Licensed to Caroline Modolo Ribeiro - [email protected] - 441.867.

408-01

360 Asia Pac J Clin Nutr 2014;23(3):360-368

Review Article

The influence of Mediterranean, carbohydrate and

high protein diets on gut microbiota composition in the
treatment of obesity and associated inflammatory state

Patricia Lopez-Legarrea PhD1,2, Nicholas Robert Fuller PhD3, María Angeles Zulet
1,4 1,4 3
PhD , Jose Alfredo Martinez PhD, MD , Ian Douglas Caterson PhD, MD
1
Department of Nutrition, Food Science & Physiology, University of Navarra, Pamplona, Spain
2
Faculty of Health Science, Universidad Autonoma de Chile, Santiago, Chile
3
The Boden Institute, the University of Sydney, NSW, Australia
4
CIBERobn, Physiopathology of Obesity and Nutrition, Carlos III Health Institute, Madrid, Spain

The role of the gut microbiota in understanding the onset and development of obesity is gaining importance. Die-
tary strategies are the main tool employed to counteract obesity, and nowadays they are focused on a wide range
of different aspects of diet and not only on calorie restriction. Additionally, diet is known to be a major factor in-
fluencing modification of the gut microbiota. Therefore the influence of both macronutrient and micronutrient
content of any dietary strategy to treat obesity on gut bacterial composition should now be taken into considera-
tion, in addition to energy restriction. This review aims to collect the available data regarding the influence of dif-
ferent dietary components on gut microbiota in relation to obesity and inflammatory states in humans. Although
more work is needed, specific dietary factors (carbohydrate, protein and Mediterranean foods) have been shown
to have an influence on the gut microbiome composition, meaning that there is an opportunity to prevent and treat
obesity based on microbiota outcomes.

Key Words: obesity, nutrition, gut microbiota, dietary strategies, inflammation

INTRODUCTION dietary factors is one way the microbiota composition can

Obesity has become a major public health problem being be shifted.8,9 Therefore, the study of the influence of dif-
described as the 21st century epidemic since the preva- ferent dietary elements on microbiota composition varia-
lence is expected to increase further.1 Overweight is not tion has become an area of growing scientific interest.
only a problem of itself, but also due to the obesity- Indeed, a relationship between the gut microbiota and
associated metabolic and mechanical disorders.2,3 Since obesity is well recognized, but the mechanisms underly-
obesity has a multi-causal aetiology, the treatment is ing these interactions remain largely uncharacterized and
complex and different factors must be taken into account more studies are needed in order to establish if changes in
to design an effective therapy. Thus, it is well known that gut microbiota are a cause rather than a consequence of
lifestyle plays a major role in the causation of this dis- obesity. In any case, the ability to manipulate the micro-
ease.1 The genetic make-up of an individual also plays a biota through diet should provide a route for delivering
part.4 More recently the gut microbiota have been pro- health benefits.10 This review paper aims to collect and
posed as contributing to both the aetiology of obesity and critically order the available data regarding the influence
accompanying metabolic related disorders (Figure 1).5 of different dietary components on gut microbiota in rela-
There have not been many human intervention trials be- tion to obesity and inflammatory states in humans. This
cause of methodological difficulties. However, studies do appraisal has been focused in a careful examination (be-
suggest that the composition of the gut microflora may tween years 2000 and 2013) of current accepted databases
influence harvesting energy from food,6 mucosal immuni- such as Pubmed and Cochrane following accepted criteria
ty, intestinal permeability, transit time, and systemic in- of search, but cannot be considered as a systematic re-
flammation,7 which all relate to obesity. A balanced gut
microbiota composition confers benefit to the host, Corresponding Author: Prof Jose A Martinez, University of
whereas microbial imbalances are associated with meta- Navarra, C/ Irunlarrea 1, 31008 Pamplona, Navarra, Spain.
bolic and immune-mediated disorders.8 Tel: 34 948425600 ext. 806424; Fax: 34 948425649
The composition of the bacterial ecosystem varies sub- Email: [email protected]
Manuscript received 4 January 2014. Initial review completed
stantially among individuals, but it is also dynamic and 20 January 2014. Revision accepted 29 March 2014.
susceptible to change in a single individual. A change in doi: 10.6133/apjcn.2014.23.3.16
Licensed to Caroline Modolo Ribeiro - [email protected] - 441.867.408-01

Gut microbiota and dietary strategies 361

Figure 1. Interplay between genetics, lifestyles and microbiota in the obesity development. Role of specific dietary components on bacte-
rial composition. CHO: carbohydrates; HP: high protein; MD: mediterranean diet; SCFA: short chain fatty acids; PUFA: polyunsaturated
fatty acids.

