Clinical Nutrition Experimental 20 (2018) 49e54

Contents lists available at ScienceDirect

Clinical Nutrition Experimental

journal homepage: http://
www.clinicalnutritionexperimental.com

Gut morphology and gene expression in obesity: Short

review and perspectives
B.A.M. Ferreira a, *, P. Sala a, D.C. Fonseca a, S.B. Heymsfield b, D.L. Waitzberg a
a
FMUSP e University of Sa
~o Paulo, School of Medicine, Department of Gastroenterology, Digestive Surgery Discipline (LIM 35), Sa
~o
Paulo, Brazil
b
Pennington Biomedical Research Center, Baton Rouge, LA, USA

articleinfo summary

Article history: Obesity, a multifactorial and polygenic condition, is considered one

Received 17 March 2018 of the great global public health problems of our time. The intes -
Accepted 24 April 2018 tinal microbiome should be considered as a set of genetic factors
Available online 4 May 2018
that, together with the host genotype and lifestyle (consumption
and energy expenditure), contribute to the pathophysiology of
obesity. Increasing evidence showed an increased proportion of
bacterial phylum Firmicutes and reduced concentrations of Bac-
teroidetes in obese as compared to normal weight humans. Studies
report that DNA methylation patterns in the blood are associated
with intestinal microbiota profiles and suggest that the microbiota
and its metabolites influence genomic reprogramming. In-
vestigations of the intestinal microbiota and its impact on genomic
changes and their relationship to the risk of developing obesity
provide opportunities to establish the basis for incorporating
biological individuality into recommendations with significant
therapeutic potential.
© 2018 The Authors. Published by Elsevier Ltd on behalf of
European Society for Clinical Nutrition and Metabolism. This is an
open access article under the CC BY-NC-ND license (http://
creativecommons.org/licenses/by-nc-nd/4.0/).

Contents

1. Introduction ................................................................................................................................................................ 50
2. Human intestinal microbiota in obesity ........................................................................................................................... 50

* Corresponding author.
E-mail address: beatriz_azfe@hotmail.com (B.A.M. Ferreira).

https://doi.org/10.1016/j.yclnex.2018.04.003
2352-9393/© 2018 The Authors. Published by Elsevier Ltd on behalf of European Society for Clinical Nutrition and Metabolism. This is
an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
50 B.A.M. Ferreira et al. / Clinical Nutrition Experimental 20 (2018) 49e54

3. Gene expression, microbiota and obesity......................................................................................................................... 51

4. Antibiotics, microbiota and obesity ................................................................................................................................... 52
5. Future perspectives ............................................................................................................................................................... 53
6. Conclusion ...................................................................................................................................................................53
Conflict of interest ......................................................................................................................................................53
Supplementary data .............................................................................................................................................................. 53
References ....................................................................................................................................................................53

1. Introduction

The prevalence of overweight and obesity has reached epidemic proportions worldwide. Obesity
is a multifactorial and polygenic condition considered to be one of the great public health chal-
lenges, especially since excess adiposity is associated with medical complications and comorbid- ities
[1,2].
Changes in eating habits, such as the increase in the consumption of foods high in fat and sugar,
appear to be related to the alteration of the genetic composition and metabolic activity of the resident
microorganisms e the human gut microbiome. Such diet-induced changes may be related to the
increasing prevalence of chronic diseases, including obesity [3,4].
The intestinal microbiome can be considered as a set of genetic factors that, together with the host
genotype and lifestyle (consumption and energy expenditure), contribute to the pathophysiology of
obesity [4].
Rankinen et al. [5] studied genotypes positively associated with obesity and identified 22 candidate
genes for obesity. The authors found 5 phenotypes related to obesity: energy expenditure, low lipid
oxidation, adipogenesis, sedentary lifestyle, and hyperphagia (i.e., regulation of hunger, appetite and
satiety).
In this review article, we will discuss hypotheses about the association between gene expression
and obesity, as well as aspects related to the intestinal microbiota.

