© Borgis - Postępy Nauk Medycznych 7/2014, s. 502-505
Udział jelitowej flory bakteryjnej w mechanizmie otyłości i miażdżycy
The intestinal microbiota in the mechanism of obesity and atherosclerosis
Department of Clinical Physiology, Medical Center of Postgraduate Education, Warszawa
Head of Department: prof. Andrzej Beręsewicz, MD, PhD
Organizm człowieka jest środowiskiem życia ogromnej ilości mikroorganizmów. Wraz z porodem przewód pokarmowy noworodka jest kolonizowany przez bakterie. Jelitowa flora bakteryjna (JFB) jest bardzo liczna, zróżnicowana gatunkowo i stopień tego zróżnicowania zależy od czynników środowiskowych, w tym od diety. JFB rozkłada różne składniki diety i, w zależności od jej składu gatunkowego, produkty tego rozkładu mogą mieć korzystne lub niekorzystne działania zdrowotne. W tym kontekście wykazano charakterystyczne różnice w składzie gatunkowym JFB między osobami szczupłymi i otyłymi. Niedawne badania u zwierząt i ludzi wykazały, że JFB uczestniczy w rozkładzie pokarmowej fosfatydylocholiny i L-karnityny oraz że produkt tego rozkładu – tlenek-N-trójetyloaminy (TMAO) – ma działanie promiażdżycowe, a TMAO w surowicy jest czynnikiem ryzyka choroby niedokrwiennej serca. Okazało się ponadto, że flawonoidy działają przeciwmiażdżycowo poprzez produkt ich bakteryjnego rozkładu – kwas protokatechowy. W prezentowanym artykule opisano związek między składem gatunkowym JFB a rozwojem otyłości i miażdżycy oraz mechanizmy, w jakich JFB wpływa na wagę ciała i powstawanie zmian miażdżycowych.
Gut flora consists of a combination of microorganism species that live in the digestive tracts of animals and is the largest reservoir of human flora. At birth, the human intestines are rapidly colonized by gut microbes. Owing to their vast number, species heterogeneity, and capacity to ferment nutrients and secret bioactive compounds, gut microbiota may affect the host’s physiology and metabolism negatively or positively. Thus, a number of studies describe characteristic differences between the composition and/or the activity of the gut microbiota of lean individuals and those with obesity. Recent studies in animals and humans have shown a mechanistic link between intestinal microbial metabolism of dietary phosphatidylcholine and L-carnitine and atherosclerosis and coronary artery disease through the production of a proatherosclerotic metabolite, trimethylamine-N-oxide. Furthermore, flavonoids have been recently demonstrated to exert their antiatherogenic activity via their gut microbiota metabolite protocatechuic acid. The following review discuss the microbiota-obesity and the microbiota-atherosclerosis relationships and proposed mechanisms by which the gut microbiota are thought to influence weight gain and to support the development of atherosclerotic lesions.
Since 2008 there has been an international research project called Human Microbiome Project analyzing the biological roles of commensalistic bacteria settled in different areas of human body. This and other research suggest involvement of intestinal bacterial flora (IBF) in the mechanisms of different diseases, including such civilization diseases like obesity (1-8) and arteriosclerosis (9, 10). In this context it was proved that the bacterial inhabitants of the human gastrointestinal tract break down various alimentary composition and that the products of this process may have beneficial or unbeneficial biological effects. There are three kinds of substances important to obesity and arteriosclerosis development:
1. Short chain fatty acids, which are produced in the disintegration of complex polysaccharides and take part in the development of obesity.
2. Trimethylamine (TMA), which is a product of lecithin and L-carnitine bacterial metabolism and which, after oxygenation by the hepatic enzyme into TMAO, has a pro-arteriosclerotic effect.
3. Protocatechuic acid (PCA), which is a product of plants flavonoids bacterial metabolism and which has an anti-arteriosclerotic effect.
The current hypothesis is that there are individual differences in the IBF composition and that some quantitative and qualitative proportion of IBF have beneficial and others unbeneficial effects. It is widely known that lean and obese people have different kinds of IBF. In this article I present IBF content and biology as well as its role in development of obesity and arteriosclerosis.
