Gut flora: get more energy from less food

2024 Author: Seth Attwood | [email protected]. Last modified: 2023-12-16 15:55

Examination of a woman with complaints of persistent diarrhea and acute abdominal pain revealed acute inflammation of the colon caused by Clostridia. Given the resistance of the bacteria to antibiotics, the patient was offered an experimental, but effective method of therapy - transplantation of donor microbiota (intestinal microflora).

After the introduction into the patient's intestines of 600 ml of a suspension of donor feces, relapses of the disease were no longer observed - the donor's microbiota successfully displaced the pathogen and occupied its niches. However, a year later, the woman complained to the doctor about the rapid weight gain, while all her life before transplantation she had a normal and stable body weight. From the moment of the procedure, the increase was 15 kg, and the total body weight reached 77 kg with a height of 155 cm. Despite fitness and diet, the patient's weight soon exceeded 80 kg. The doctor noted that a generally healthy donor is also overweight and allowed the possibility of "contamination" of obesity through the microbiota. At first glance, such a bold assumption has a solid evidence base. In this article, I will talk about the effect of microbiota on digestion, and why its species diversity decreases, and uniformity increases the risk of obesity.

glagolas.

Introduction

The probability of inheriting obesity reaches 80%, but individual differences in the nuclear genome account for less than 2% of the variability in body weight in the population. In addition, the nuclear genome is passed to the child almost equally from each parent, but children inherit obesity with a significantly higher frequency from their mothers. This phenomenon is often explained by the influence on the metabolism of mitochondria, which have their own DNA and which are absent in the sperm head; therefore, the mitochondrial genome is inherited by the embryo only from the mother's egg. However, the results of a study of the mitochondrial genome explain even fewer cases of inheritance of obesity. Thus, if the inheritance of this disease is only partially mediated by the nuclear and mitochondrial genomes, then maybe obesity is transmitted to children mainly through the third human genome - the microbiome (a set of genes of the microbiota), which is also inherited from the mother?

Microbiome inheritance and variability

Intrauterine development is accompanied by absolute sterility of the fetus, which for the first time receives microbiota, overcoming the birth canal during natural childbirth. Therefore, naturally born babies have a more diverse microbiota than those extracted by cesarean section. Also, studies have shown that children born by caesarean have a greater risk of obesity. Nevertheless, the composition of the microbiota in these children is gradually normalizing under the condition of breastfeeding, which ensures the dominance of bifidobacteria and lactobacilli, which suppress the populations of opportunistic bacterioids and clostridia. Natural birth and breastfeeding form the backbone of the microbiota, which usually lasts for life. Further enrichment of the microbiota with other types of bacteria depends on the lifestyle.

So, for example, visiting kindergarten is a significant and independent factor in increasing the species diversity of the microbiota. On the other hand, the widespread use of antibiotics and antiseptics, as well as strict sanitary and hygiene standards, reduce the exchange rate of microbiota between people and its diversity (read more about the effect of antibiotics on microbiota and bad breath here). Thus, we can talk about the heritability and variability of the microbiome.

Microbiota structure

With age, the number of bacterial cells in the intestine gradually reaches 100 trillion, which exceeds the number of the body's own cells in an adult by 10 times. At the same time, due to the small size of bacteria, the entire microbiota weighs up to 2 kg and fits in the large intestine.

About 60% of the contents of the rectum are microorganisms, the colonies of which grow on the fibers of plant food (cellulose), using them as food and a skeleton, thereby forming a lumpy consistency of feces. Despite the significant number of bacteria, their interaction with the human body has long been considered by scientists strictly within the framework of commensalism, in which the microorganism benefits from the relationship, and the macroorganism receives neither benefit nor harm. However, with the development of genotyping methods, the concept of microbiota has changed significantly.

It was found that the species diversity of microbiota reaches 300-700 species of microorganisms, and their total genome consists of 10 million genes, which is 300 times greater than the human genome. Such a summation of the genes of the microbiome and a comparison of their number with that in humans is not just a catchword here. Many bacterial genes functionally complement the human nuclear genome, and the interspecies interaction of microorganisms is so close that some species literally cannot live without each other. Recent discoveries in this direction made it possible to talk about the mutually beneficial relationship between man and the microbiota, and the totality of its genes is called the microbiome or the third human genome. To illustrate, I will give a specific example.