2. Human intestinal microbiota in obesity

In recent years there has been increased interest in the study of the human intestinal microbiota
since intestinal microorganisms appear as potential contributors to the increased prevalence of
obesity [4].
The ecosystem consists mainly of bacteria, but also viruses, protozoa, fungi and archea. The microbiota of
the human intestine is mainly composed of Bacteroidetes, Firmicutes and Proteobacteria, as a minor but
important component. The intestinal microbiota plays an important role in host health, shaping the devel-
opment of the immune system, metabolizing dietary nutrients (such as fatty acids, glucose and bile acids) and
drugs, digesting complex polysaccharides, and synthesizing vitamins and bioactive molecules [6,7].
The mechanisms by which the intestinal microbiome can influence energy metabolism and ho-
meostasis include regulating the use of energy from food, interacting with signaling molecules
involved in the metabolism of microorganisms, modifying intestinal permeability, releasing intestinal
hormones, and chronic inflammation [4,8].
Diversity in intestinal microbial ecology among humans may be an important factor affecting en-
ergy homeostasis; that is, individuals predisposed to obesity may have intestinal communities that
promote the extraction and/or storage of energy from a particular diet. Studies have reported that the
prevalence of obesity was lower in individuals with greater microbial diversity. This hypothesis that
intestinal microbial diversity is linked to obesity deserves further exploration in humans since it may
generate new treatment strategies [9].
Most of the findings on the relationship between the microbiome and obesity are based on studies
with rodents. However, increasing evidence shows an increased proportion of bacteria of the phylum
Firmicutes and reduced concentrations of Bacteroidetes in obese as compared to normal weight
 B.A.M. Ferreira et al. / Clinical Nutrition Experimental 20 (2018) 49e54 51

humans [4,6,7,9,10]. Ley et al. [9] showed a reduction in the Firmicutes/Bacteroidetes ratio in obese
humans after weight loss with a controlled diet; the relative abundance of Bacteroidetes increased as
obese individuals lost weight with a hypocaloric diet that included a restriction of fat or carbohydrates.
The increased ratio of Firmicutes to Bacteroidetes bacteria may help promote adiposity or alter-
natively represent a host-mediated adaptive response to limit energy absorption/storage (e.g., reducing
the ability to ferment polysaccharides) [9]. Most of the studies report that the increase of bacteria of the
phylum Firmicutes is linked to the risk of disease, predominantly to cardiovascular diseases and
specifically to lipid metabolism, obesity, and inflammatory response [7].
Nutritional factors, such as energy intake, may affect the composition of the intestinal microbiota,
which also appears to be modulated by genetic and environmental factors. Energy balance is composed
of the amount of energy absorbed from the food and the amount expended during rest as well as the
thermic effects of food, physical activities, and the energy lost in feces and urine. The change in energy
storage efficiency of the diet produced by changes in intestinal microbial ecology appears to contribute
to obesity, since small changes in energy balance over long time periods can result in significant
changes in body weight [4].
The main challenges of science in this area are to determine the proper understanding of genetic
and environmental influences on the microbiota and also the consequences of structural and functional
changes on metabolic and inflammatory diseases.

3. Gene expression, microbiota and obesity

Evidence suggests that variations in genes and species pattern of the intestinal microbiome may
help define subgroups of individuals who are at increased risk of developing metabolic diseases,
including obesity. About 40e70% of the inter-individual variability in the body mass index, commonly
used to assess obesity, is attributed to genetic factors. Recent studies suggest that adiposity may in-
fluence DNA methylation, a key regulator of gene expression and molecular phenotype; methylation is
predominantly the consequence of adiposity rather than cause [11,12].
Obesity-related genes may alter the encoded amino acid sequence, as well as the concentration and
activity of translated proteins, modifications that may also be associated with distinct eating patterns
that influence individual susceptibility to weight gain in specific environments [13].
Epigenetics encompasses genomic changes that are due to environmental factors. The intestinal
microbiota plays an important role in human metabolism and may be a significant environmental
factor affecting the epigenome. However, there are few studies in humans that have correlated the
microbiota and epigenetic changes in obesity [7].
One of the first studies that highlighted the association of predominant bacterial phylum in the
intestine with methylation patterns to investigate the relationship of the intestinal microbiota with
epigenetic alterations was reported by Kumar et al. (2014) [7]. Eight pregnant women were selected
for evaluation based on their predominant intestinal microbiota for a study on the methylation
profile at six months postpartum. The authors observed that DNA methylation patterns in blood
were associated with intestinal microbiota profiles and suggested that the microbiota and its me-
tabolites influence genomic reprogramming [7]. Some studies report that the bacterial phylum
Firmicutes are major contributors of butyrate, which regulates gene expression by histone modifi-
cations. Lipopolysaccharide (LPS) is another microbial factor that may play a significant role in the
epigenetic regulation of immune and intestinal cells. LPS is widely recognized as an inflammatory
molecule [7,14]. The findings of this study are intriguing and may offer a new basis for prevention
and treatment strategies involving the intestinal microbiota and its impact on long-term genomic
changes [7]. Further longitudinal studies targeting individual microbial species or metabolites are
recommended to give us a deeper insight into the molecular mechanism of such epigenetic
modifications.
The main studies that have evaluated the interaction between gene expression, microbiota and
obesity are described below in Table 1.
52 B.A.M. Ferreira et al. / Clinical Nutrition Experimental 20 (2018) 49e54

