulin resistance, was also reported [47]. Apoe/ mice that were
supplemented with L. reuteri ATCC exhibited reduced body weight gain, reduced adipose and liver
weights, and increased expression of carnitine palmitoyl transferase1a (cpt1a), suggesting higher he-
patic b-oxidation [48].
There are relatively few studies that couple changes in microbiota composition upon probiotic
supplementation with anti-obesity functions. Supplementation of L. rhamnosus GG and L. sakei NR28
Table 1
Anti-obesity effects of probiotic supplementation in animal and human studies.

Animal Diet Probiotic strain Dose Mode of Effects Reference

strain or delivery
human
1. C57/BL6J HFD L. rhamnosus PL60 1  107or PBS YBWG, YAT mass, [37]
mice 1  109 cfu/day No change in FI
2. C57/BL6J HFD L. plantarum PL62 1  107or PBS YBWG, YAT, [38]
mice 1  109 cfu/day No change in FI
3. Sprague– HFD L. gasseri SBT2055 6  107 cfu/g diet Fermented YAdipocyte size, [39]
Dawley milk powder No change in BWG,
rats added to diet AT mass
in 20%
concentration
4. Zucker HFD L. gasseri SBT2055 6  107 cfu/g diet Fermented YAT, YAdipocyte [41]
obese and milk powder size in lean rats,
lean rats added to diet No effect on BWG,
in 20% FI
concentration
5. C57/BL6 HFD L. plantarum 14 1  108 cfu/mouse PBS YAdipocyte size, [40]
mice YAT, No effect on
BWG
6. Sprague– HCD L. gasseri BNR 17 2  109/ml PBS YBWG, YAT, [104]
Dawley rats No effect on FI
7 10
7. db/db Regular L. gasseri BNR 17 10 –10 cfu/day PBS YBWG, YFI [105]
mice diet
9. Sprague– HFD VSL#3 (Lactobacilli, 1.5  109 Water YAT, No change in [66]
Dawley Bifidobacterium cfu/mouse BWG, FI
rats spp. & S. salivarius
ssp. thermophilus)
10. Wistar HFD L. paracasei ST11 5  108/ml Water YBWG, YAT, [45]
rats (NCC2461) No change in FI
11. Sprague– HFD B. pseudocatenulatum 108–109 cfu PBS YBWG, YAT, [106]
Dawley SPM 1204, B. longum No change in FI
rats SPM 1205, and
B. longum SPM 1207
12. Wistar HFD B. longum 2  109/ml Saline YBWG, YAT, [107]
rats Yblood
glucose
14. Sprague– HFD L. plantarum DSM 109 cfu/day Water YBWG, YAT, [108]
Dawley 15313 Yleptin
rats
15. C57/BL6J HFD L. acidophilus 5  107–9  107/ml Yoghurt [Bifidobacterium [50]
mice NCDC13 spp., No change
in FI, BWG, AT
16. C57/BL6J Normal L. sakei NR28 or 108 cfu/10 ml Oral gavage YFirmicutes – [49]
mice Chow L. rhamnosus GG particularly
Clostridium
cluster XIVa,
YBWG, YAT
17. Balb/c Normal L. ingluviei 4  1010 Gastric [Firmicutes, [51]
mice Chow lavage Lactobacillus spp.,
[BWG
18. Apoe/ High-fat L. reuteri ATCC PTA 109 cfu/mouse Drinking YBWG, YAT, Yliver [48]
mice western 4659, DSM 17938 per day water weight
diet – 0.2% (DSM), L6798
cholesterol
19. Healthy, Regular L. gasseri SBT2055 5  1010 cfu/100 g Fermented YVisceral, [52]
overweight diet product subcutaneous fat,
subjects YBWG, YBMI
20. Infants Formula L. rhamnosus GG 107 cfu/g Formula diet [Length, [weight [53]
diet
21. Pregnant Regular L. rhamnosus GG 1  1010 Capsules YBWG in children [54]
women diet

