The Gut Microbiota and Obesity
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CHAPTER 11. The gut microbiota and obesity Hervé M. Blottière CHAPTER 11 CHAPTER The human microbiota is com- portance outside the gut, especially a definition [3]. In a healthy symbi- posed of about as many microorgan- after the pioneering work of Gordon otic state, the colonic microbiota isms as there are cells in the human and collaborators [1]. is an important organ, interacting body. It is a very diverse ecosystem Recently, the development of with food (in particular dietary fibre, comprising more than 100 trillion mi- molecular tools and subsequently of enabling energy harvest from oth- crobes living in the intestines, the next-generation sequencing enabled erwise indigestible dietary com- mouth, the skin, the vagina, and the richness of the intestinal ecosys- pounds), interacting with cells (in- elsewhere in the body. Although it tem to be revealed [2]. Each individ- cluding immune cells, but also the was previously called the gastroin- ual harbours hundreds of different metabolic and nervous systems), testinal flora or microflora, the more species, most of which have not and protecting against pathogens pragmatic term “microbiota” is now yet been cultured. Studies have re- by acting as a barrier to infection preferred. vealed that 70–80% of the dominant (Fig. 11.1). The microbiome, the “other ge- species have no representative in nome” or “second genome” of the culture collections. Only a few doz- Gene catalogues of gut human body, is composed of about en species are conserved between microbiota 10 million genes, compared with about individuals, representing a core that 23 000 genes in the human genome, seems to be a stable community un- The first draft of the human genome and thus provides a very rich function- der healthy conditions. Although this was published in 2000. In 2010, the al potential. The colonic microbiome view is controversial, some people Metagenomics of the Human Intes- is the most diverse and also the best consider the gut microbiota to be tinal Tract (MetaHIT) consortium re- characterized microbial community. a true organ; as such, it could be leased the first catalogue of human Although the human microbiome transplanted. The recent success gut microbial genes, obtained after has fantastic potential, it has only of faecal microbiota transplantation, sequencing whole faecal microbiota been about 10 years since the sci- especially in the context of Clostridi- metagenomes from 124 European indi- entific community first realized its im- um difficile infection, argues for such viduals [4]. Interestingly, the 3.3 million Chapter 11. The gut microbiota and obesity 89 Fig. 11.1. The gut microbiota. The gut microbiota • An average of 650 000 genes per microbiome Human physiology • About 25–30 times as many genes as the human genome About 500–1000 dominant species per • Intestinal Immun e individual Nutrition microbiota defence s • A true organ Barrier agains t pathogen s gut bacterial genes in the MetaHIT ation when attempting to extrapolate [10], although Proteobacteria, Ver- catalogue were also well represent- results obtained in mouse models to rucomicrobia, and Fusobacteria are ed in the other metagenomes that the situation in humans. present to a lesser extent. About were available at the time, from 50% of individuals harbour Archaea faecal samples of individuals in the Colonization in their microbiota, especially Meth- USA and Japan. In parallel, the Hu- anobrevibacter smithii, which is re- man Microbiome Project published a The colonization process starts at sponsible for methane excretion. A catalogue of 178 reference bacterial birth, and the delivery type is the first core of species has been identified genomes distributed among different factor that has an impact. For infants as being present in most individuals, body sites and including 151 repre- that are vaginally delivered, the initial but with different relative abundanc- sentative gastrointestinal species gut microbiota resembles the moth- es. The number of species identi- [5]. er’s vaginal microbiota, dominated fied in the core depends on the an- In 2014, the MetaHIT consortium by bacteria of the genera Lacto- alytical method used: 66 from 16S published an integrated catalogue bacillus, Prevotella, and Sneathia, rDNA sequencing [11] or 57 from of 10 million bacterial genes de- whereas for infants delivered by whole-metagenome sequencing [5]. rived from 1267 human gut metage- caesarean section, the initial gut mi- Under healthy conditions, the in- nomes obtained from individuals crobiota resembles the mother’s skin testinal microbiota is considered to on three continents, including 760 microbial community, composed of be a stable community, influenced samples from Europe. As expect- Staphylococcus, Corynebacterium, by dietary habits as well as by the ed, the number of frequent genes and Propionibacterium [8]. Coloniza- physiology of its host. stopped increasing, whereas the tion is also strongly affected by the number of rare genes, present in administration of antibiotics in early Enterotypes not more than 1% of the cohort, life [9]. During the first 3 years of life, continued to increase [6]. Analyses the infant’s gut microbiota is highly Further analysis of several metage- of this close-to-complete catalogue unstable and is largely influenced nomes led to the discovery of three revealed country-specific signatures by feeding habits. Key factors are balanced ecological arrangements, for xenobiotic metabolism and nutri- the type of feeding (breastfeeding termed enterotypes; the three en- ent consumption for samples from or formula feeding), the weaning terotypes are dominated by Bac- individuals in China and Denmark. time and process, and food compo- teroides, Prevotella, and Rumino- More recently, a catalogue of sition, as well as the hygiene of the coccus, respectively [12]. The third the mouse gut metagenome was environment. enterotype is also linked to the pres- established, emphasizing the host By the time an individual reaches ence of M. smithii. This description specificity of the microbiota [7]. Only adulthood, the intestinal microbiota of community types is not limited to about 4.0% of the mouse gut micro- is composed of several hundreds of the gut [13]. These enterotypes or bial genes were shared with those different species, belonging only to a community types emerged as being of the human gut microbiome. It is few phyla, predominantly Firmicutes, independent of sex and country of important to take this into consider- Bacteroidetes, and Actinobacteria origin but probably associated with 90 long-term dietary habits [14]. Wu et to be essential for the maintenance of 60% increase in body fat mass, ac- al. [14] were able to associate con- a healthy state, and several reports companied by increased leptin and sumption of protein and animal fat have shown that a state of dysbiosis insulin levels and linked to increased with the Bacteroides enterotype and is often associated with diseases, in- absorption of monosaccharides from consumption of carbohydrates with cluding inflammatory bowel disease, the gut lumen, with resulting induc- the Prevotella enterotype. Interest- allergies, colorectal cancer, and liver tion of hepatic de novo lipogenesis ingly, by analysing samples from diseases, as well as obesity, diabe- [16]. A comparison of the microbiota volunteers randomized to a high-fat, tes, and cardiovascular diseases [2]. of lean and obese mice revealed that low-fibre diet or a low-fat, high-fibre Dysbiosis may be defined as an im- in obese mice (ob/ob animals), the diet for 10 days, this study revealed balanced microbiota, including four relative abundance of Bacteroidetes rapid changes in microbiome com- types of imbalance: (i) loss of key- was lower and that of Firmicutes was position; however, the enterotype stone species, (ii) reduced richness higher [17]. Moreover, transplanting of an individual did not seem to be or diversity, (iii) increased pathogens microbiota from obese animal to affected by this relatively short-term or pathobionts, or (iv) modification germ-free mice resulted in a greater dietary intervention. Transit time of or shift in metabolic capacities [9] increase in total body fat compared food through the gut has also been (Fig. 11.2). with transplanting microbiota from correlated with enterotypes [15]. lean animals, highlighting the con- The link with obesity tributory role of microbiota to obesity Dysbiosis [18]. In a study comparing the mi- The first link between gut microbio- crobiota from a dozen obese people The human gut microbiota is very ta and obesity came from studies in with that of a few lean controls, the complex and diversified. The micro- germ-free rodents. These animals authors reported that the decreased biome of an individual has more than eat more, move less, develop less proportion of Bacteroidetes and the 25 times as many genes as there are fat content, and are resistant to di- increased proportion of Firmicutes in the human genome. The fitness of et-induced obesity. Conventionaliza- observed in obese mice were also this well-balanced symbiosis seems tion of germ-free mice resulted in a observed in obese people [19]. They Fig. 11.2. Intestinal microbiota dysbiosis in obesity and physiological perturbation. AngPTL4, angiopoietin-like 4; 11 CHAPTER BA, bile acids; FA, fatty acids; GLP-1, glucagon-like peptide 1; LPL, lipoprotein lipase; LPS, lipopolysaccharide; PYY, peptide YY; SCFA, short-chainInt efattyst iacids;nal TG,mi ctriglycerides;robiot aTMA, dy trimethylamine;sbiosis TMAO, trimethylamine N-oxide. Dysbiosis: • Loss of keystone species • Loss of richness • Increased pathobionts • Metabolic shift in the ecosystem Brain Reduced satiety Liver SCFA, Increased gluconeogenesis TMA, Increase TMAO production Increased inflammation BA, Reduced PYY, GLP-1 LPS, Increased permeability etc. Increased endotoxaemia Adipose tissue Increased metabolite Increased LPL activity absorption Increase TG incorporation Reduced AngPTL4 Increased inflammation Muscle Reduced FA oxidation Immune system Recruitment of cells Cell activation Cytokine secretion Chapter 11. The gut microbiota and obesity 91 also reported that obese people los- count and those with high bacterial insulin resistance are diverse.