view given the heterogeneity and difficulties for compari- for the microbiota-induced deposition of triglycerides in
son of the available studies. The following terms “gut adipocytes was proposed as a possible mechanism.17 Fur-
microbiota, carbohydrate diets, high-protein diets, Medi- thermore, interesting differences in the microbiota com-
terranean diet” were individually screened and crossed position were reported when genetically obese mice to
with “nutrition, obesity, inflammation and weight loss”. normal-weight mice were compared.18 The obese mice
had a greater presence of bacteria with a higher expres-
GUT MICROBIOTA sion of enzymes related to energy extraction, bowel fer-
The mammalian gastrointestinal tract, particularly the mentation and to the reduction in stool residual calories.
large bowel, is colonized by a diverse collection of bacte- In a subsequent work, the microbiota from obese mice
was transplanted to normal-weight mice and it was found
ria, viruses and archaea, collectively known as gut micro-
that the latter developed obesity within two weeks,18 in
biota.11 The gut of the fetus is sterile, but is colonized by
agreement with the original hypothesis. These findings
bacteria from the mother and the environment at birth and
evidenced that the gut microbiota is a dynamic ecosystem
thereafter.12 The type of feeding and hygiene measures of living microorganisms susceptible to environmental
have also been shown to play a role in the composition of and pathophysiological alterations.18 Dietary habits, life-
the microbiota as it colonises the gut of the newborn. The style, age, host genotype and exposure to antibiotics may
gut microbiota is estimated to consist of more than 104 affect the composition of the gut microflora.19 Translating
microorganisms, with approximately 1100 prevalent spe- and extending the findings from these animal studies to
cies, and within any individual there are approximately humans is currently an important area of research because
160 such species.13 The exact composition remains un- of links to the systemic health of the host.
known, but recent investigations have shown that the ma- Indeed, the gut microbiota is nowadays considered a
jority of the bacterial phylotypes are members of two metabolic organ, which performs a wide range of func-
phyla: the Firmicutes (eg Clostridium, Enterococcus, tions including an important role in the physiology of
Lactobacillus, Ruminococcus) making up 60% of the gut energy homeostasis.20 Commensal bacteria contribute to
microbiota, and the Bacteroidetes (eg Bacteroides and the digestion of nutrients otherwise inaccessible to hu-
Prevotella) making up 15%. These strains are followed mans, such as resistant starch, some oligosaccharides,
by the Actinobacteria (eg Bifidobacterium) and the Pro- unabsorbed sugars, alcohols and protein/amino acids.
teobacteria (eg Helicobacter, Escherichia), as reported Carbohydrate fermentation leads to the generation of
elsewhere.5,14 The bacterial diversity tends to decrease short-chain fatty acids (SCFA) including butyrate, acetate
with age.15 The number of cells in the microbiota exceeds and propionate. These are an important energy source for
the number of human cells and contains 100 times more the host, providing up to 10%-15% of a human’s daily
genes than the human genome.16 energy supply. They also influence cell differentiation
The association between the gut microflora composi- and proliferation, ion absorption or vitamin production
tion and obesity was noted in observational studies. which and contribute to the supply of amino acids required by
compared germ-free mice to normal mice.17 Thus, it was human beings.11 In the presence of fermentable carbohy-
observed that control animals had 42% more adipose tis- drate substrates, colonic bacteria grow and synthesize
sue compared with germ-free ones.17 Subsequently, the protein and somewhere between 1% and 20% of circulat-
microflora from normal mice was transferred to the germ-
ing plasma lysine and threonine in adults is derived from
free mice and it was noted that the germ-free mice devel-
the intestinal microbiota.21 Proteolytic fermentation gen-
oped overweight in a period of two weeks, with an in-
erates polyphenols that induce anti-inflammatory, anti-
crease of 57% in their total body fat, despite no change in
energy consumption or energy expenditure. The suppres- oxidative and anti-ageing effects and also a proportion of
sion of a circulating lipoprotein lipase inhibitor, essential the pool of SCFA, derived from amino acid fermentation.
On the other hand, anaerobic metabolism of peptides and
Licensed to Caroline Modolo Ribeiro - [email protected] - 441.867.408-01