AT: Adipose tissue, BWG: Body weight gain, FI: Food intake, HCD: High-carbohydrate diet, HFD: High-fat diet, PBS: Phosphate
buffered saline.
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reduced the relative abundance of both Firmicutes and Clostridium cluster XIVa in the small intestine of
mice and was accompanied by reduced body weight gain, epididymal fat mass and expression of
hepatic stearoyl-CoA desaturase-1 (scd-1), fas and acetyl-CoA carboxylase (acc) enzymes involved in
lipogenesis [49]. However, supplementation with L. acidophilus NCDC13 in diet-induced obese mice
increased total bifidobacteria in caecal contents as well as feces but did not decrease adiposity [50]. In
yet another study, inoculation with L. ingluviei enriched total fecal Lactobacillus spp. and Firmicutes in
mice and, in contrast to other studies, resulted in increased body weight gain, liver weight, and
metabolism [51].
In healthy overweight subjects, administration of L. gasseri SBT2055 resulted in reduction of
abdominal visceral and subcutaneous fat [52]. Supplementation of L. rhamnosus GG in the infant for-
mula for six months resulted in better growth with higher weight gain [53]. However, in a follow up
study, pre- and postnatal administration of L. rhamnosus GG inhibited excessive weight gain in children
[54]. Thus, the physiological effects of probiotics are highly strain-dependant. The variations in out-
comes between different studies appear to be due to choice of probiotic strain, route of administration
and length of study.

Probiotic effect on liver function

Hepatic steatosis is closely linked to metabolic syndrome. It is characterized by aberrant lipid

storage in liver and subsequent hepatic inflammation. Ischemia/reperfusion is a model of acute liver
injury which leads to disruption of gut microbiota composition with increases in Enterococci and
Enterobacteria and concomitant decreases in Lactobacillus spp. and Bifidobacterium spp., eventually
resulting in higher plasma endotoxin levels. In addition, bacterial translocation to the kidney has been
reported [55]. Colonization of GF mice with microbiota from hyperglycaemic mice has been shown to
contribute to the development of fatty liver disease independent of obesity [56]. Probiotics have also
been implicated in the improvement of liver functions. These effects are mediated by the role of
probiotic bacteria in normalization of intestinal microbiota composition, immunomodulation and
maintenance of gut barrier function [57].
L. paracasei F19 supplementation protected rats from ischemia/reperfusion-induced liver injury by
restoring ileal lactobacilli and bifidobacteria numbers and intestinal barrier [58]. Supplementation
with different lactobacilli strains (L. acidophilus NM1; L. rhamnosus ATCC 53103, and L. rhamnosus DSM
6594 þ L. plantarum DSM 9843) [59] or with the combination of L. fermentum and B. catenulatum [60]
prevented bacterial translocation and decreased Enterobacteriaceae in a rat model of acute liver injury.
However, B. animalis increased the bacterial translocation to mesenteric lymph nodes with no effect on
liver damage [59]. L. rhamnosus GG ameliorated alcohol-induced liver disease by reducing inflam-
mation and oxidative stress in both liver and colon [61]. It also reduced alcohol-induced gut leakiness,
increased expression of ileal tight junction proteins maintaining the epithelial integrity [62], and
decreased endotoxemia preserving the gut barrier function [62]. The effects exerted by the probiotic
were found to be dependant on hypoxia-inducible factor [63]. Supplementation with VSL#3, another
multistrain probiotic, mediated a natural killer T cell-dependant improvement in diet-induced stea-
tosis and hepatic insulin signalling, resulting in improved insulin sensitivity [64]. VSL#3 supplemen-
tation also reduced c-jun kinase activity and hepatic lipogenesis in leptin deficient ob/ob mice [65]. The
antioxidative effects of VSL#3, coupled with reductions in inflammatory enzymes like inducible
nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2, have also been shown to protect against liver
damage in mice [66].

