Gut Microbiota and Obesity | Encyclopedia MDPI

Gut Microbiota and Obesity: Comparison

Please note this is a comparison between Version 3 by Ludovico Abenavoli and Version 2 by Peter Tang.

Obesity is one of the most prevalent human health problems. Research from the last 30 ydearcades has clarified the role of the imbalance between energy intake and expenditure, unhealthy lifestyle, and genetic variability in the development of obesity. The composition and metabolic functions of gut microbiota have been proposed as being able to affect obesity development.

metabolism
gut microbiota
dysbiosis
obesity

1. Introduction

Changes in dietary habits and the increased availability of high-caloric foods have made overweightness and obesity some of the most serious health issues of our era. In 2016, the World Health Organization (WHO) estimated that 39% of individuals older than 18 were overweight, and the worldwide prevalence of obesity almost tripled between 1975 and 2016. It has been reported that nearly 2.8 million deaths annually are a consequence of overweight and obesity-associated conditions: blood hypertension, dyslipidemia, and insulin resistance lead to an increased risk of coronary heart disease, ischemic stroke, type 2 diabetes mellitus, as well as cancer development ^[1]. Obesity is caused by an imbalance between energy intake and expenditure: increasing the intake of fattening food and other lifestyle changes pushed its prevalence to epidemic proportions. On the other hand, several works have proven a significant genetic role in determining the obesity risk ^[2][3][4]. On top of the genetic factors clearly contributing to determining body weight and fat mass, the drastic boost in obesity prevalence has also suggested a prominent contribution in the development and maintenance of obesity caused by environmental elements.

In recent years, changes in bacterial strains, hosted in the human intestine, were proposed to have a causative role in obesity ^[3][5][6]. Intriguingly, the microbiome is a fingerprint of both the environment and human heritable genetic material ^[7]. In fact, it has been proposed that the genetic pool of the microbiota represents an extension of the nuclear and mitochondrial genomes, leading to the definition of the meta-genome to describe such extension ^[8].

2. Historical and Current Perspectives

The complex interaction involving the diet, intestinal microbiota, and human host has been investigated for over a century. Acceptance of the germ theory of disease development led to an original classification of a number of human disorders as caused by microbes, including conditions that were eventually going to be reconsidered as non-infectious. The initial proponent of such theories was the immunologist Elie Metchnikoff, considered by many as the father of probiotics. In his 1907 article, ‘‘Essais optimistes’’, Metchnikoff proposed a causative link between microbes and aging mechanisms and suggested a central role in senescence progression for compounds resulting from microbial intestinal putrefaction ^[9]. Furthermore, he firstly noted the beneficial effect of consuming fermented food on human health. Therefore, he hypothesized that fermented foods could avoid intestinal proteins putrefaction and thus senility.

Over the past century, several studies have demonstrated the influence of gut microbiota on the pathophysiology of many extra-intestinal conditions. More specifically, the exhaustive description of human microbiota’s relationship with health and disease has become the major challenge of research in the twenty-first century ^[10]. In recent years, the number of annual publications on this topic has almost quadrupled, as compared to 2005, when Eckburg et al. published the first large-scale gut metagenomic study that, starting from genetic fragments, allowed the reconstruction of entire genomic germ profiles ^[11].

Gut microbiota is the most complex ecosystem in nature since it harbors large bacterial populations in the intestine and colon, with around 1011–1012 microorganisms/gram of the intestinal content and mostly are anaerobes (95% of the total organisms) ^[12]. The first studies on the composition of intestinal microbiota were based on microscopic observation and culture-based methods, and showed as predominant cultivable species Bacteroides spp., Eubacterium spp., Bifidobacterium spp., Peptostreptoccocus spp., Fusobacterium spp., Ruminococcus spp., Clostridium spp. and Lactobacillus spp. ^[13]. Subsequently, Gill et al. obtained the first metagenomic sequencing of the distal gut microbiome in two subjects, showing microbial genomic and genetic diversity and identifying some of the distinctive features of this subpopulation of microbiome ^[14].

To date, genetic tests have led to the generation of large new datasets on gut microbiota, including information on the composition and functional properties of greater numbers of microbial strains. In this frame, US National Institutes of Health (NIH), founded the Human Microbiome Project (HMP) Consortium. HMP follows into the footsteps of the Human Genome Project, being constituted by multiple projects that bring together scientific experts worldwide to explore microbial communities to characterize the composition of the normal microbiome and the relationship with human organism ^[15]. Characterizing the microbial genes has led to the description of a human microbiome core ^[16]. It is established by a set of genes shared by microbes colonizing most habitats in humans. Interestingly, core genes present in a limited habitat and in a smaller set of humans can be modified by a combination of factors, such as host genotype, immune system physiology, disease state, lifestyle, diet, and also the presence of other microorganisms. This core microbiome is not present in shared big microbial populations but is involved in several essential metabolic functions for the bugs hosted in our intestine ^[17].

3. Gut Environment: Microbiota Evolutionary Development

The microbes detected in the human intestinal tract can be divided into three domains based on molecular phylogeny (i.e., 16S ribosomal ribonucleic acid [rRNA] sequence similarities and differences): eukarya, bacteria, and archaea. Eukarya includes organisms whose cells contain complex structures surrounded by membranes, primarily the nucleus. On the other hand, bacteria are the predominant strains of the gut microbiota (Table 1). About 90% of the fecal bacteria belong to two of the major phylogenetic lineages: Firmicutes and Bacteroidetes. However, the gastrointestinal tract of adult humans has been estimated to contain approximately 500–1000 distinct bacterial species ^[16]. In addition, Methanobrevibacter smithii is the dominant methanogenic archaeon species within the microbes in our digestive system ^[11].

Table 1. Main bacteria and Archaea in the human gut microbiota.