362 P Lopez-Legarrea, NR Fuller, MA Zulet, JA Martinez and ID Caterson

proteins, known as putrefaction, produces some potential- perturbations.32

ly toxic substances including ammonia, amines, phenols, In recent times, dietary strategies to counteract obesity
thiols, and indols.11 Additionally, commensal bacteria and overweight states have been focused not only on the
induce lipolysis leading to increased fat storage, hepatic amount of calories prescribed, but also on the macronutri-
de-novo synthesis of triglycerides and the alteration of ent composition (eg increased protein intake), the type of
bile acid metabolites with consequences to lipid metabo- food (eg glycemic index or load) or the presence of spe-
lism in the host.3 cific bioactive compounds (omega-3 fatty acids, fibre or
The gut microbiota has also been shown to have a role polyphenols). Therefore, future studies to evaluate the
in the obesity-linked low grade chronic inflammatory dietary influence on microbiota composition should also
state of the host.22 Specifically the overgrowth of Proteo- take such new aspects into account.
bacterium produces reduction of the gut barrier protective
bacteria.23 These microorganisms act by altering the sig- CARBOHYDRATE DIETS
naling pathways that link obesity with inflammation. Carbohydrates have been one of the most studied dietary
Thus, bacterial lipopolysaccharide (LPS) has been pro- components in relation to microbiota modifications. Gut
posed as a mediator for this outcome,6,24 since LPS is part microbes are known to be involved in the absorption of
of the outer membrane of gram-negative bacteria and is monosaccharides and it is generally accepted that carbo-
an endotoxin for the host.25 Infiltration of LPS from the hydrate fermentation results in beneficial effects for the
gut lumen into the bloodstream induces cytokines and host because of the generation of SCFA (Table 1).33
triggers an inflammatory response.14 Such increased LPS Moreover, shifts in the composition of the gut microbiota
levels have been described as “metabolic endotoxemia”24 in response to the total quantity of carbohydrate intake in
and many obesity-related comorbidities have been report- obese people have been reported.34 Thus, Bifidobacteria
ed to correlate with circulating LPS concentrations.25 In- showed a significant reduction with decreased carbohy-
deed, the microbiota can influence intestinal permeability drate intake as well as some Clostridium subgroups
and the physiological functioning of the intestinal barrier, (Roseburia and Eubacterium rectale), which correlated
which is essential to avoid LPS infiltration. strongly with the reduction in stool butyrate levels (Table
1). The same outcome was found also in an obese group
DIETARY STRATEGIES when analyzing high-protein/carbohydrate-reduced di-
Dietary strategies have been the mainstay of treatments to ets.35 This kind of diet reduced Roseburia/E. rectale con-
counteract overweight and obesity.26 Diet is considered to comitant with a decrease in the proportion of butyrate in
be a major environmental factor influencing gut micro- faecal SCFA and a major reduction of fibre-derived anti-
biota diversity and functionality.20 Therefore, the effect of oxidant phenolic acids (Table 1). These results were in
dietary patterns on gut microbiota conjointly and on agreement with those from a previous study where a low-
weight-loss outcomes may become potential therapeutic carbohydrate to a fat-restricted diet were compared re-
strategies in managing metabolic health. Altered dietary vealing a decreased Bacteroidetes number, which corre-
intake not only affects energy balance but also has a ma- lated with the carbohydrate-restricted diet.36 The out-
jor impact upon gut microbial composition and this can comes suggested that different dietary compositions have
promote obesity and increase the risk of developing met- different influences on bacterial shifts and evidenced that
abolic diseases,6 or vice versa, appropriate changes in the it is necessary to take the dietary components into consid-
gut microbiota may promote weight loss and beneficial eration in future studies.
metabolic change. A weight loss intervention program, Increased fibre intake has shown to have several bene-
based on a calorie-restricted diet and increased physical ficial effects on metabolic markers, although the mecha-
activity in an obese adolescent population, was demon- nisms responsible are not completely understood. Thus,
strated to induce changes in the gut microbiota content decreasing sugar and cholesterol absorption, the produc-
and some of these changes correlated with weight loss tion of phytochemicals and other bioactive compounds, as
and BMI z-score reductions.20 This outcome is in agree- well as anti-inflammatory properties have been proposed
ment with other studies, showing that levels of Bifidobac- as processes involved in the healthy properties of fibre.3
terium were reduced in infants who became overweight at Bacterial fermentation of undigestible components of
7 years old compared with the higher level of Bifidobac- whole-grain products is another key issue in trying to
terium in normal weight children.27 explain the effects found, as whole grains affect both the
In previous studies with adults, it has been also shown microbiota and obesity itself, and the interplay between
that obese people had fewer Bacteroidetes and more Fir- them. Microbial fermentation of plant fibre produces
micutes than lean controls before diet therapy.28,29 Subse- phenolic compounds with antioxidant and antitumoral
quently, decreases in Firmicutes and increases in Bac- activities (Table 1).35 High fibre content diets have been
teroidetes were correlated with body weight loss.6,30 It positively associated with Bacteroidetes and Actinobacte-
was also reported that changes in the faecal bacteria ria presence, 31 and with a reduced Firmicutes-to-
population began one week after caloric restriction,6 Bacteroidetes ratio,37 while dietary resistant starch might
while another similar study found detectable changes reduce the formation of harmful nitrogenous compounds.
within 24 hours of initiating a dietary intervention.31 Thus, arabinoxylan-oligosaccharides enriched bread was
These findings confirmed the hypothesis derived from observed to increased total bacterial populations and fae-
animals that the gut microbiota is dynamic, although cal butyrate concentrations in healthy volunteers.38 Addi-
these studies disagreed with some earlier investigations, tionally, the treated group showed a trend to reduced pro-
which had suggested stability over time and resistance to tein-fermentation derived harmful acids. Furthermore,
Licensed to Caroline Modolo Ribeiro - [email protected] - 441.867.408-01

Gut microbiota and dietary strategies 363

Table 1. Shifts in gut microbiota derived from different dietary strategies of dietary modifications.

Dietary strategy Basis/Mechanism Affected species Observed effects References

Carbohydrate ↓ Related with beneficial effects because of the association Bifidobacteria ↓ Decrease SCFA: Butyrate production. 33, 34, 35, 36
with SCFA production and phenolic compounds, known Clostridium ↓ Decrease fiber-derived phenolic acids.
to have anti-inflammatory effects. Bacteroidetes ↓

Protein ↑ Proteolitic fermentation produces beneficial compounds, Bacteroidetes ↑ Amelioration of obesity, inflammation 11, 31, 35
but putrefaction is considered detrimental for the host´s Lactobacillus ↑ and metabolic complications.
health. Bifidobacterium ↑

Mediterranean ↑ Widely accepted as a healthy dietary pattern, with many Polyphenols: Improvement of obesity, lipid profile and 6, 8, 52, 53, 54
specific components (polyphenols, PUFA). Prevotella ↑ inflammation.
Enterococcus ↑ An adults’ microbiome is not particularly
Bifidobacteria ↑ enriched in genes involved in fatty acid
Lactobacillus ↑ metabolism.
Bacteroides ↑
Clostridium ↓
PUFA:
Lactobacillus ↑

SCFA: short chain fatty acids; PUFA: polyunsaturated fatty acids.