Prebiotics

Metabolic interactions of prebiotics with gut microbiota

Prebiotics are defined as dietary ingredients that promote ‘the selective stimulation of growth and/or
activity(ies) of one or a limited number of microbial genus(era)/species in the gut microbiota that
confer(s) health benefits to the host’ [67]. Dietary fibres are known to exhibit prebiotic effects as they are
utilized by specific bacteria, resulting in their proliferation, which are considered beneficial to the host.
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The most studied prebiotic supplements are inulin and related variants such as fructooligosaccharides,
which have different degrees of polymerization. Inulin is generally bifidogenic in nature, i.e. it enhances
the growth of Bifidobacterium spp. and some Lactobacillus spp. in different murine models. This effect is
coupled with a reduction in body weight gain and improvements in glucose homeostasis [68–70] and
obesity-related inflammation called metabolic endotoxemia [71,72]. However, pyrosequencing revealed
that oligofructose feeding resulted in changes in more than 100 taxa, of which 16 taxa displayed more
than ten fold change [73]. One of the identified species was Akkermansia muciniphila, which was
negatively correlated with body weight [19]. Other studies have also shown that prebiotic fibre
decreased the Firmicutes to Bacteroidetes ratio in obese rats [74]. Supplementation of fungal chitin
glucan increased the number of bacteria closely related to Clostridium cluster XIVa including Roseburia
spp., which was accompanied by reduced weight gain and fat mass development [75]. Wheat derived
arabinoxylans also restored the levels of Bacteroides–Prevotella spp. and Roseburia spp. and markedly
increased caecal bifidobacteria content, in particular B. animalis lactis, in high-fat diet fed mice [76].
In healthy humans, the consumption of polydextrose and soluble corn fibre led to greater fecal
Clostridiaceae and Veillonellaceae and lower Eubacteriaceae. The abundance of Faecalibacterium, Phas-
colarctobacterium, and Dialister was greater following prebiotic intake [77]. Addition of inulin to the
diet increased Bifidobacterium spp. and Faecalibacterium prausnitzi and decreased Bacteroides intesti-
nalis, Bacteroides vulgatus and Propionibacterium in obese women [78]. Consumption of gal-
actooligosaccharides for 12 weeks induced increases in several lineages of Bifidobacterium spp. at the
expense of Bacteroides in healthy human subjects [79].

Anti-obesity potential of prebiotics

Prebiotics exhibit anti-obesity potential owing to their fermentation in distal gut and impact on gut
microbiota composition, which have different physiological prospects. The underlying mechanisms
driving the response are not clear. However, there are some links associated with production of SCFAs,
decrease in bacterial derived lipopolysaccharides and alteration in gut hormones production. The
major studies reflecting anti-obesity effects of prebiotics in both humans and animal models are
presented in Table 2.
The major effect of inulin supplementation appears to be its influence on production of gastroin-
testinal hormones like glucagon like peptide-1 (GLP-1), peptide YY (PYY), ghrelin and other related
peptide hormones both in rodents [70,74,80] and in humans [81–83]. These hormones modulate
several physiologic functions such as insulin secretion (incretin effect), gastrointestinal motility and
appetite regulation by modulating secretion of neuropeptides in major hypothalamic appetite centers.
These factors may all contribute to the anti-obesity potential of prebiotics. Microbial production of
SCFAs has been proposed to play a role in increasing secretion of gut hormones like GLP-1 [84,85].
Inulin supplementation has also been reported to reduce fat mass accumulation in different adipose
tissue depots and to affect adipose tissue metabolism. It reduces lipolysis in subcutaneous adipose
tissue and blunts the expression of GPR43, a G-protein coupled receptor that regulates adipogenesis in
diet-induced obese mice [86]. A link between the endocannabinoid system (eCB), changes in gut
microbiota composition and adipogenesis has also been suggested. The eCB system is overexpressed in
obesity [87]. Inulin supplementation in ob/ob mice decreased adiposity and was coupled with reduced
anadamide content and cannabinoid receptor-1 expression in adipose tissue [88].
Prebiotic supplementation has been shown to influence not only fat mass but also host energy ho-
meostasis. When gnotobiotic mice were colonized with microbiota from human infants and supple-
mented with L. paracasei and galactooligosaccharides, global metabolites analysis revealed increased
levels of glutamate, glutamine, branched-chain amino acids and alanine in the liver as well as accumu-
lation of hepatic glycogen, suggesting increased gluconeogenesis and glycogenesis [89]. It also increased
SCFAs production and excretion of protein breakdown metabolites [90]. The increased excretion of energy-
rich metabolites upon supplementation of inulin and beta-glucan was also shown in high-fat fed mice [91].
A role for prebiotic fibres in appetite regulation has also been demonstrated. The central hypo-
thalamic brain centers like arcuate nucleus, ventromedial hypothalamus, paraventricular nucleus and
brainstem regions involved in appetite regulation were shown to be differentially activated upon
prebiotic feeding. A satiating effect of resistant starch, supported by reduced neuronal activity in
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Table 2
Anti-obesity effects of prebiotic supplementation in animal and human studies.