Table 1
Summary of the main studies involving gene expression, microbiota and obesity.

Experimental design/aim Sample Methods Main results

[reference]

Metatranscriptome sequence
analysis to examine the
potential of host genotype
and diet in the influence of
microbial community
structure and function [15]
Transcriptomic analysis in
different parts of the
gastrointestinal tract of two
models of obese rats [16]
Investigation of changes in
intestinal microbiota and
gene expression in metabolic
disease after high
fat diet [17]
Analysis of global gene
expression and intestinal
microbiota composition in
response to a high fat/high
sucrose diet (HF/HS) [18]
Analysis of the effects of
dietary fat intake on gene
expression in terms of
linear or non-linear
responses [19]
Longitudinal analyzes of
responses to interactions
between host genetics,
diet and the intestinal
microbiota of three strains
of mice [20]
C57BL/6 (WT) Feeding for 4 days: The host genotype can modulate the
and Plin2-null 1. High fat (HFD, 60% fat, 20% function of the microbiome without
mice. protein, 20% carbohydrate) affecting the community structure.
2. Low fat (LFD, 10% fat, 20% protein,
70% carbohydrate).
Mice ob/ob High fat diet e HFD e 54.8% Significant changes in the
(B6.V-Lepob/J) Gastrointestinal tissues (stomach expression of genes in the stomach
and C57BL/6J and about 1 cm of samples from the that have strong associations with
males. middle of each part of the intestine). obesity, diabetes and insulin
Microarray analysis. resistance.
C57BL/6 male Feeding for 30 days: HTD, 72% fat. HFD-induced ileus microbiota
mice. Analysis of ileal samples by dysbiosis reduced intestinal IL17/
microarray. RORgt-CD4 T cells, IL17/RORgt-
deficient CD4 T cells induce obesity.
Strains of Feeding for 8 weeks with HF/HS diet Eleven genetic loci associated with
consanguineous (31.8% fat and 51.4% sucrose) obesity were identified and capable
mice. GWAS analysis. of responding to food alterations.
Rats obtained These overlap with loci identified in
from The studies in humans.
Jackson Mice fed HF/HS showed abundance
Laboratory. of several genera classified by order
Clostridiales in Phyla Firmicutes and
lower abundances of Bacteroidetes.
Male C57BL/6J Tissue studied: proximal, middle A higher number of genes that
mice. and distal sections of the small presented a linear transcriptomic
intestine. response to fat intake was found in
Dietary intervention: mice at 16 the middle section of the small
weeks of age were divided into four intestine.
groups that received 10, 20, 30 or Nonlinear patterns of gene
45% fat for 4 weeks. expression triggered by different
Transcriptomic data analysis of levels of dietary fat were observed.
microarrays of intestinal mucosa of
mice.
C57Bl/6J, 129S1/ Diet CD (14% fat, 24% protein and Diet HFD has increased the relative
SvImJ and 62% carbohydrates) or HFD abundance of Firmicutes.
129S6/SvEvTac (composed of 60% fat). After the Host genetics determine changes in
mice. feces were collected at 1, 8 and 22 the intestinal microbiota in
weeks. response to the high fat diet:
C57Bl/6J mice: fed with HFD for 1 Mice (129S6/SvEvTac) presented
week. Subsequently, they were environmental remodeling in the
colonized with cecal microbiota microbiota, which can significantly
collected from paired donors of improve the development of
129S1/SvImJ and 129S6/SvEvTac. metabolic syndrome characteristics,
After colonization, they were fed whereas in other contexts (such as
HFD for 8 weeks. C57B/6J), strong genetic influences
may be dominant.