THE composition AND BIOLOGY OF INTESTINAL BACTERIAL FLORA
Alimentary tract of a newborn mammal is sterile. With birth the process of alimentary tract colonization by bacteria begins. In humans the more or less final composition of IBF is settled when the child is introduced on the same diet as adult family members (11). The amount of intestinal bacteria in an adult human is estimated to 1013-1014 microorganisms (~1 kg of bacteria), which means that we have ~10 times more bacteria that our own cells in the intestines only (12). Human IBF (but also mice’s) contain mainly anaerobic bacteria belonging to five phyla: Firmicutes (64%), Bacteroidetes (23%), Proteobacteria, Actinobacteria i Verrucomicrobia, consisting of totally 1000-1500 bacterial species (13). In human intestine there are also viruses, protozoons, archeons and fungi (14).
There are individual differences in IBF composition. These may be quantitative differences (in the percentage of different phyla/species in the whole amount of bacteria) and qualitative (in the amount of IBF species). The differences in IBF species composition are determined by: geographical area of origin, environmental hygiene conditions and genetics (in uniovular twins the differences in IBF composition are minimal) (1). The species composition of the human intestinal microbiota is also determined by: (a) prematurity – in premature infants there were mainly anaerobes (Klebsiella, Enterobacter) and Bifidobacterium, Enterobacteriaceae and Lactobacillus bacteria occur much later than in children born in term (15); (b) the kind of delivery – natural vs by cesarean section (16); (c) the kind of feeding – in children fed with breast milk there are mainly Bifidobacterium bacteria and in children fed with modified milk IBF is more differentiated (16, 17); (d) feeding habits in adult period, e.g. “carnivores” vs vegetarians/vegans (9, 18, 19); (e) undergoing antibiotic therapy (20); (f) past bariatric operation (21); (g) pregnancy (22-24) and (h) ageing (25).
IBF has numerous beneficial biological effects, including intestinal peristalsis stimulation, influences the development of intestinal villi and rebuilding of epithelium and has also positive effect on maturation and activity of alimentary tract immunological system (26). Lately there have been numerous reports on the role of IBF in development of different pathologies.
BACTERIAL ORIGINS OF OBESITY
There are the following arguments for the engagement of IBF in obesity development:
1. Germ-free mice (deprived of intestinal microflora) are thinner than mice with IBF even if they are fed in the same way. It partly is a result of the fact that germ-free individuals do not have intestinal villi developed, which may impair intestinal absorption. Another reason is that IBF takes part in digestion of complex polysaccharides (like fiber), which are not digested by the host’s alimentary tract. The products of bacterial fermentation of these substances are short-chain fatty acids (acetic acid, lactic acid, propionic acid, butyric acid), which when absorbed are the additional source of energy. In humans, IBF “delivers” about 80 to 200 kcal per day, which is 4-10% of the daily energy demand (2). The same fatty acids are, additionally, agonists of specific G protein-coupled receptors – GPR41 and GPR43. These receptors are also known as the free fatty acids receptors – FFAR3 and FFAR2. Their activation causes increased intestinal absorption and adjusting fat tissue metabolism into increased fat accumulation (27).
2. Infection of control mice group with IBF from the obese mice (mice ob/ob deprived of the leptin gene) caused faster weight gaining of control mice, apart from the fact that both groups were fed in the same way (2). At the same time it was proved that in IBF of ob/ob mice the percentage of Firmicutes bacteria was lowered and Bacteroidetes bacteria was increased in comparison with control mice (28).
3. In humans the composition of IBF also correlates with obesity. It was proved that in obese people, in comparison with control group, IBF is richer in Firmicutes bacteria and poorer in Bacteroidetes bacteria and that this composition normalizes within a year of weight-loss diet application (18). In MetaHIT research in Denmark including 169 obese patients and 123 lean patients there was a group with a large amount of genes in their IBF (which means a lot of species in the IBF) and a group with little amount of genes (which means little species in IBF). It occurred that less species differentiation of IBF is a risk factor of obesity occurrence, insulin resistance, dyslipidemia and pro-inflammatory phenotype (29).
INVOLVEMENT OF BACTERIAL PRODUCTS OF PHOSPHATIDYLCHOLINE AND L-CARNITINE DISINTEGRATION IN ARTERIOSCLEROSIS MECHANISM
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