Animal strain Diet/period Prebiotic Dose Effects Reference

or human
1. Wistar rats, Regular Raftilose P95 100 g/kg diet Improve glycaemia and plasma [70]
male diet/six (OFS based) insulin, [plasma portal GLP-1, YFI
weeks
2. Wistar rats, HFD/five OFS 100 g/kg diet [plasma portal GLP-1, [serum GIP, [80]
male weeks YBWG
3. C57/BL6J mice, HFD/four OFS 100 g/kg diet Yfasted and fed blood glucose, YBWG [68]
male weeks
4. C57/BL6J mice, HFD/14 OFS Not described Restored Bifidobacterium spp. levels, [71]
male weeks improved blood glucose
5. ob/ob C57/BL6J HFD/eight OFS 0.3 g/mouse YFirmicutes, [Bacteroidetes, [73]
mice weeks per day YProteobacteria, [Verrucomicrobia,
[L-cell number, improved glucose
tolerance and lipid metabolism, YLPS
6. C57/BL6J mice, HFD/four AX 100 g/kg diet [Bifidobacterium spp. (e.g. B. animalis [76]
male weeks lactis), restored Roseburia spp. and
Bacteroides–Prevotella spp. levels,
YBWG, Yfat mass development, YAT
7. C57/BL6J mice, HFD/ weeks Chitin-glucan 100 g/kg diet [Firmicutes (Clostridium cluster XIVa – [75]
male fibre Roseburia spp.), YBWG, Yfat mass
development, Yfasting glucose,
improved glucose tolerance, Y hepatic
triglycerides, Y cholesterol
8. C57/BL6J mice, HFD/eight AXOS 75 g/kg diet [Bifidobacterium spp., YLactobacillus [109]
male weeks spp., YBWG, Ycaloric intake, Yfat mass,
[PYY, [GLP-1, YLPS
9. Lean and obese Regular Inulin-OFS 0%, 10% and 20% [Firmicutes, YBacteroidetes, dose [74]
JCR:LA-cp rats, diet/six Inulin–OFS mix dependant [Bifidobacterium spp. and
male weeks Lactobacillus spp., dose dependant
[satiety hormones
10. Men and Regular OFS 2  8.0 g/day [satiety after breakfast and dinner, [110]
women diet/two Yhunger and YFI following dinner
weeks
11. Men and Regular Orafti 2  8.0 g/day Yhunger, [satiety, [breath H2, [81]
women diet/two Synergy1 [GLP-1, [PYY
weeks
12. Men and Regular AXOS 2  5.0 g/day [Bifidobacterium spp., Yp-cresol urine [111]
women diet/three excretion
weeks
13. Men and Regular GOS 0.0 g, 2.5 g, GOS dose dependant [Bifidobacterium [79]
women diet/12 5.0 g, 10.0 g/day spp.
weeks
14. Men and Regular Chitin-glucan 1.5 g/day or YLDL oxidation, YLDL cholesterol [112]
women diet/six fibre 4.5 g/day
weeks
15. Obese Regular Inulin type 16 g/day [Actinobacteria (Bifidobacterium spp.), [78]
women diet/12 fructan [Firmicutes (Clostridium leptum group
weeks – Faecalibacterium prausnitzii),
YBacteroidetes
(B. intestinalis and B. vulgatus),
YPropionibacterium, YLPS
16. Men and Regular AXOS 0.0 g, 2.2 g, Dose dependant [Bifidobacterium spp., [113]
women diet/three 4.8 g/day Dose dependant [ferulic acid
weeks
17. Men and Regular GOS 2  4.0 g/day [Bifidobacterium spp. [114]
women diet/three
weeks

