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Objective Nutrition

Intestinal microbiota and obesity


OBJECTIF NUTRITION 89 (SEPTEMBER 2008)
Dr Gérard Corthier
Unit of Ecology and Physiology of the Digestive Tract
French National Institute for Agricultural Research (INRA), Jouy en Josas



Throughout evolution, man has often had insufficient quantities of food for his nourishment. Those individuals who survived food shortages had heightened means of survival. In the present day, the majority of the population in the United States and Europe has access to food, and a simultaneous increase in obesity can be observed across these countries. Researchers have very recently highlighted a possible effect of commensal bacteria on weight regulation. It is possible that the co-evolution of man and his microbiota has favoured the maximum extraction of energy from scarce food. Current obesity could therefore be partly linked to this “over effective” symbiosis.

FOCUS

The microbiota, formerly termed “gut flora”, is not equally distributed along the human digestive tract. Its presence is relatively discreet in the first two divisions of the small intestine, where transit is quick. It increases sharply in the ileum to reach populations that are a hundred times greater in the colon and rectum.

The “good health” of humans depends on the balance of this microbiota, which protects us from the ingestion of pathogenic bacteria and stimulates the immune system. Among the major bacterial groups of the microbiota, the balance between Firmicutes and Bacteroidetes would appear to be a key factor.

THE DIVERSITY OF THE HUMAN MICROBIOTA

Man lives in symbiosis with a significant microbiota population that colonises his digestive tract. These bacteria feed on residues of food, secretions, and desquamation of the mucous membranes. They were for a long time considered to be potential sources of harmful effects, if not diseases. They were even termed “putrefying flora”. Suspicions then arose, which have recently been proved correct, that the microbiota has beneficial effects on our health.

It is estimated that 70% of bacteria that comprise the human microbiota cannot be cultivated by current techniques. Strictly anaerobic, they have unknown requirements in terms of culturing conditions. To characterise these populations, techniques based on certain DNA sequences, which do not require their culture, are therefore used. It would appear that one individual alone has a diversity of bacterial microbiota of as many as one thousand species. Furthermore, it has been remarked that only one common species will be found in ten different people. Extrapolation to the individuals who live on planet Earth suggests an extraordinary diversity of the microbiota in terms of species. It could be said that every human being is unique with regard to the microbiota that lives in him. Bacterial species can be regrouped by type and then into major groupings (“phyla”). At these two overall levels, similarities can be seen in the human microbiotas. Put simply, the microbiota of a non-obese human adult is characterised by an approximate 10:1 ratio of Firmicutes phylum to Bacteroidetes phylum. This ratio is different in the obese, the young, and the elderly.
TABLE 1: THE FIRMICUTES/BACTEROIDETES RATIO OF THE MICROBIOTA: A BALANCE TO BE MAINTAINED

Firmicutes/Bacteroidetes
Healthy adult (20–50 years)
Infant (0.7 to 10 months)
Senior citizen (70–90 years)
Obese adult
Adult with CIID*
Ratio
10:1
5:1
5:1
100:1
1:1 to 3:1

* CIID: Chronic Inflammatory Intestinal Diseases
MICROBIOTA AND OBESITY IN THE MOUSE

In 2004, the team of Jeffrey Gordon (Washington University, USA) published the first evidence of the effect of the microbiota on weight gain using axenic, or microbiota-free, mice. These mice, taken sterilely in utero and then placed in a sterile environment, were first fed on sterilised mouse milk prior to solid foods that had also been sterilised. Researchers found that mice that had been reared conventionally consumed less food than axenic mice, and that they had 60% more fatty tissue. They observed, therefore, that resident microbiota contributed to weight gain. This study and the following ones show that the microbiota enables conventional mice to digest, at least in part, dietary fibres and extract more energy than axenic mice. Furthermore, the transfer of the microbiota from conventional mice to axenic mice leads to an increase in their fatty tissue in the fortnight following inoculation. Preliminary work by the same team had shown that the presence of the microbiota favours the development of the blood network around the intestine (angiogenesis). The energy extracted from food residues is thought, therefore, to be more easily assimilated. The authors also evidenced another action of the microbiota on its host: its presence reduces the expression of a gene in the cells of the intestinal epithelium, leading to an increase in lipase activity and the storage of triglycerides in adipocytes. The presence of the microbiota therefore offers an advantage in the case of dietary restrictions.