Domain	Phylum	Class	Order	Family	Genus

Clostridia ^[23]. A crucial determinant of gut microbiota development is the infant feeding. Several studies have shown different qualitative compositions of the bacterial flora in the breastfed subjects compared to the artificially fed ones. In breastfed infants, Bifidobacterium prevails (60%–90% of the fecal flora) vs. less than 1% of lactic-acid bacteria. In addition, there is a decrease in pH and inhibition of putrefactive flora growth with advantage for fermentative one development. This microbial switch improves intestinal digestive and absorptive functions of nutrients, in particular vitamins, with a consensual stimulation of immune system, namely gastrointestinal associated immune system (GALT), that reduces the risk of contracting allergies ^[24]. After the first six months of life, the weaning period begins with an enlarged diet composition and the introduction of the solid foods that leads to a further differentiation of microorganisms present in adults ^[25]. More specifically, these bugs belong to Firmicutes and Bacteroidetes (26). In the first year of life, levels of Escherichia coli and Enterococci range between 106 and 108 CFU/g of feces—there is a reduction in Clostridia and an increase in anaerobic flora, that undergoes a gradual diversification ^[24][25]. Interestingly, the initial colonization of the intestinal tract by microbes is important for defining the bacterial flora of the adult age. In fact, once the adult microbiota is constituted remains stable, with the exception of possible variations, following several factors such as a change in eating habits or the onset of diseases ^[26]. In adolescent children, a significantly higher representation of genera Bifidobacterium and Clostridium has been reported, as compared to adult levels ^[25][26]. A decline in the microbial abundance and species diversity, has been reported in the elderly, with lower levels of bifidobacteria and higher levels of Enterobacteriaceae ^[27].

4. Gut Microbiota Distribution and Its Relationship with Obesity

Differences in composition have been noticed in the microbial populations along the gastrointestinal tract ^[28]. These differences add a horizontal stratification, with the presence of diverse microbial communities in the intestinal lumen, in the layer of mucus of the intestinal crypts and directly adherent to the epithelial cells. In quantitative terms, esophagus and stomach carry the lowest bacterial load and the predominant cultivable bacteria are facultative anaerobes that derive from the oral cavity (e.g., Streptococci and Lactobacilli). Bacterial load increases progressively along the intestinal tract as the redox potential drops. Moreover, the genus Streptococcus is the most represented among the microbiota of jejunum ^[28]. However, a significantly higher population of bacteria (108–109/g of feces) characterizes specifically the ileo-cecal area. In fact, the small intestine is enriched by the subgroup Bacillus bacteria (phylum Firmicutes, mainly Streptococcaceae, corresponding to 23% of the genomic sequences identified compared with 5% in the colon). In addition, up to 8% of genomic sequences belong to members of the phylum Actinobacteria and, in particular, to the subgroups Actinomycinaeae and Corynebacteriaceae. In the small intestine, a small percentage Bacteroidetes and Lachnospiraceae has been identified vs. their concentration in the colon ^[29]. The largest number of bacteria and the vastest microbial diversity (1011–1012/mL of luminal contents) in human gut have been observed in the distal section of the ileum and the colon. The greatest portion is composed by strictly anaerobic, often non-spore-forming, mainly Gram-positive (Bacteroides and Clostridium). There are also facultative anaerobes such as Lactobacillus, Enterococcus and Enterobacteriaceae ^[29][30]. This substantially higher concentration of bacteria is due to a slower motility characterized by anti-peristaltic contractions that allow retention of colonic content for long periods. In addition, the intestinal pH is buffered through the secretion of bicarbonate that makes the environment more favorable to the bacterial colonization ^[31].

The hypothesis that the intestinal microbiota can constitute to a relevant environmental factor in the pathogenesis of obesity has led to the investigation of gut microbial communities in overweight individuals. The first evidence indicating an association between obesity and intestinal microbes was produced by studies applying DNA sequencing methods on a large scale to allow the screening of the entire gut microbiome. The first link between gut microbial environment and obesity was hypothesized by Ley et al. that analyzed the gut microbiota of leptin-deficient mice at major phyla level ^[32]. Results from 16S rRNA gene sequencing in mouse models indicated as the two most abundant bacterial phyla were Firmicutes (60%–80%) and Bacteroidetes (20%–40%), and showed how mice homozygous for an aberrant leptin gene ob/ob, carried a different proportion of bacteria in the ceca compared to lean wild-type (+/+) or heterozygous (ob/+) mice. In particular, the ob/ob mice had a 50% decrease in the population of Bacteroidetes and a proportional increase in Firmicutes (p < 0.05).

Similarly, Turnbaugh et al. published a study on mouse models using the newer shotgun metagenomic sequencing technique on cecal microbial DNA (ob/ob, ob/+ and +/+) ^[33]. This study confirmed the increased ratio of Firmicutes vs. Bacteroidetes in obese mice, as compared to lean ones. Moreover, ob/ob mice had a higher proportion of Archaea within the cecal gut microbial communities. There was also a higher representation of genes involved in energy extraction from food in the obese host microbiota compared to lean host microbes. Works in another mammalian models noticed a lower abundance of Bacteroidetes associated with obesity ^[34][35]. Other works have associated mouse obesity with specific bacteria, in particular Halomonas and Sphingomonas, and the reduction in the Bifidobacteria number ^[36]. In order to assess if microbial communities can similarly affect weight gain or loss in humans, several studies have investigated various cohorts of obese and lean individuals, but the results have not always been consistent (Table 2).

Table 2. Gut microbial population and obesity: relationship, causality and effects in human studies.