4. Antibiotics, microbiota and obesity

Antibiotics, discovered in the early twentieth century, were largely used after World War II, showing
substantial public health benefits. However, there is an increasing concern that long term exposure to
antibiotics may be unhealthy [21].
Antibiotic treatment alters the composition of intestinal microbiota and, recently, there are evi-
dences of a link between increasing use of antibiotics and weight gain or acquired obesity in humans
[22].
 B.A.M. Ferreira et al. / Clinical Nutrition Experimental 20 (2018) 49e54 53

Changes in the intestinal microbiota after short-term antibiotic therapy can be partially resolved;
however, this does not happen with long term use which may bring permanent microbiota change.
Intestinal bacteria richness and diversity can be reduced, and in some patients, specific bacterial
communities are eliminated. It has also been described Firmicutes to be the dominant phylum in a
long-term administration of antibiotics [21e23].
Prophylactic or therapeutic use of antibiotics is associated to an imbalance between host and in-
testinal microbiota, that may be influenced by its time of administration, dose, and type, pharmaco-
kinetics and pharmacodynamics and antibiotic inactivation. However, due to the complexity of
bacterial communities, the antibiotic effects may be unpredictable [22,24].
Antibiotics affect intestinal microbiota direct or indirect action. These are observed in different
classes of antibacterial agents, such as macrolides, tetracyclines and penicillins [21,22].
The gastrointestinal tract is also a local process of hormone production, including those controlling
glucose homeostasis (glucagon, leptin and ghrelin) and growth (glucose-dependent insulinotropic
polypeptide (GIP) and glucagon-like peptide 1 (GLP-1)). Alterations in gastrointestinal microbiota may
alter intra-community metabolic interactions and affect host metabolic, hormonal and immune ho-
meostasis globally [21,25,26].
Obesity is associated with a chronic inflammatory response characterized by abnormal adipocy-
tokines production, activation of proinflammatory signaling pathways and the induction of inflam-
matory biomarkers. Insulin may signal the adiposity degree in medium and long term. An indicator of
adiposity, plasma leptin concentration correlates with adipocytes number and fat content [22,27].
Therapeutic antibiotic treatment alters gastrointestinal microbiota composition and host responses
to specific microbial signals [21,24].

5. Future perspectives

There are many inconsistencies in the results of studies investigating the intestinal microbiota and
its impact on genomic changes and their relationship to the risk of developing obesity. However,
technological advances have made these investigations possible. These advances provide opportunities
to establish the basis for incorporating biological individuality into recommendations with significant
therapeutic potential.

6. Conclusion

The global obesity epidemic stems from changes in lifestyle, environment, intestinal microbiota and
genetic traits, as well as interactions between these factors. In recent years, research on obesity has
contributed to clarify mechanisms related to this condition and consequently generate new treatment
strategies.

Conflict of interest

None.

Appendix A. Supplementary data

Supplementary data related to this article can be found at https://doi.org/10.1016/j.yclnex.2018.04.

003.

References

[1] [WHO] World Health Organization. Obesity: preventing and managing the global epidemic. Report of a WHO Consultation.
WHO technical report series, vol. 894; 2000. p. 252.
[2] Canella DS, Levy RB, Martins AP, Claro RM, Moubarac JC, Baraldi LG, et al. Ultra-processed food products and obesity in
Brazilian households (2008e2009). PLoS One 2014;9(3):e92752.
[3] Ley RE, Turnbaugh PJ, Klein S, Gordon JI. Microbial ecology: human gut microbes associated with obesity. Nature 2006;
444:1022e3.
54 B.A.M. Ferreira et al. / Clinical Nutrition Experimental 20 (2018) 49e54