Microbiota physiology

With plant foods, we consume fructose polymers (fructans), which we do not have our own enzymes to break down into simple sugars. Untreated fructans are not absorbed, and their accumulation in the intestines causes severe disorders, and in the oral cavity they are used by carious bacteria to attach to tooth enamel. We are helped by bifidobacteria and lactobacilli, which have enzyme genes for splitting fructans into lactate and acetate. These metabolites create more acidic conditions that reduce the proliferation of acid-sensitive and diarrhea-causing opportunistic bacteria. In addition, lactate and acetate use other types of friendly microflora as an energy source, which produce butyrate - the main source of energy for intestinal epithelial cells and an inhibitor of the penetration of intracellular pathogens into them, and this compound also reduces the risk of developing ulcerative colitis and colon cancer. So, just a few types of bacteria synthesize a healing substance from food components dangerous for the body, and, protecting their niche from competitors, as a bonus to a person, suppress the growth of pathogens in his intestines! Now imagine how dozens and hundreds of species of microorganisms are combined into longer and more branched metabolic chains that produce essential amino acids, vitamins and other metabolites, thereby modulating digestion, immunity and even our behavior, including food.

Microbiota and obesity

The significant effect of microbiota on obesity was first demonstrated in completely devoid of microorganisms and raised under sterile conditions. Typically, sterile mice typically have 42% less adipose tissue than comparable mice with microflora. At the same time, thinner sterile mice consume 29% more food than their more complete counterparts with microflora. Researchers transferred microflora from normal to sterile mice and observed a 57% increase in adipose tissue within two weeks, despite a 27% decrease in food intake!

The authors concluded that microflora helps extract more energy from less food. At the same time, the energy efficiency of digestion with microflora increases so much that the resulting excess of calories is stored in adipose tissue.

The results obtained in this study are due to the low variety of glycosidases independently synthesized by the mammalian body - enzymes for cleaving bonds in complex carbohydrate molecules such as vegetable fiber. For comparison, if in our genome there are only 20 genes for the synthesis of glycosidases, then the bacterioid species alone synthesizes 261 types of glycosidases, and the entire microbiome contains 250,000 genes for the synthesis of these enzymes. Thus, in the absence of microbiota, energy-rich fiber leaves the body with feces, not meeting the calorie needs, so sterile mice eat more and weigh less than their counterparts with normal microflora. The results of these studies unwittingly give rise to the idea of a method for treating obesity by the total destruction of the microbiota with antibiotics. However, the co-evolution of humans and microbiota has gone so far that the implementation of this idea is impossible, and from a clinical point of view, it is very dangerous.

First, unlike mice, we cannot afford to live in sterile conditions. The environment contains many pathogenic microorganisms that will be happy to occupy niches free from natural microflora. For example, a woman whose clinical case was given at the beginning of the article got an infection with Clostridia just after being treated for bacterial vaginosis with high doses of antibiotics. Secondly, I already mentioned that without microbiota, we are not able to break down fructans on our own, the accumulation of which is fraught with severe digestive disorders. And finally, thirdly, the use of antibiotics in practice shows the opposite effect - obesity is aggravated, and a more diverse and rich in composition microbiota protects against obesity.

Antibiotics and obesity

Since the middle of the last century, antibiotics have been widely used in agriculture to accelerate the weight gain of livestock. For this purpose, the preparations are added to the feed on an ongoing basis, as a result of which 70% of the antibiotics produced is spent on animal husbandry.

The positive effect of antibiotics on body weight has long been attributed to the prevention of infections, because a healthy animal gains weight faster. But later it was proved that this dependence is mediated by changes in the composition of the microbiota. A similar effect of antibiotics on human body weight was considered unlikely, since antibiotic therapy is used for a short time and sporadically. Meanwhile, 10 years ago in studies it was found that even a single course of antibiotics leads to a decrease in the diversity of the human microbiota within 4 years. A 2017 meta-analysis of studies on nearly 500,000 people found that antibiotic use in infancy significantly increased the risk of obesity later in life, with antibiotic dose positively correlating with obesity. Thus, the expected decrease in body weight as a result of suppression of the microbiota does not occur, but in the future, on the contrary, the development of obesity is observed. Presumably, antibiotics, selectively destroying representatives of normal microflora sensitive to them, form a kind of "obesity microbiota".