Source	Study Subjects	Comparison	No. of Subjects	Methods	Community Measured	Major Findings
Bacteria	Bacteroidetes
Ley et al. ^[32]	Human adults	Bacteroidia	Bacteroidales	Obese vs. controls	Bacteroidacee		12 obese, 2 normal weight	Bacteroides
	16S rRNA sequencing			Bacteroidetes Firmicutes		Significantly reduced level of Bacteroidetes in obese subjects.
Collado et al.		^[			^37]	Prevotellacee	Prevotella
	Pregnant women	Obese vs. lean pregnant	18 overweight, 36 normal weight pregnant women	FCM-FISH qPCR	Bacteroides Bifidobacteria Staphylococcus aureus	High numbers of Bacteroides group and S.aureus in the overweight pregnant women.						Xylanibacter
Zhang et al. ^[38]	Human adults	Obese vs. control vs. after RYGB	3 normal weight, 3 obese, 3 post-gastric bypass	16S Pyrosequencing qPCR	Firmicutes Bacteroidetes Proteobacteria Actinobacteria Fusobacteria Verrucomicrobia	More Bacteroidetes in obese subjects (not significant). Prevotellacee (phylum Bacteroidetes) and Coriobacteriacee (phylum Actinobacteria) increased in obese. Significant increase in Methanobacteriales in obese subjects.
Kalliomaki et al. ^[39]		Human children	Overweight/obese Normal weight		25 overweight: 7 obese, 24 normal weight	Rikenellacee	FISH	Rikenella
	Bifidobacteria Lactobacilli Clostridia Staphylococcus aureus			Lower number of bifidobacteria and greaternumber of	S. aureus	predict Obese/overweight phenotype.
Duncan et al. ^[40]	Firmicutes		Human male	Clostridia		Obese vs. normal weight	Clostridiales	15 obese, 14 lean	Clostridiacee	Clostridium
		FISH			Bacteroides Firmicutes E.rectale/C. coccoides	No differences in Bacteroides level in obese and normal weight subjects. Significant diet-dependent reduction in Eubacterium rectale/C. coccoides (phylum Firmicutes) levels in obese subjects.
Turnbaugh et al. ^[33]	Human twins		Obese and normal twins, mothers	Ruminococcae		154 subjects: 31 monozygotic twin pairs, 23 dizygotic twin pairs, 46 mothers	Faecalibacterium
	16S pyrosequencing V2 and V6 variable region			Bacteroidetes Firmicutes Proteobacteria Actinobacteria		Significantly reduced levels of Bacteroidetes in obese and increased level of Actinobacteria. Nearly half of the lean-enriched genes are from Bacteroidetes.
Armougom et al. ^[41]			Human adults	Anorexic, normal weight and obese			Ruminococcus
	20 normal weight, 20 obese, 9 anorexic			qPCR	Lactobacillus M. smithii Bacteroidetes Firmicutes	Significantly reduced levels of Bacteroidetes in obese subjects versus healthy subjects (p < 0.01). Firmicutes data are similar in the three categories. Significantly higher levels of Lactobacillus. Increase of M. smithii in anorexic subjects (p < 0.05).
Mai et al. ^[42]	Human adults		Peptostreptococcae		Peptostreptococcus
	African American and Caucasian American		98 subjects	FISH qPCR	Bacteroidetes Clostridia cluster XIV (Firmicutes)	No significant difference in Bacteroidetes numbers between obese and normal-weight subjects.
Nadal et al. ^[		⁴³			Fusibacter
^]	Human adolescents	Before and after 10 weeks of calorie-restricted diet	39 overweight adolescents	FISH	Bacteroidetes/Prevotella Bifidobacterium C. histolyticum E. rectale/C. coccoides Lactobacillus/En-terococcus	Greater weight loss after a multidisciplinary treatment program associated with: significant reduction of Eubacterium rectale, Clostridium coccoides and C. histolyticum; significant increase in Bacteroides/Prevotella.
Santacruz et al. ^[44]	Human adolescents		Eubacteriacee		Eubacterium
	Before and after diet and exercise for 10 weeks		36 obese adolescents	qPCR	Bacteroides fragilis Lactobacillus C. coccoides C. leptum Bifidobacterium Escherichia coli	After an obese group submitted to a weight program lost >4 Kg: significant reduction in C.coccoides; increase in the Bacteroides fragilis and Lactobacillus group.
Schwiertz et al. ^[45]	Human adults		Obese vs. overweight vs.normal weight	98 subjects: 30 lean, 35 overweight, 33 obese subjects	Veillonellacee		qPCR	Veillonella
	Firmicutes Bacteroidetes	Bifidobacteria			Significantly increased level of Bacteroidetes in obese subjects and decreased level of Firmicutes. Significant decrease in	Bifidobacteria and Methanobrevibacter spp. in obese subjects.
Balamurugan et al. ^[46				^]		Human children	Lachnospiraceae	Obese vs. non obese		15 obese, 13 normal weight	qPCR	Roseburia
	Bacteroidetes	Bifidobacterium Lactobacillus acidophilus E. rectale F. prausntzi			No significant difference in	Bacteroides/Prevotella and Bifidobacterium spp. Significant increase of Fecalibacterium prausntzi levels (Firmicutes species) in obese subjects.
Santacruz et al. ^[		Bacilli	^47]	Bacillales	Bacillaceae	Bacillus
	Pregnant women	Overweight/obese pregnant women vs. normal weight women	16 overweight pregnant, 34 normal weight pregnant women	qPCR	Bifidobacterium Lactobacilli Bacteroidetes Escherichia coli Staphilococcus	Significant reduction of Bifidobacterium and Bacteroides numbers in obese pregnant women. Increased levels of Staphilococcus and E. coli in overweight women.
Abdallah Ismail et al. ^[48]		Human children and adults	Obese vs. normal weight	Lysteriaceae	Lysteria
	79 subjects: 51 obese, 28 normal weight			qPCR	Bacteroidetes Firmicutes	Significantly increased distribution of Bacteroidetes and Firmicutes in the obese group.					Staphylococcaceae
Furet et al. ^[49]	Obese after RYGB	Obese subjects enrolled in a bariatric-surgery program	30 obese after RYGB, 13 lean		qPCR	Staphylococcus
	Bacteroides/Prevotella E. Coli F. Prausnitzii Bifidobacterium Lactobacilli			Bacteroides	/	Prevotella group was lower in obese subjects than in control subjects and increased after 3 months. Escherichia coli species after 3 months and inversely correlated with fat mass and leptin levels. F. prausnitzii species was lower in subjects with diabetes and associated negatively with inflammatory markers.