The following work focused on obese mice whose leptin gene (regulating lipogenesis) had been inactivated. This type of deficiency, which is rare in man, also leads to obesity. The Firmicutes/Bacteroidetes ratio of these mice was revealed to be in the region of 100:1 instead of 10:1 in the same non-obese mice, suggesting different microbiota.


It was also shown that less energy could be extracted from the caecal contents of obese mice than those of lean mice. The comparison of part of the genes of the microbiota of these two lines of mice shows that the microbiota of obese mice is more adapted to the absorption of dietary fibres. The authors transferred the microbiota of obese and of lean mice to receiving axenic mice: weight gain was greater in the mice that received the microbiota of obese mice.

We can conclude from these works that the microbiota of obese mice has been shown to be highly effective in terms of energy recovery from food residues. This property is transferable to other mice via the microbiota.

The Firmicutes/Bacteroidetes ratio may be a marker of this microbiota, which is linked to obesity.

MICROBIOTA AND OBESITY IN MAN

The team of J. Gordon then conducted a study on obese patients following a low-fat or low-sugar diet for one year. The weight losses observed were in the region of 20% and of 10% respectively according to the diet. A good correlation can be observed between weight loss and the abundance of Bacteroidetes. A more detailed analysis of the microbiota shows an evolution of the Firmicutes/Bacteroidetes ratio during the diet: the initial ratio of 95:5 nears that of “lean” individuals, i.e. 70:30, after one year of dieting. The authors mention that this ratio changes further to weight loss in the region of 6% with low-fat diets and of 2% with low-sugar diets. The comparison over time of the microbiotas of these patients shows a “relationship” between the samples from one and the same individual. This suggests that the “unique” and “individual specific” nature of each microbiota does not change, but the balance that is unique to the subject is modified during weight loss.

On the basis of this trial in man, we cannot say if the modification of the Firmicutes/Bacteroidetes ratio is a cause or consequence of weight loss.

MAIN FUNCTIONS OF THE HUMAN MICROBIOTA

∙ The microbiota digests for its benefit the residues in transit in the colon. The most spectacular consequence is the production of gas (flatulence), but it also produces numerous metabolites that can be assimilated by the digestive mucous and can break down certain food residues that are harmful to man.

∙ Resident bacterial populations are “opposed to” colonisation by pathogenic bacteria and other bacteria that are in transit with food. Inappropriate antibiotic treatment can therefore disturb the balances of the microbiota and favour the implantation of pathogenic bacteria.

∙ The microbiota plays a major role in the permanent stimulation of the immune system. This vital balance is disturbed during some inflammatory intestinal diseases.

∙ The microbiota plays a role in weight gain and obesity.
HOW CAN THE MICROBIOTA INFLUENCE OBESITY?

According to work carried out on mice with controlled microbiota, it would appear that the presence of a microbiota:

∙ favours the vascularisation around the small intestine (angiogenesis)

∙ enables better digestion of food residues

∙ stimulates the assimilation of lipids.

The microbiota of obese mice appears to be more effective than that of lean mice in energy recuperation. The balance of bacterial populations is different between “obese” and “lean” microbiota.
It is possible that the food residues available for the microbiota modify this balance. Nonetheless, the aforementioned work in mice suggests a causal relationship. It would be tempting to research the conditions that are likely to change this relationship and to determine its influence on human obesity.

We ourselves have observed a modification of this relationship under pathological conditions by studying modifications in the balance of the microbiota in cases of Chronic Inflammatory Intestinal Disease (CIID), such as Crohn’s disease or haemorrhagic rectocolitis. The Firmicutes/Bacteroidetes ratio can be established at in the region of 1:1 to 3:1 instead of approximately 10:1 in a healthy subject.
CONCLUSION

In mice, studies clearly show that a modification of the microbiota, particularly the Firmicutes/Bacteroidetes ratio, has an influence on weight gain. In man, during weight loss subsequent to dietary changes, this ratio is modified in the same way as in mice, suggesting a relationship between the balance of the human microbiota and obesity. In cases of CIID, the loss of a subpopulation of Firmicutes appears to be linked to the pathology, underlining once again the necessity of maintaining a balance within the microbiota. All of these works indicate that intestinal microbiota must be taken into account in the management of the “global epidemic” that is human obesity at international level. A new lead would appear then to be breaking in research on obesity, which is no longer thought to be due to genetics and behaviour alone.
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