AT: Adipose tissue, AX: Arabinoxylan, AXOS: Arabinoxylan-oligosaccharide, BWG: Body weight gain, FI: Food intake, GIP: Gastric
inhibitory peptide, GLP-1: Glucagon like peptide-1, GOS: Galactooligosaccharide, HFD: High-fat diet, LDL: Low density lipo-
protein, LPS: lipopolysaccharide, OFS: Oligofructose, PYY: Peptide YY.
68 P. Kovatcheva-Datchary, T. Arora / Best Practice & Research Clinical Gastroenterology 27 (2013) 59–72

ventromedial and paraventricular hypothalamic nuclei, was shown [92]. Supplementation with beta-
glucan also resulted in reduced activity in the arcuate nucleus and related appetite centers, which
could explain the reduced weight gain in animals [91]. On the contrary, inulin supplementation was
shown to increase neuronal activity in the arcuate nucleus; however, a reduction in body weight gain
was consistently observed [93].

Prebiotics effect on liver function

Prebiotics may also ameliorate liver diseases by decreasing hepatic de novo lipogenesis [94]. A number
of studies have shown reductions in enzymes like acc, malic enzyme, ATP citrate lipase and fas upon
prebiotic supplementation [95–98]. However, other studies have not found any effect on fatty acid
synthase, but rather on enzymes expression involved in b-oxidation of lipids [99,100]. Reduction in free
fatty acid esterification to triglycerides in hepatocytes has also been reported [101]. Prebiotics may also
contribute in this regard by altering the acetate:propionate ratio [102,103]. As acetate is lipogenic in
nature, production of more propionate compared to acetate may decrease the hepatic lipogenic potential.

Conclusion

The prevalence of obesity and allied disorders such as metabolic syndrome are becoming a great
challenge for health care throughout the world. Diet and lifestyle are crucial factors influencing the
development and progression of obesity. Recent insights have examined obesity aetiology with a new
perspective and found that our own microbiota might be involved in the development of these disor-
ders. The plexus surrounding diet and the microbiome in mammals remains to be unravelled. More
controlled human and animal studies are necessary to clarify these complex interactions. One possibility
is the combination of metagenomic and metabolomic approaches in order to further elucidate the
metabolic interactions between diet, the microbiota and the host and to understand how the micro-
biome is altered in obesity. Those approaches, combined with more mechanistic studies in animal
models, will help to further describe in situ functions of distinct microbial groups or individual species of
the gut microbiota and to understand their roles in human physiology including metabolic diseases.

Practice points

 Nutrition is a driving factor in shaping gut microbiota composition and its functional
maturation from the early stages of life.
 The gut microbiota has been recognized as an important contributor to pathological condi-
tions such as obesity and metabolic disorders.
 Alterations of the composition and functional properties of the gut microbiota have been
associated with obesity.
 Increasing Bifidobacterium spp. by dietary means may have anti-obesity effects.

Research agenda

 The mechanisms by which the gut microbiota contributes to the development or mainte-
nance of obesity are not well understood.
 The underlying mechanisms by which probiotics and prebiotics exert their anti-obesity
effects need to be deduced.
 There is a need for well-controlled studies with regard to gut microbiota modulation, changes
in microbial metabolites and corresponding anti-obesity effects following probiotic
supplementation.
 P. Kovatcheva-Datchary, T. Arora / Best Practice & Research Clinical Gastroenterology 27 (2013) 59–72 69

Acknowledgements

We thank Anita Wichmann for editing the manuscript and Anna Hallén for the graphical design. We
thank Fredrik Bäckhed for the helpful comments on the article.

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