Licensed to Caroline Modolo Ribeiro - [email protected] - 441.867.408-01

364 P Lopez-Legarrea, NR Fuller, MA Zulet, JA Martinez and ID Caterson

arabinogalactan has been associated with a statistically effect of high protein intake and microbiota changes.
significant increase in the concentration of total bacteria, Generally, the protein proportion of the diet is increased
Bacteroidetes, Faecalibacterium prausnitzii, a delayed by a reduction in the carbohydrate content, so that the
bifidogenic effect and a decrease of the pathogenic Clos- consequences of such a carbohydrate reduction are found
tridium perfringens.39 On the other hand, fructo- in high-protein diets as well as with protein fermentation
oligosaccharides leads to a strong lactobacillogenic ef- toxic products. Additionally, a diet enriched in protein
fect.39 So, much interest in relation to prebiotics has been favours the Bacteroidetes group (Table 1).31 Fermentation
focused on non-digestible oligosaccharides, which have of amino acids derived from dietary or host-derived pro-
been described to change microbial composition.21 Actu- teins yields a much wider range of products. Faecal
ally, biological effects depend on gut microbiota compo- branched-chain fatty acids are indicative of fermentation
sition and the subsequently derived metabolites. of branched-chain amino acids and their faecal concentra-
Moreover, in a study comparing diet impact on gut mi- tions increase on high-protein diets,10 which can influence
crobiota in European children and those from rural Africa, beneficial microbiota. In this context, dietary controlled
it was observed that in Rural Africa, where the diet is rich studies in obese men following high protein/low carbohy-
in fibre, the children had a significant enrichment in Bac- drate intake during 3-4 weeks detected microbial changes,
teroidetes and a depletion in Firmicutes, with a unique particularly reduction in Collinsella aerofaciens, E. rec-
abundance of bacteria from the genus Prevotella and Xy- tale, Roseburia, and Bifidobacterium spp.34,35 A recent
lanibacter (which are known to contain a set of bacterial study assessing zonulin, a protein that increases intestinal
genes for cellulose and xylan hydrolysis), while these permeability and participates in the development of intes-
species were completely lacking in the European chil- tinal innate immunity, showed that plasma zonulin was
dren.40 They also found more SCFA in the African chil- inversely proportional to protein percentage dietary in-
dren, suggesting that the gut microbiota has co-evolved take.44 Zonulin is considered as a potential marker of in-
with the polysaccharide-rich diet of African individuals, testinal permeability, therefore, suggesting that protein
allowing them to maximize energy intake from fibres, intake may be associated with a reduction in intestinal
while also protecting them from inflammation and non- permeability.
infectious colonic diseases.40 In addition to meat, dairy products are another im-
Carbohydrates are considered to have beneficial effects portant source of protein in our diet. There may be a role
on inflammation because of bacterial production of SCFA for these foods with microbiota modifications as they are
like butyrate, with the Clostridium cluster the most im- a good matrix for probiotics, which when administered in
portant in this aspect. Hence, SCFA are known to have adequate amounts, may confer a healthy benefit to the
anti-inflammatory effects that result from inhibition of host, through different mechanisms.45 In particular, Lac-
transcription factor NF-κB leading to a decreased secre- tobacillus and Bifidobacterium have been shown to ame-
tion of proinflammatory cytokines (Table 1).6 An increase liorate obesity, inflammation, and associated metabolic
in the Clostridium group presence (Faecalibacterium complications (Table 1).11 The mechanisms affecting
prausnitzii, specifically), linked to higher resistant starch health issues include inhibition of intestinal bacterial en-
intake, has been associated with lower levels of circulat- zymes, stimulation of host immunity, competition for
ing inflammatory parameters in patients after bariatric limited nutrients, inhibition of bacteria mucosal adher-
surgery. In contrast, lower proportions of this group of ence and epithelial invasion, protection of intestinal per-
microorganisms were found in patients with type 2 diabe- meability and control of bacterial translocation from the
tes and were related to a worsening of their low-grade gut to the bloodstream.11 There are few well controlled
inflammation and higher insulin resistance.6 Interestingly, studies in humans, but it has been shown that 200 g per
in the same study, a negative association was also seen day of a fermented milk containing the probiotic organ-
between F. Prausnitzii and HOMA-IR. ism Lactobacillus gasseri over 12 weeks produced signif-
icantly greater reductions in abdominal, visceral and sub-
HIGH-PROTEIN DIETS cutaneous fat, body weight and waist circumference com-
Increasing protein content of the diet has been one of the pared with consuming fermented milk alone.46
most intensely assessed variations in macronutrient dis-
tribution in order to manage body weight.36 Available MEDITERRANEAN DIETS
results are controversial but the prevalent idea is that The Mediterranean diet is widely accepted as a healthy
moderately high protein diets help weight loss and/or dietary pattern, with demonstrated benefits for obesity
weight maintenance.41 In relation to the gut microbiota, treatment and improvement in associated cardiovascular
proteolytic fermentation produces beneficial compounds, risk markers.47 A beneficial fatty acid profile,48 with par-
but putrefaction is considered detrimental for the host’s ticular focus on monounsaturated fatty acids (MUFA) and
health (Table 1).42 This situation occurs in the distal bow- polyunsaturated fatty acids (PUFA) a higher antioxidants
el generating potentially toxic substances such as ammo- intake,49 and the presence of other components such as
nia, amines, phenols and sulfides.11 fibre, vegetable protein and low glycemic foods are the
Epidemiological studies have associated meat-rich di- main characteristics of this diet.50 In relation to the specif-
ets with colorectal cancer35 and fermentation-derived tox- ic foods consumed in the traditional Mediterranean diet,
ic agents with dietary protein intake.43 However, despite there is a high intake of olive oil, fruits, nuts, vegetables,
these indications, the relationship between gut health and and cereals; a moderate intake of fish and poultry; a low
protein fermentation has not been thoroughly investigated intake of dairy products, red meat, processed meat and
and there are not many human studies focusing on the sweets; and a moderate consumption of red wine with
Licensed to Caroline Modolo Ribeiro - [email protected] - 441.867.408-01