		Zuo et al. ^[50]			Human adults	Obese vs. normal weight	Pasteuriaceae	Pasteuria
	52 obese, 52 normal weight			Culture	Bacteroides Clostridium perfringens	Significantly reduced levels of Clostridium perfringens and Bacteroides in obese population.
Payne et al. ^[		^51]	Human children		Obese vs. normal weight children	Lactobacillales	Lactobacillaceae		30 subjects: 15 obese, 15 normal weight	qPCR TGGE	Lactobacillus
	Bacteroides Firmicutes	Roseburia/E.rectale Lactobacillus Bifidobacterium Enterobacteriacee F. prausnitzii			No significant differences for any population tested between obese and normal weight children.
Vael et al. ^[52]		Enterococcaceae			Enterococcus
	Human children	Children at 3, 26 and 52 weeks of age	138 subjects	Culture	Bacteroides fragilis Bifidobacterium Lactobacillus Enterobacteriacea Staphylococcus Clostridium	High intestinal Bacteroides fragilis and low Staphylococcus concentrations in infants between the age of 3 weeks and 1 year are associated with a higher risk of obesity later in life.
Patil et al. ^[53]	Streptococcaceae		Human adults	Lean, normal, obese and surgically-treated obese subjects	20 subjects: 5 lean, 5 normal, 5 obese, 5 surgically treated	qPCR	Streptococcus
	Bacteroidetes Firmicutes			Bacteroides	are prominent among the obese subjects.
Zupancic et al. ^[54	Actinobacteria	^]	Actinobacteria	Human adults	Stratified by BMI	Bifidobacteriales	Bifidobacteriaceae	Bifidobacterium
	310 adult subjects			16S rRNA pyrosequencing V1-V3	Bacteroidetes spp. Firmicutes spp.	Bacteroidetes/ Firmicutes ratio is not associated with BMI or metabolic syndrome traits.
Xu et al. ^[55]	Human children	Normal, overweight and obese subjects	175 children: 91 normal, 62 overweight, 22 obese		qPCR	Gardnerella
	Bacteroidetes Firmicutes			Reduction of Bacteroidetes level in obese group (	p	= 0.002).No differences in Firmicutes level between lean and obese children (p = 0.628).				Actinomycetales	Actinomycetaceae	Actynomices
Munukka et al. ^[56]	Premenopausal women	Overweight/obese women with and without metabolic disorders	85 premenopausal women	FISH	Bacteroidetes Bifidobacterium spp. Enterobacteriacee E. rectale/C. coccoides F. prausnitzii	Proportion of E. rectale/C. coccoides is higher in MDG women compared to NMDG and NWG women. Certain members of E. rectale/C. coccoides are associated with obesity related metabolic disease, not obesity per se.		Proteobacteria
Million et al. ^[57]		Human adults	Deltaproteobacteria	Obese vs. normal weight	Desulfobacteriales	Desulfobulbaceae		115 subjects: 68 obese, 47 controls	Desulfovibrio
	Culture (	Lactobacillus	spp.) qPCR		Lactobacillus spp. Bacteroidetes Firmicutes M. smithii	L. paracasei is significantly associated with lean status. L. reuteri, L. gasseri are significantly associated with obesity. M. smithii is less abundant in human obesity. Bacteroidetes are lower in obeses (not significant, p = 0.25)			Gammaproteobacteria	Enterobacteriales
Simões et al. ^[58]		Human twins	Enterobacteriaceae	Obese, overweight, normal weight		20 twin pairs	qPCR DGGE	Escherichia
		Eubacterium rectale group Clostridium leptum group Lactobacillus group Bacteroides	spp.			The abundance and diversity of the bacterial groups not differ between normal weight, overweight and obese individuals. Diet plays an important role in the modulation of the stool microbiota, in particular Bacteroides spp. and Bifidobacteria
Ferrer et al. ^[59]	Human adolescents		Enterobacter
						Klebsiella
Lean and obese subjects							Proteus
	1 obese, 1 lean individual			qPCR	Bacteroidetes Firmicutes Actinobacteria Proteobacteria	Lower Bacteroidetes abundance and greater frequencies of Clostridia (Firmicutes spp.) in obese subjects.
Million et al. ^[45]	Humans adults	Obese, overweight, lean and anorexic subjects	263 individuals: 134 obese, 38 overweight, 76 lean, 15 anorexic	qPCR	Bacteroidetes Firmicutes, M. smithii Lactobacillus spp. E.coli	L. reuterii was positively correlated with BMI. M. smithii was negatively associated with BMI. Bacteroidetes was not correlated with BMI.
Bervoets et al. ^[60]	Human children	Obese, overweight and morbidly obese (O/O group) and normal-weight, thinness (C group)	26 overweight/obese, 27 lean	qPCR Mass spectrometry	Bacteroides Bifidobacterium Clostridium Staphylococcus Lactobacillus	Higher concentration of Lactobacillus spp. in obese microbiota. Increased concentration of Firmicutes and decreased concentration of Bacteroidetes in obese children.			Epsilonproteobacteria
Tims et al. ^[61]		Campylobacteriales		Campylobacteriaceae	Campylobacter
	Human twins	Concordant and discordant BMI twin pairs	40 subjects: 20 discordant BMI 20 concordant BMI twin pairs	HITChip phylogenetic microarrays	Bacteroidetes Firmicutes Actinobacteria at phylotype level	MZ twins have more similar GI microbiota compared with unrelated subject. Inverse correlation between Clostridium cluster IV diversity and BMI; positive correllation between					Helycobacteriaceae	Helycobacter
	Fusobacteria	Fusobacteria	Fusobacteriales	Fusobacteriaceae	Fusobacterium
	Verrucomicrobia	Verrucomicrobiae	Verrucomicrobiales	Verrucomicrobiaceae	Verrucomicrobium
	Synergistetes	Synergistia	Synergistales	Synergistaceae	Synergistes
	Spirochaetes	Spirochaetes	Spirochaetales	Spirochaetaceae	Spirochaeta
					Treponema
	Cyanobacteria	Cyanobacteria
Archaea	Euryarchaeota	Methanobacteria	Methanobacteriales	Methanobacteriaceae	Methanobrevibacter
					Methanobacterium
					Methanosphaera