[4] Turnbaugh PJ, Ley RE, Mahowald MA, Magrini V, Mardis ER, Gordon JI. An obesity-associated gut microbiome with
increased capacity for energy harvest. Nature 2006;444:1027e31.
[5] Rankinen T, Zuberi A, Chagnon YC, Weisnagel SJ, Argyropoulos G, Walts B, et al. The human obesity gene map: the 2005
update. Obesity 2006;14:529e644.
[6] Oriach CS, Robertson RC, Stanton C, Cryan JF, Dinan TG. Food for thought: the role of nutrition in the microbiota-gut-brain
axis. Clin Nutr Expl 2016;6:25e38.
[7] Kumar H, Lund R, Laiho A, Lundelin K, Ley RE, Isolauri E, et al. Gut microbiota as an epigenetic regulator: pilot study based
on whole-genome methylation analysis. mBio 2014;5(6):e02113e4.
[8] Tilg H, Kaser A. Gut microbiome, obesity, and metabolic dysfunction. J Clin Investig 2011;121:2126e32.
[9] Ley RE, Ba€ckhed F, Turnbaugh P, Lozupone CA, Knight RD, Gordon JI. Obesity alters gut microbial ecology. Proc Natl Acad
Sci U S A 2005;102(31):11070e5.
[10] Clercq NC. Gut microbiota in obesity and undernutrition. Adv Nutr 2016;7:1080e9.
[11] Wahl S, Drong A, Lehne B, Loh M, Scott WR, Kunze S, et al. Epigenome-wide association study of body mass index, and the
adverse outcomes of adiposity. Nature 2017;541:80e100.
[12] Locke AE, Kahali B, Berndt SI, Justice AE, Pers TH, Day FR, et al. Genetic studies of body mass index yield new insights for
obesity biology. Nature 2015;518:1e24.
[13] Ordovás MJM. Predictors of obesity: the “power” of the omics. Nutr Hosp 2013;5:63e71.
[14] Van OC, Groen AK, Nieuwdorp M. Role of intestinal microbiome in lipid and glucose metabolism in diabetes mellitus. Clin
Ther 2015;37:1172e7.
[15] Xiong X, Bales ES, Ir D, Robertson CE, McManaman JL, Frank DN, et al. Perilipin-2 modulates dietary fat-induced microbial
global gene expression profiles in the mouse intestine. Microbiome 2017;5:1e17.
[16] Chen J, Chen L, Sanseau P, Freudenberg JM, Rajpal DK. Significant obesity-associated gene expression changes occur in the
stomach but not intestines in obese mice. Physiol Rep 2016;4(10):1e15.
[17] Garidou L, Pomié C, Klopp P, Waget A, Charpentier J, Aloulou M, et al. The gut microbiota regulates intestinal CD4 T cells
expressing RORgt and controls metabolic disease. Cell Metabol 2015;22:100e13.
[18] Parks BW, Nam E, Org E, Kostem E, Norheim F, Hui ST, et al. Genetic control of obesity and gut microbiota composition in
response to high-fat, high-sucrose diet in mice. Cell Metabol 2013;17(1):141e52.
[19] Nyima T, Müller M, Hooiveld GJEJ, Morine MJ, Scott M. Nonlinear transcriptomic response to dietary fat intake in the small
intestine of C57BL/6J mice. BMC Genom 2016;17:1e13.
[20] Ussar S, Griffin NW, Bezy O, Fujisaka S, Vienberg S, Softic S, et al. Interactions between gut microbiota, host genetics and
diet modulate the Predisposition to obesity and metabolic syndrome. Cell Metabol 2015;22:516e30.
[21] Cho I, Yamanishi S, Cox L, Methé BA, Zavadil J, Li K, et al. Antibiotics in early life alter the murine colonic microbiome and
adiposity. Nature 2012;488:621e5.
[22] Angelakis E, Merhej V, Raoult D. Related actions of probiotics and antibiotics on gut microbiota and weight modificátion.
Lancet Infect Dis 2013;13:889e99.
[23] Robinson CJ, Young VB. Antibiotic administration alters the community structure of the gastrointestinal microbiota. Gut
Microb 2010;1:279e84.
[24] Sullivan A, Edlund C, Nord CE. Effect of antimicrobial agents on the ecological balance of human microflora. Lancet Infect
Dis 2001;1:101e14.
[25] Hansotia T, Drucker DJ. GIP and GLP-1 as incretin hormones: lessons from single and double incretin receptor knockout
mice. Regul Pept 2005;128:125e34.
[26] Gesta S, Tseng Y, Kahn CR. Developmental origin of fat: tracking obesity to its source. Cell 2007;131:242e56.
[27] Hotamisligil GS, Erbay E. Nutrient sensing and inflammation in metabolic diseases. Nat Rev Immunol 2008;8:1e26.