Gut microbiota and dietary strategies 365

meals.47 Polyphenols antioxidants are specifically con- It remains widely accepted that diet has a large influence
sumed in the diet through different products such as tea, on the gut microbiota composition, although mechanistic
coffee, wine, fruit, vegetables and chocolate.51 A recent studies are needed in order to determine those bioactive
study in healthy humans comparing red wine intake with constituent(s) or metabolite(s) coming from the gut bacte-
de-alcoholized red wine and gin intake observed changes ria that are responsible for the described effects. Among
in the distribution ratio of different genera within the Bac- the different dietary components, carbohydrates, specifi-
teroidetes and Firmicutes.8 The investigations reported cally the non-digestible starches, seem to play a key role,
that drinking red wine induced an increase in the number particularly related to the formation of SCFA. The poly-
of Enterococcus, Bacteroides and Prevotella as well as an phenols occurring in the typical Mediterranean diet have
important decrease in the Clostridium genera, including shown certain beneficial properties. More studies are
Clostridium perfringens, an important pathogen associat- needed to determine a possible effect of protein intake on
ed with obesity, among others diseases (Table 1).52 This microbiota composition changes. What is even more ob-
was explained by the increase in Proteobacteria known to vious is that more studies in humans are needed examin-
degrade uric acid. The polyphenol-induced increase in ing every component of the diet to assess the effects on
Bifidobacteria was associated with a reduction of plasma the microbiota and to evaluate these effects in the context
cholesterol concentrations. A study with red wine- of a whole diet.
polyphenols also found that Bifidobacterium growth pre- More research is needed regarding diet-microbiota-
dicted a decrease in C-reactive protein, a marker of in- inflammation associations, as there are not many studies
flammation and a predictor of cardiovascular event risk in that explore this connection. Probiotic therapy offers an
healthy subjects.8 So, red wine polyphenol intake may be intriguing approach to promote host health via delivering
related to an improvement in the obesity-related inflam- anti-inflammatory mediators.
matory state. Although more work is needed, specific dietary factors
Another excellent source of antioxidants is fruit. In this (carbohydrate, protein and Mediterranean food) have
context, the study of the bacterial metabolism of pome- been shown to have an influence on the gut microbiome
granate demonstrated that a pomegranate product signifi- composition, meaning that there is an opportunity to pre-
cantly enhanced the growth of Bifidobacteria and Lacto- vent and treat obesity.
bacilli, associated with various health benefits at the cel-
lular and systemic levels (Table 1).52 This modulation of ACKNOWLEDGEMENTS
the gut microbiota could mediate the reduction of the All authors contributed to the literature review as well as the
high-fat diet induced hypercholesterolaemia. When con- preparation of the manuscript at various stages. Government of
Navarra provided a pre-doctoral research grant to PLL
sidering total fat intake, a reduction in the Bacteroide-
(233/2009).
tes/Firmicutes ratio after high fat diets has been reported,6
while fat restricted diets (together with higher carbohy- AUTHOR DISCLOSURES
drate intake) increased both Bacteroides and Bifidobacte- There are no conflicts of interest with respect to any of the au-
rium (Table 1).53 Also, it has been found that high fat thors.
diets, independently of being high-saturated or high-
monounsaturated, decreased total faecal microbiota.53 REFERENCES
However, it was not clear whether the crucial factor af- 1. McAllister EJ, Dhurandhar NV, Keith SW, Aronne LJ,
fecting microbiota is the elevated/reduced fat or the re- Barger J, Baskin M et al. Ten putative contributors to the
duced/elevated carbohydrate content. Interestingly, in- obesity epidemic. Crit Rev Food Sci Nutr. 2009;49:868-913.
creased endotoxemia was found to be associated with doi: 10.1080/10408390903372599.
2. de Luis DA, Aller R, Gonzalez Sagrado M, Conde R, Izaola
increased fat consumption in obese humans6 leading to an
O, de la Fuente B. Serum visfatin levels and metabolic syn-
increased inflammation state.54 Some studies have shown drome criteria in obese female subjects. Diabetes Metab Res
that a higher fat content of a diet involves a higher intes- Rev. 2013;29:576-81. doi: 10.1002/dmrr.2430.
tinal permeability and consequently, an increase in plas- 3. Martinez I, Lattimer JM, Hubach KL, Case JA, Yang J,
ma LPS levels.55 This phenomenon has been explained by Weber CG et al. Gut microbiome composition is linked to
the fact that the insoluble fraction contained in the LPS whole grain-induced immunological improvements. ISME J.
structure can be incorporated into micelles and absorbed 2013; 7:269-80. doi: 10.1038/ismej.2012.104.
into the chylomicrons in the postpandrial period after a 4. Martinez JA, Parra MD, Santos JL, Moreno-Aliaga MJ,
fatty meal.56 Specifically, saturated fats have been posi- Marti A, Martinez-Gonzalez MA. Genotype-dependent re-
tively associated with the Bacteroides group.31 An adult’s sponse to energy-restricted diets in obese subjects; towards
microbiome is not particularly enriched in genes involved personalized nutrition. Asia Pac J Clin Nutr. 2008;17 (Suppl
1) :119-22.
in fatty acid metabolism, but some interactions between
5. Diamant M, Blaak EE, de Vos WM. Do nutrient-gut-
PUFA and the microbiota have been described, suggest- microbiota interactions play a role in human obesity, insulin
ing that these fatty acids can positively influence the ad- resistance and type 2 diabetes? Obes Rev. 2011;12:272-81.
hesion of Lactobacillus to the jejuna mucosa and these doi: 10.1111/j.1467-789X.2010.00797.x.
bacteria may have a potential regulatory effect on PUFA 6. Furet JP, Kong LC, Tap J, Poitou C, Basdevant A, Bouillot
absorption (Table 1).57 Nevertheless there is a lack of JL et al. Differential adaptation of human gut microbiota to
human studies regarding the role of specific fat types on bariatric surgery-induced weight loss; links with metabolic
the gut microbiota. and low-grade inflammation markers. Diabetes. 2010;59:
3049-57. doi: 10.2337/db10-0253.
Conclusions 7. Ley RE. Obesity and the human microbiome. Curr Opin
Licensed to Caroline Modolo Ribeiro - [email protected] - 441.867.408-01