More specifically, the subclass distribution of gut microbiota are composed by: Bacteroidetes (23%) that comprise the genus Bacteroides, Firmicutes (64%) that includes Bacilli, Clostridia and Mollicutes (the majority of microorganisms in this phylum are closely related to genus Streptococcus and Clostridium); Proteobacteria (8%), Gram-negative bacteria such as Escherichia coli and Helicobacter pylori; Fusobacteria, Verrucomicrobia and Actinobacteria (3%) that include species such as Bifidobacterium ^[18][19][20]. Over 20 genera of Bacteroidetes have been described, with Bacteroidales being the most studied one, in particular the genus Bacteroides. Firmicutes are Gram-positive bacteria, divided into three classes: Clostridia, Bacilli, and Mollicutes (Table 1).

Childhood is characterized by the microbial plasticity that resembles the physiologic process of progressive gut colonization by microbes over time. The colonization of the digestive apparatus begins at birth and is different from individual to individual ^[21]. This process recognizes three steps: from birth to weaning, from weaning to a normal diet assumption that is characteristic of adulthood, and elderly. More particularly, at birth, the human gut is essentially free from bacteria, but, immediately after delivery, the intestine begins to be populated by a series of microorganisms—this process is influenced by exogenous and endogenous factors (e.g., mother’s vaginal and fecal microbiota, environment, skin bacterial flora) ^[22]. During the first 12–24 h of extra-uterine life, gut colonists are especially facultative anaerobic bacteria such as Escherichia coli, Enterococci and Streptococci ^[22]. Subsequently, from the second to the third day, these bacteria generate an anaerobic environment promoting the growth of obligate anaerobes (Lactobacilli and mainly Bifidobacteria), perhaps through reduction of the redox environment potential (low oxygen concentration). Within two weeks, this bacterial population expands from 108 to 1010 per gram of feces and establishes itself as species Bacteroides and

Eubacterium ventriosum/Roseburia intestinalis

and BMI. No consistent Bacteroidetes/Firmicutes ratio were observed in pair-wise comparison of lower- and higher-BMI siblings.

5. MFuture Pechanism Linking the Microbiota to Obrspectivesity

Thes debate shreds of evidence altogether have confirmed a statistical associon the significance of the correlation between obesity and gut microbiota peculiar composition. A number of mechanisms has been proposed forimbalance and obesity is one of the hottest topics in medicine. Although several molecular pathways have widened the view on the causative association between gut microbiota causative action inalterations and obesity physiopathology. In fact, gut commensal bacteria interact with our metabolism at several points: it helps to convert ingested complex nutrients to SCFAs, transforms mucins and dietary fibers into simple sugars ready for absorption, stimulatesdevelopment, this linkage remains very complex. On the other hand, the obesity pandemic asks for a solid response able to restore the significant gut microbial imbalance present in these patients. Thus, these findings imply the possibility and need for therapeutic manipulation of intestinal epithelial proliferation, favors nutrients absorption and microbiota to prevent or treat obesity and its metabolism, it is the main actor in the shaping of gut crucial defense barrierc manifestations. The correlation between Firmicutes/Bacteroidetes ratio and obesity constituted by systemic and mucosal immune system, and it activates bio-inactive compounds ^[62]s strong evidence arising from three decades of research in this filed. NHowevertheless, gut microbiota plays an important role in human adipose tissue formation and de, several recent studies have highlighted the complexity of the altered composition. Indeed, our of intestinal bacteria are able to maintain the human body energy balance mainly because of their amicrobiota in obese patients compared with lean subjects. Therefore, each study has linked obesity to species- or genus-specific composition profiles. The extreme variability to share otherwise indigestible components of mammalians dieof the results can be attributed to the different ^[63].

Gexperim-free (GF) mice have provided a complementary approach for characterizing the properties of human guental designs, microbiota fingerprinting, and genome analyses. We must also mention the different populations or sub-populations studied.

Part microbiota in the frameularly, the heterogeneity of metabolic processes. Backhed et al. have suggested thathods used to quantify the levels of gut microbiota may regulate energy storage through host signaling pathways, analyzing GF and conventionalized micedoes not allow a proper comparison of the results generated by different studies, as every technique is biased by accuracy, sensitivity or specificity issues. Thus, there is the need for ^[64].a Colostandardization of adult GF mice with a normaltechniques to be used to detect and classify gut microbiota harvested from the cecucomposition in obese subjects.

In m of conventionally raised animals produced a 57% increase in total body fat content and 61% increase of epididymal fat pads weight, despite reduced food intake. Moreover, the presence of microbiota increased serum levels of glucose and SCFAs that induced triglyceride production in the liver,re recent years, the attention of researchers has focused on the understanding of the specific metabolic patterns linked to the obesity physiopathology. Intestinal bacteria are an important part of these integrated functional networks. It has derived an increased adiposity, and reduced glucose tolerance. The authors observed also that the presenceing interest of investigators for the impact of gut microbes promoted an increased monosaccharide uptake from the gut, and an increased ability to degradeiota modulation by the diet in these metabolic processes.

In pcolysaccharides.

Lemnclusion, further investigations et al. analyzed the relationship between human milk hormones, namely leptin and insulin, and both the taxonomic organiz using standardized next-generation sequencing technologies should be conducted on the real association and metabolic properties of the infant of gut microbiota ^[65]. The aucomposithiors found increased levels of lipoprotein lipase (LPL) in epididymal fat pads of conventionalized mice. LPL, a key regulator of fatty acid release from triglyceride-rich lipoproteins, lead to the increased cellular uptake of fatty acids and adipocyte triglyceride accumn and specific obesity-related phenotypes. Moreover, the complex interaction of intestinal bacteria with the host has to be unraveled, as well as the possible effect of variables such as diet, age, gender or physical activity. Future evidences can help, using the modulation. Another study consolidated evidence showing that of these variables in order to re-shape gut microbiota is able to influence an important gut-derived host lipid metabolism factor, namely fasting-induced adipose factor (Fiaf), a circulating lipoprotein lipase inhibitor whose gene expression is normally selectively suppressed in the gut epithelium only by microbes although it is produced in liver and adipose tissuen a healthier profile. Indeed, it remains possible to directly modulate gut microbiota with probiotics, prebiotics, antibiotics, or other therapeutic interventions. Although several randomized clinical trials on probiotics in obesity setting have been carried out ^[66]. Iandeed, GF mice showed increased gut expression of Fiaf, but administration of microbes from a normal mouse decreases such expression and leads to larger deposits of triglycerides in adipose tissuetheir results are not yet convincing. Thus, more randomized placebo-controlled are lacking in this topic.

References

WHO. Overweight and Obesity. Available online: http://www.who.int/gho/ncd/risk_factors/overweight/en/ (accessed on 1 June 2019).
Abenavoli, L.; Milic, N.; Di Renzo, L.; Preveden, T.; Medić-Stojanoska, M.; De Lorenzo, A. Metabolic aspects of adult patients with nonalcoholic fatty liver disease. World J. Gastroenterol. 2016, 22, 7006–7016.
Castaner, O.; Goday, A.; Park, Y.M.; Lee, S.H.; Magkos, F.; Shiow, S.T.E.; Schröder, H. The Gut Microbiome Profile in Obesity: A Systematic Review. Int. J. Endocrinol. 2018, 2018, 4095789.
Bell, C.G. The Epigenomic Analysis of Human Obesity. Obesity 2017, 25, 1471–1481.
Festi, D.; Schiumerini, R.; Eusebi, L.H.; Marasco, G.; Taddia, M.; Colecchia, A. Gut microbiota and metabolic syndrome. World J. Gastroenterol. 2014, 20, 16079–16094.
Kobyliak, N.; Virchenko, O.; Falalyeyeva, T. Pathophysiological role of host microbiota in the development of obesity. Nutr. J. 2016, 15, 43.
Tomasello, G.; Mazzola, M.; Jurjus, A.; Cappello, F.; Carini, F.; Damiani, P.; Gerges Geagea, A.; Zeenny, M.N.; Leone, A. The fingerprint of the human gastrointestinal tract microbiota: A hypothesis of molecular mapping. J. Biol. Regul. Homeost. Agents 2017, 31, 245–249.
Cani, P.D. Human gut microbiome: Hopes, threats and promises. Gut 2018, 67, 1716–1725.
Metchnikoff, E.; Mitchell, P.C. The Prolongation of Life: Optimistic Studies; G.P. Putnam’s Sons: New York, NY, USA; London, UK, 1908.
Green, E.D.; Watson, J.D.; Collins, F.S. Human Genome Project: Twenty-five years of big biology. Nature 2015, 526, 29–31.
Eckburg, P.B.; Bik, E.M.; Bernstein, C.N.; Purdom, E.; Dethlefsen, L.; Sargent, M.; Gill, S.R.; Nelson, K.E.; Relman, D.A. Diversity of the human intestinal microbial flora. Science 2005, 308, 1635–1638.
Preveden, T.; Scarpellini, E.; Milić, N.; Luzza, F.; Abenavoli, L. Gut microbiota changes and chronic hepatitis C virus infection. Expert Rev. Gastroenterol. Hepatol. 2017, 11, 813–819.
Moore, W.E.; Holdeman, L.V. Human fecal flora: The normal flora of 20 Japanese-Hawaiians. Appl. Microbiol. 1974, 27, 961–979.
Gill, S.R.; Pop, M.; Deboy, R.T.; Eckburg, P.B.; Turnbaugh, P.J.; Samuel, B.S.; Gordon, J.I.; Relman, D.A.; Fraser-Liggett, C.M.; Nelson, K.E. Metagenomic analysis of the human distal gut microbiome. Science 2006, 312, 1355–1359.
Kolde, R.; Franzosa, E.A.; Rahnavard, G.; Hall, A.B.; Vlamakis, H.; Stevens, C.; Daly, M.J.; Xavier, R.J.; Huttenhower, C. Host genetic variation and its microbiome interactions within the Human Microbiome Project. Genome Med. 2018, 10, 6.
Nash, A.K.; Auchtung, T.A.; Wong, M.C.; Smith, D.P.; Gesell, J.R.; Ross, M.C.; Stewart, C.J.; Metcalf, G.A.; Muzny, D.M.; Gibbs, R.A.; et al. The gut mycobiome of the Human Microbiome Project healthy cohort. Microbiome 2017, 5, 153.
Turnbaugh, P.J.; Gordon, J.I. The core gut microbiome, energy balance and obesity. J. Physiol. 2009, 587, 4153–4158.
Sommer, F.; Anderson, J.M.; Bharti, R.; Raes, J.; Rosenstiel, P. The resilience of the intestinal microbiota influences health and disease. Nat. Rev. Microbiol. 2017, 15, 630–638.
Corfield, A.P. The Interaction of the Gut Microbiota with the Mucus Barrier in Health and Disease in Human. Microorganisms 2018, 6, 78.
Gagliardi, A.; Totino, V.; Cacciotti, F.; Iebba, V.; Neroni, B.; Bonfiglio, G.; Trancassini, M.; Passariello, C.; Pantanella, F.; Schippa, S. Rebuilding the Gut Microbiota Ecosystem. Int. J. Environ. Res. Public Health 2018, 15, 1679.
Tanaka, M.; Nakayama, J. Development of the gut microbiota in infancy and its impact on health in later life. Allergol. Int. 2017, 66, 515–522.
Francino, M.P. Birth Mode-Related Differences in Gut Microbiota Colonization and Immune System DevelopmenT. Ann. Nutr. Metab. 2018, 73, 12–16.
Dzidic, M.; Boix-Amorós, A.; Selma-Royo, M.; Mira, A.; Collado, M.C. Gut Microbiota and Mucosal Immunity in the Neonate. Med. Sci. 2018, 6, 56.
Goldsmith, F.; O’Sullivan, A.; Smilowitz, J.T.; Freeman, S.L. Lactation and Intestinal Microbiota: How Early Diet Shapes the Infant Gut. J. Mammary Gland Biol. Neoplasia 2015, 20, 149–158.
Le Doare, K.; Holder, B.; Bassett, A.; Pannaraj, P.S. Mother’s Milk: A Purposeful Contribution to the Development of the Infant Microbiota and Immunity. Front. Immunol. 2018, 9, 361.
Voreades, N.; Kozil, A.; Weir, T.L. Diet and the development of the human intestinal microbiome. Front. Microbiol. 2014, 5, 494.