366 P Lopez-Legarrea, NR Fuller, MA Zulet, JA Martinez and ID Caterson

Gastroenterol. 2010;26:5-11. doi: 10.1097/MOG.0b013e328 D et al. Metabolic endotoxemia initiates obesity and insulin
333d751. resistance. Diabetes. 2007;56:1761-72. doi: 10.2337/db07-
8. Queipo-Ortuno MI, Boto-Ordonez M, Murri M, Gomez- 1262.
Zumaquero JM, Clemente-Postigo M, Estruch R et al. Influ- 25. Spreadbury I. Comparison with ancestral diets suggests
ence of red wine polyphenols and ethanol on the gut micro- dense acellular carbohydrates promote an inflammatory mi-
biota ecology and biochemical biomarkers. Am J Clin Nutr. crobiota, and may be the primary dietary cause of leptin re-
2012;95:1323-34. doi: 10.3945/ajcn.111.02784. sistance and obesity. Diabetes Metab Syndr Obes. 2012;5:
9. Tachon S, Zhou J, Keenan M, Martin R, Marco ML. The 175-89. doi: 10.2147/DMSO.S33473.
intestinal microbiota in aged mice is modulated by dietary 26. Cardoso GA, Salgado JM, Cesar Mde C, Donado-Pestana
resistant starch and correlated with improvements in host re- CM. The effects of green tea consumption and resistance
sponses. FEMS Microbiol Ecol. 2012;83:299-309. doi :10. training on body composition and resting metabolic rate in
1111/j.1574-6941.2012.01475.x. overweight or obese women. J Med Food. 2013;16:120-7.
10. Flint HJ, Scott KP, Louis P, Duncan SH. The role of the gut doi: 10.1089/jmf.2012.0062
microbiota in nutrition and health. Nat Rev Gastroenterol 27. Santacruz A, Collado MC, Garcia-Valdes L, Segura MT,
Hepatol. 2012;9:577-89. doi: 10.1038/nrgastro.2012.156. Martin-Lagos JA, Anjos T et al. Gut microbiota composition
11. Compare D, Coccoli P, Rocco A, Nardone OM, De Maria S, is associated with body weight, weight gain and biochemical
Carteni M et al. Gut-liver axis; the impact of gut microbiota parameters in pregnant women. Br J Nutr. 2010;104:83-92.
on non alcoholic fatty liver disease. Nutr Metab Cardiovasc doi: 10.1017/S0007114510000176.
Dis. 2012;22:471-6. doi: 10.1016/j.numecd.2012.02.007. 28. Ley RE, Turnbaugh PJ, Klein S, Gordon JI. Microbial ecol-
12. Greiner T, Backhed F. Effects of the gut microbiota on obe- ogy; human gut microbes associated with obesity. Nature.
sity and glucose homeostasis. Trends Endocrinol Metab. 2006;444:1022-3. doi: 10.1038/4441022a.
2011;22:117-23. doi: 10.1016/j.tem.2011.01.002. 29. Brignardello J, Morales P, Diaz E, Romero J, Brunser O,
13. Sekirov I, Russell SL, Antunes LC, Finlay BB. Gut microbi- Gotteland M. Pilot study; alterations of intestinal microbiota
ota in health and disease. Physiol Rev. 2010;90:859-904. in obese humans are not associated with colonic inflamma-
doi: 10.1152/physrev.00045.2009. tion or disturbances of barrier function. Aliment Pharmacol
14. Cani PD, Delzenne NM. Interplay between obesity and as- Ther. 2010;32:1307-14. doi: 10.1111/j.1365-2036.2010.047
sociated metabolic disorders: new insights into the gut mi- 45.x.
crobiota. Curr Opin Pharmacol. 2009;9:737-43. doi: 10.1016 30. Santacruz A, Marcos A, Warnberg J, Marti A, Martin-
/j.coph.2009.06.016 Matillas M, Campoy C et al. Interplay between weight loss
15. Claesson MJ, Jeffery IB, Conde S, Power SE, O’Connor and gut microbiota composition in overweight adolescents.
EM, Cusack S et al. Gut microbiota composition correlates Obesity (Silver Spring). 2009;17:1906-15. doi: 10.1038/oby.
with diet and health in the elderly. Nature. 2012;488:178-84. 2009.112
doi:10.1038/nature11319. 31. Wu GD, Chen J, Hoffmann C, Bittinger K, Chen YY,
16. Sanz Y, Santacruz A, Gauffin P. Gut microbiota in obesity Keilbaugh SA et al. Linking long-term dietary patterns with
and metabolic disorders. Proc Nutr Soc. 2010;69:434-41. gut microbial enterotypes. Science. 2011;334:105-8. doi:
doi: 10.1017/S0029665110001813. 10.12968/gasn.2011.9.8.12a.
17. Backhed F, Ding H, Wang T, Hooper LV, Koh GY, Nagy A 32. Zoetendal EG, Akkermans AD, De Vos WM. Temperature
et al. The gut microbiota as an environmental factor that gradient gel electrophoresis analysis of 16S rRNA from hu-
regulates fat storage. Proc Natl Acad Sci USA. 2004;101: man fecal samples reveals stable and host-specific commu-
15718-23. doi: 10.1073/pnas.0407076101. nities of active bacteria. Appl Environ Microbiol. 1998;
18. Ley RE, Backhed F, Turnbaugh P, Lozupone CA, Knight 64:3854-9.
RD, Gordon JI. Obesity alters gut microbial ecology. Proc 33. Sanz Y. Effects of a gluten-free diet on gut microbiota and
Natl Acad Sci USA. 2005;102:11070-5. doi: 10.1073/pnas. immune function in healthy adult humans. Gut Microbes.
0504978102. 2010;1:135-7. doi: 10.4161/gmic.1.3.11868.
19. Gomez-Hurtado I, Santacruz A, Peiro G, Zapater P, 34. Duncan SH, Belenguer A, Holtrop G, Johnstone AM, Flint
Gutierrez A, Perez-Mateo M et al. Gut microbiota dysbiosis HJ, Lobley GE. Reduced dietary intake of carbohydrates by
is associated with inflammation and bacterial translocation obese subjects results in decreased concentrations of butyr-
in mice with CCl4-induced fibrosis. PLoS One. 2011;6: ate and butyrate-producing bacteria in feces. Appl Environ
e23037. doi: 10.1371/journal.pone.0023037. Microbiol. 2007;73:1073-8. doi: 10.1128/AEM.02340-06.
20. Nadal I, Santacruz A, Marcos A, Warnberg J, Garagorri M, 35. Russell WR, Gratz SW, Duncan SH, Holtrop G, Ince J,
Moreno LA et al. Shifts in clostridia, bacteroides and immu- Scobbie L et al. High-protein, reduced-carbohydrate weight-
noglobulin-coating fecal bacteria associated with weight loss loss diets promote metabolite profiles likely to be detri-
in obese adolescents. Int J Obes (Lond). 2009;33:758-67. mental to colonic health. Am J Clin Nutr. 2011;93:1062-72.
doi: 10.1038/ijo.2008.260. doi: 10.3945/ajcn.110.002188.
21. Laparra JM, Sanz Y. Interactions of gut microbiota with 36. Brinkworth GD, Noakes M, Clifton PM, Bird AR. Compara-
functional food components and nutraceuticals. Pharmacol tive effects of very low-carbohydrate, high-fat and high-
Res. 2010;61:219-25. doi: 10.1016/j.phrs.2009.11.001. carbohydrate, low-fat weight-loss diets on bowel habit and
22. Lam YY, Mitchell AJ, Holmes AJ, Denyer GS, Gummesson faecal short-chain fatty acids and bacterial populations. Br J
A, Caterson ID et al. Role of the gut in visceral fat inflam- Nutr. 2009;101:1493-502. doi: 10.1017/S000711450809465
mation and metabolic disorders. Obesity (Silver Spring). 8.
2011;19:2113-20. doi: 10.1038/oby.2011.68. 37. Kim MS, Hwang SS, Park EJ, Bae JW. Strict vegetarian diet
23. Cani PD, Bibiloni R, Knauf C, Waget A, Neyrinck AM, improves the risk factors associated with metabolic diseases
Delzenne NM et al. Changes in gut microbiota control met- by modulating gut microbiota and reducing intestinal in-
abolic endotoxemia-induced inflammation in high-fat diet- flammation. Environ Microbiol Rep. 2013;5:765-75. doi: 10.
induced obesity and diabetes in mice. Diabetes. 2008;57: 1111/1758-2229.12079.
1470-81. doi: 10.2337/db07-1403. 38. Walton GE, Lu C, Trogh I, Arnaut F, Gibson GR. A ran-
24. Cani PD, Amar J, Iglesias MA, Poggi M, Knauf C, Bastelica domised, double-blind, placebo controlled cross-over study
Licensed to Caroline Modolo Ribeiro - [email protected] - 441.867.408-01