Pérez Martínez, G.; Bäuerl, C.; Collado, M.C. Understanding gut microbiota in elderly’s health will enable intervention through probiotics. Benef. Microbes 2014, 5, 235–246.
Hillman, E.T.; Lu, H.; Yao, T.; Nakatsu, C.H. Microbial Ecology along the Gastrointestinal Tract. Microbes Environ. 2017, 32, 300–313.
De Faria Ghetti, F.; Oliveira, D.G.; de Oliveira, J.M.; de Castro Ferreira, L.E.V.V.; Cesar, D.E.; Moreira, A.P.B. Influence of gut microbiota on the development and progression of nonalcoholic steatohepatitis. Eur. J. Nutr. 2018, 57, 861–876.
Ottman, N.; Smidt, H.; de Vos, W.M.; Belzer, C. The function of our microbiota: Who is out there and what do they do? Front. Cell. Infect. Microbiol. 2012, 2, 104.
Sittipo, P.; Lobionda, S.; Lee, Y.K.; Maynard, C.L. Intestinal microbiota and the immune system in metabolic diseases. J. Microbiol. 2018, 56, 154–162.
Ley, R.E.; Bäckhed, F.; Turnbaugh, P.; Lozupone, C.A.; Knight, R.D.; Gordon, J.I. Obesity alters gut microbial ecology. Proc. Natl. Acad. Sci. USA 2005, 102, 11070–11075.
Turnbaugh, P.J.; Ley, R.E.; Mahowald, M.A.; Magrini, V.; Mardis, E.R.; Gordon, J.I. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 2006, 444, 1027–1031.
Pedersen, R.; Ingerslev, H.C.; Sturek, M.; Alloosh, M.; Cirera, S.; Christoffersen, B.Ø.; Moesgaard, S.G.; Larsen, N.; Boye, M. Characterisation of gut microbiota in Ossabaw and Göttingen minipigs as models of obesity and metabolic syndrome. PLoS ONE 2013, 8, e56612.
Hansen, A.K.; Hansen, C.H.; Krych, L.; Nielsen, D.S. Impact of the gut microbiota on rodent models of human disease. World J. Gastroenterol. 2014, 20, 17727–17736.
Waldram, A.; Holmes, E.; Wang, Y.; Rantalainen, M.; Wilson, I.D.; Tuohy, K.M.; McCartney, A.L.; Gibson, G.R.; Nicholson, J.K. Top-down systems biology modeling of host metabotype-microbiome associations in obese rodents. J. Proteome Res. 2009, 8, 2361–2375.
Collado, M.C.; Isolauri, E.; Laitinen, K.; Salminen, S. Distinct composition of gut microbiota during pregnancy in overweight and normal-weight women. Am. J. Clin. Nutr. 2008, 88, 894–899.
Zhang, H.; DiBaise, J.K.; Zuccolo, A.; Kudrna, D.; Braidotti, M.; Yu, Y.; Parameswaran, P.; Crowell, M.D.; Wing, R.; Rittmann, B.E.; et al. Human gut microbiota in obesity and after gastric bypass. Proc. Natl. Acad. Sci. USA 2009, 106, 2365–2370.
Kalliomäki, M.; Collado, M.C.; Salminen, S.; Isolauri, E. Early differences in fecal microbiota composition in children may predict overweight. Am. J. Clin. Nutr. 2008, 87, 534–538.
Duncan, S.H.; Lobley, G.E.; Holtrop, G.; Ince, J.; Johnstone, A.M.; Louis, P.; Flint, H.J. Human colonic microbiota associated with diet, obesity and weight loss. Int. J. Obes. 2008, 32, 1720–1724.
Armougom, F.; Henry, M.; Vialettes, B.; Raccah, D.; Raoult, D. Monitoring bacterial community of human gut microbiota reveals an increase in Lactobacillus in obese patients and Methanogens in anorexic patients. PLoS ONE 2009, 4, e7125.
Mai, V.; McCrary, Q.M.; Sinha, R.; Glei, M. Associations between dietary habits and body mass index with gut microbiota composition and fecal water genotoxicity: An observational study in African American and Caucasian American volunteers. Nutr. J. 2009, 8, 49.
Nadal, I.; Santacruz, A.; Marcos, A.; Warnberg, J.; Garagorri, J.M.; Moreno, L.A.; Martin-Matillas, M.; Campoy, C.; Martí, A.; Moleres, A.; et al. Shifts in clostridia, bacteroides and immunoglobulin-coating fecal bacteria associated with weight loss in obese adolescents. Int. J. Obes. 2009, 33, 758–767.
Santacruz, A.; Marcos, A.; Wärnberg, J.; Martí, A.; Martin-Matillas, M.; Campoy, C.; Moreno, L.A.; Veiga, O.; Redondo-Figuero, C.; Garagorri, J.M.; et al. EVASYON Study Group. Interplay between weight loss and gut microbiota composition in overweight adolescents. Obesity 2009, 17, 1906–1915.
Schwiertz, A.; Taras, D.; Schäfer, K.; Beijer, S.; Bos, N.A.; Donus, C.; Hardt, P.D. Microbiota and SCFA in lean and overweight healthy subjects. Obesity 2010, 18, 190–195.
Balamurugan, R.; George, G.; Kabeerdoss, J.; Hepsiba, J.; Chandragunasekaran, A.M.; Ramakrishna, B.S. Quantitative differences in intestinal Faecalibacterium prausnitzii in obese Indian children. Br. J. Nutr. 2010, 103, 335–338.
Santacruz, A.; Collado, M.C.; García-Valdés, L.; Segura, M.T.; Martín-Lagos, J.A.; Anjos, T.; Martí-Romero, M.; Lopez, R.M.; Florido, J.; Campoy, C.; et al. Gut microbiota composition is associated with body weight, weight gain and biochemical parameters in pregnant women. Br. J. Nutr. 2010, 104, 83–92.
Abdallah Ismail, N.; Ragab, S.H.; Abd Elbaky, A.; Shoeib, A.R.; Alhosary, Y.; Fekry, D. Frequency of Firmicutes and Bacteroidetes in gut microbiota in obese and normal weight Egyptian children and adults. Arch. Med. Sci. 2011, 7, 501–507.
Furet, J.P.; Kong, L.C.; Tap, J.; Poitou, C.; Basdevant, A.; Bouillot, J.L.; Mariat, D.; Corthier, G.; Doré, J.; Henegar, C.; et al. Differential adaptation of human gut microbiota to bariatric surgery-induced weight loss: Links with metabolic and low-grade inflammation markers. Diabetes 2010, 59, 3049–3057.
Zuo, H.J.; Xie, Z.M.; Zhang, W.W.; Li, Y.R.; Wang, W.; Ding, X.B.; Pei, X.F. Gut bacteria alteration in obese people and its relationship with gene polymorphism. World J. Gastroenterol. 2011, 17, 1076–1081.
Payne, A.N.; Chassard, C.; Zimmermann, M.; Müller, P.; Stinca, S.; Lacroix, C. The metabolic activity of gut microbiota in obese children is increased compared with normal-weight children and exhibits more exhaustive substrate utilization. Nutr. Diabetes 2011, 1, e12.
Vael, C.; Verhulst, S.L.; Nelen, V.; Goossens, H.; Desager, K.N. Intestinal microbiota and body mass index during the first three years of life: An observational study. Gut Pathog. 2011, 3, 8.
Patil, D.P.; Dhotre, D.P.; Chavan, S.G.; Sultan, A.; Jain, D.S.; Lanjekar, V.B.; Gangawani, J.; Shah, P.S.; Todkar, J.S.; Shah, S.; et al. Molecular analysis of gut microbiota in obesity among Indian individuals. J. Biosci. 2012, 37, 647–657.
Zupancic, M.L.; Cantarel, B.L.; Liu, Z.; Drabek, E.F.; Ryan, K.A.; Cirimotich, S.; Jones, C.; Knight, R.; Walters, W.A.; Knights, D.; et al. Analysis of the gut microbiota in the old order Amish and its relation to the metabolic syndrome. PLoS ONE 2012, 7, e43052.
Xu, P.; Li, M.; Zhang, J.; Zhang, T. Correlation of intestinal microbiota with overweight and obesity in Kazakh school children. BMC Microbiol. 2012, 12, 283.
Munukka, E.; Wiklund, P.; Pekkala, S.; Völgyi, E.; Xu, L.; Cheng, S.; Lyytikäinen, A.; Marjomäki, V.; Alen, M.; Vaahtovuo, J.; et al. Women with and without metabolic disorder differ in their gut microbiota composition. Obesity 2012, 20, 1082–1087.
Million, M.; Maraninchi, M.; Henry, M.; Armougom, F.; Richet, H.; Carrieri, P.; Valero, R.; Raccah, D.; Vialettes, B.; Raoult, D. Obesity-associated gut microbiota is enriched in Lactobacillus reuteri and depleted in Bifidobacterium animalis and Methanobrevibacter smithii. Int. J. Obes. 2012, 36, 817–825.
Simões, C.D.; Maukonen, J.; Kaprio, J.; Rissanen, A.; Pietiläinen, K.H.; Saarela, M. Habitual dietary intake is associated with stool microbiota composition in monozygotic twins. J. Nutr. 2013, 143, 417–423.
Ferrer, M.; Ruiz, A.; Lanza, F.; Haange, S.B.; Oberbach, A.; Till, H.; Bargiela, R.; Campoy, C.; Segura, M.T.; Richter, M.; et al. Microbiota from the distal guts of lean and obese adolescents exhibit partial functional redundancy besides clear differences in community structure. Environ. Microbiol. 2013, 15, 211–226.
Bervoets, L.; Van Hoorenbeeck, K.; Kortleven, I.; Van Noten, C.; Hens, N.; Vael, C.; Goossens, H.; Desager, K.N.; Vankerckhoven, V. Differences in gut microbiota composition between obese and lean children: A cross-sectional study. Gut Pathog. 2013, 5, 10.
Tims, S.; Derom, C.; Jonkers, D.M.; Vlietinck, R.; Saris, W.H.; Kleerebezem, M.; de Vos, W.M.; Zoetendal, E.G. Microbiota conservation and BMI signatures in adult monozygotic twins. ISME J. 2013, 7, 707–717.
Sanmiguel, C.; Gupta, A.; Mayer, E.A. Gut Microbiome and Obesity: A Plausible Explanation for Obesity. Curr. Obes. Rep. 2015, 4, 250–261.
Stephens, R.W.; Arhire, L.; Covasa, M. Gut Microbiota: From Microorganisms to Metabolic Organ Influencing Obesity. Obesity 2018, 26, 801–809.
Bäckhed, F.; Ding, H.; Wang, T.; Hooper, L.V.; Koh, G.Y.; Nagy, A.; Semenkovich, C.F.; Gordon, J.I. The gut microbiota as an environmental factor that regulates fat storage. Proc. Natl. Acad. Sci. USA 2004, 101, 15718–15723.
Lemas, D.J.; Young, B.E.; Baker, P.R., 2nd; Tomczik, A.C.; Soderborg, T.K.; Hernandez, T.L.; de la Houssaye, B.A.; Robertson, C.E.; Rudolph, M.C.I.D.; Patinkin, Z.W.; et al. Alterations in human milk leptin and insulin are associated with early changes in the infant intestinal microbiome. Am. J. Clin. Nutr. 2016, 103, 1291–1300.
Bäckhed, F.; Manchester, J.K.; Semenkovich, C.F.; Gordon, J.I. Mechanisms underlying the resistance to diet-induced obesity in germ-free mice. Proc. Natl. Acad. Sci. USA 2007, 104, 979–984.