Gut microbiota and dietary strategies 367

to determine the gastrointestinal effects of consumption of protection: the role of nitrite, polyunsaturated fatty acids,
arabinoxylan-oligosaccharides enriched bread in healthy and polyphenols. Nutrition. 2011;27:733-44. doi: 10.1016/
volunteers. Nutr J. 2012;11:36. doi: 10.1186/1475-2891-11- j.nut.2010.12.006.
36. 49. Lopez-Legarrea P, de la Iglesia R, Abete I, Bondia-Pons I,
39. Terpend K, Possemiers S, Daguet D, Marzorati M. Arabino- Navas-Carretero S, Forga L et al. Short-term role of the die-
galactan and fructo-oligosaccharides have a different fer- tary total antioxidant capacity in two hypocaloric regimes on
mentation profile in the Simulator of the Human Intestinal obese with metabolic syndrome symptoms: the RESMENA
Microbial Ecosystem (SHIME (R)). Environ Microbiol Rep. randomized controlled trial. Nutr Metab (Lond). 2013;10:22.
2013;5:595-603. doi: 10.1111/1758-2229.12056. doi: 10.1186/1743-7075-10-22.
40. De Filippo C, Cavalieri D, Di Paola M, Ramazzotti M, Poul- 50. Abete I, Goyenechea E, Zulet MA, Martinez JA. Obesity
let JB, Massart S et al. Impact of diet in shaping gut micro- and metabolic syndrome: potential benefit from specific nu-
biota revealed by a comparative study in children from Eu- tritional components. Nutr Metab Cardiovasc Dis. 2011;21(
rope and rural Africa. Proc Natl Acad Sci USA. 2010;107: Suppl 2):B1-15. doi: 10.1016/j.numecd.2011.05.001.
14691-6. doi: 10.1073/pnas.1005963107. 51. Casas-Agustench P, Bullo M, Salas-Salvado J. Nuts, in-
41. Gogebakan O, Kohl A, Osterhoff MA, van Baak MA, Jebb flammation and insulin resistance. Asia Pac J Clin Nutr.
SA, Papadaki A et al. Effects of weight loss and long-term 2010;19:124-30.
weight maintenance with diets varying in protein and gly- 52. Bialonska D, Ramnani P, Kasimsetty SG, Muntha KR, Gib-
cemic index on cardiovascular risk factors: the diet, obesity, son GR, Ferreira D. The influence of pomegranate by-
and genes (DiOGenes) study: a randomized, controlled trial. product and punicalagins on selected groups of human intes-
Circulation. 2011;124:2829-38. doi: 10.1161/CIRCULATIO tinal microbiota. Int J Food Microbiol. 2010;140:175-82.
NAHA.111.033274. doi: 10.1016/j.ijfoodmicro.2010.03.038.
42. Alemany M. The problem of nitrogen disposal in the obese. 53. Fava F, Gitau R, Griffin BA, Gibson GR, Tuohy KM,
Nutr Res Rev. 2012;25:18-28. doi: 10.1017/S09544224110 Lovegrove JA. The type and quantity of dietary fat and car-
00163. bohydrate alter faecal microbiome and short-chain fatty acid
43. Magee EA, Richardson CJ, Hughes R, Cummings JH. Con- excretion in a metabolic syndrome “at-risk” population. Int J
tribution of dietary protein to sulfide production in the large Obes (Lond). 2013;37:216-23. doi: 10.1038/ijo.2012.33.
intestine: an in vitro and a controlled feeding study in hu- 54. Clemente-Postigo M, Queipo-Ortuno MI, Murri M, Boto-
mans. Am J Clin Nutr. 2000;72:1488-94. Ordonez M, Perez-Martinez P, Andres-Lacueva C et al. En-
44. Zak-Golab A, Kocelak P, Aptekorz M, Zientara M, Juszczyk dotoxin increase after fat overload is related to postprandial
L, Martirosian G et al. Gut microbiota, microinflammation, hypertriglyceridemia in morbidly obese patients. J Lipid
metabolic profile, and zonulin concentration in obese and Res. 2012;53:973-8. doi: 10.1194/jlr.P020909.
normal weight subjects. Int J Endocrinol. 2013;2013:674 55. Erridge C, Attina T, Spickett CM, Webb DJ. A high-fat
106. doi: 10.1155/2013/674106. meal induces low-grade endotoxemia: evidence of a novel
45. Minocha A. Probiotics for preventive health. Nutr Clin mechanism of postprandial inflammation. Am J Clin Nutr.
Pract. 2009;24:227-41. doi: 10.1177/0884533608331177 2007;86:1286-92. doi: 10.1016/S0084-3741(08)79070-X.
46. Kadooka Y, Sato M, Imaizumi K, Ogawa A, Ikuyama K, 56. Laugerette F, Vors C, Geloen A, Chauvin MA, Soulage C,
Akai Y et al. Regulation of abdominal adiposity by probiot- Lambert-Porcheron S et al. Emulsified lipids increase endo-
ics (Lactobacillus gasseri SBT2055) in adults with obese toxemia: possible role in early postprandial low-grade in-
tendencies in a randomized controlled trial. Eur J Clin Nutr. flammation. J Nutr Biochem. 2011;22:53-9. doi: 10.1016/
2010;64:636-43. doi: 10.1038/ejcn.2010.19. j.jnutbio.2009.11.011.
47. Estruch R, Ros E, Salas-Salvado J, Covas MI, Corella D, 57. Bomba A, Nemcova R, Gancarcikova S, Herich R, Guba P,
Aros F et al. Primary prevention of cardiovascular disease Mudronova D. Improvement of the probiotic effect of mi-
with a Mediterranean diet. N Engl J Med. 2013;368:1279- cro-organisms by their combination with maltodextrins,
90. doi: 10.1056/NEJMoa1200303. fructo-oligosaccharides and polyunsaturated fatty acids. Br J
48. Nadtochiy SM, Redman EK. Mediterranean diet and cardio- Nutr. 2002;88(Suppl 1):S95-9. doi: 10.1079/BJN2002634.
Licensed to Caroline Modolo Ribeiro - [email protected] - 441.867.408-01

368 P Lopez-Legarrea, NR Fuller, MA Zulet, JA Martinez and ID Caterson

Review Article

The influence of Mediterranean, carbohydrate and

high protein diets on gut microbiota composition in the
treatment of obesity and associated inflammatory state

Patricia Lopez-Legarrea PhD1,2, Nicholas Robert Fuller PhD3, María Angeles Zulet
1,4 1,4 3
PhD , Jose Alfredo Martinez PhD,MD , Ian Douglas Caterson PhD,MD
1
Department of Nutrition, Food Science & Physiology, University of Navarra, Pamplona, Spain
2
Faculty of Health Science, Universidad Autonoma de Chile, Santiago, Chile
3
The Boden Institute, the University of Sydney, NSW, Australia
4
CIBERobn, Physiopathology of Obesity and Nutrition, Carlos III Health Institute, Madrid, Spain

地中海、碳水化合物和高蛋白饮食在治疗肥胖时对肠道
微生物组成的影响和相关炎症状态

肠道微生物的作用在理解肥胖发生和发展的过程越来越重要。膳食策略被用作
减肥的一个主要工具，现今，其专注点不仅仅是限制卡路里，而是涉及到膳食
的各个方面。此外，饮食是影响肠道微生物组成的一个重要因素。因此，除限
制能量摄入之外，治疗肥胖的饮食策略还要考虑到宏观营养和微观营养对肠道
微生物组成的影响。本综述的目的旨在收集整理不同的饮食组成对人类肥胖和
炎症相关的肠道微生物影响的现有数据。虽然还需要更多的工作，已有证据显
示特定的饮食因素（碳水化合物，蛋白质和地中海食物）对肠道微生物的组成
确有影响，意味着有可能通过改变肠道微生物来预防和治疗肥胖。

关键词：肥胖、营养、肠道微生物、饮食计划、炎症