The concept of the continuous metabolic chain and the "obesity microbiota"

A complete microbiota is a continuous metabolic chain of reactions that breaks down energy-rich fiber into energy-poor compounds. In this case, each intermediate metabolite still containing energy is assimilated by the next bacterium in the metabolic chain, capable of synthesizing enzymes for its breakdown, absorbing its portion of energy. The final metabolites of the functioning of the continuous metabolic chain are short-chain fatty acids, which are mainly catabolized by intestinal cells and are not sublimated in adipose tissue, and some of them even inhibit lipogenesis and suppress appetite. Thus, a full-fledged microbiota almost completely utilizes the energy of fiber and protects the host from obesity, even if he abuses fast carbohydrates.

Unlike normal microflora, the "obesity microbiota" is monotonous due to the missing species, genera or entire families of bacteria, therefore it is not able to form a continuous metabolic chain. Since different types of fiber are broken down by many representatives of the microbiota, the absence of some of them does not block the beginning of the metabolic chain and dietary fiber is safely broken down to intermediate metabolites. In turn, the absence of bacterial species that specifically break down intermediate metabolites leads to the accumulation of the latter in the intestinal lumen. Unlike fiber, intermediate metabolites are able to be absorbed by the body, including increasing the reserves of adipose tissue. Thus, the "obesity microbiota" contains a kind of gaps through which energy "flows" into the human body.

The alleged "obesity microbiota" has been supported by experiments on the transplantation of faeces from people of different physiques to sterile mice. To exclude other factors, the microbiota for transplantation was recruited from 8 twins, whose pairs differed in the presence and absence of obesity, and mice, which received microbiota from people with different physiques, lived separately. The microbiota derived from obese twins had a sparse species composition compared to the more diverse microbiota of normal-bodied twins.

As a result of the experiment, mice that received the "obesity microbiota" showed a significant gain in body fat already on the 8th day after transplantation. At the same time, the mass of fat in mice that received microbiota from twins with normal body weight remained without significant changes throughout the experiment.

In addition, the authors of this study decided to test the contagiousness of obesity. For this, the mice obtained as a result of transplantation of different microbiota were placed in a common cage after 5 days. The control of body weight and body composition on the 10th day of cohabitation showed that mice that received the "obesity microbiota" gained less fat than similar mice in the first part of the experiment (living in isolation), and practically did not differ from cohabiting mice that received microbiota from twins with a normal physique. Microbiome analysis showed an increase in microbiota diversity in mice that initially received a uniform "obesity microbiota." Importantly, skinny mice that initially received a diverse microbiota did not contract obesity from their cohabitants.

Analysis of metabolites in the gut showed that after cohabitation in mice that initially received the "obesity microbiota", there was a decrease in disaccharides and an increase in short-chain fatty acids. Thus, it was found that a diverse microbiota protects against the development of obesity, and the transplantation or natural transfer of such microbiota to obese mice leads to a normalization of body weight.

Conclusion

It should be noted that mice are coprophages, which greatly facilitates the natural exchange of microbiota between cohabitants. However, the results of studies on the microbiota and epidemiology of obesity in humans can also be explained by the exchange of microflora through social interactions. Above, I talked about how going to kindergarten increases the diversity of the microbiota, but the exchange of microflora can also occur through other social connections and potentially affect the risk of obesity. For example, an analysis of the medical records of 1,519 families of American servicemen made it possible to establish that the body mass index of family members after being assigned to a new duty station within 24 months changed in accordance with the indicators of the population of the area. The authors of this and 45 other similar studies suggest that differences in our physique from that of the immediate environment can increase psychological discomfort, and this, in turn, affects eating behavior and physical activity. However, attempts to prove this causal relationship have so far been unsuccessful. Meanwhile, the exchange of microbiota through the environment and direct contacts can explain this phenomenon.

In this context, my life experience can also be interesting. I myself am still drish and the saying "not for a horse feed" is about me! And since I met my wife, she began to lose weight from year to year. True, she never had obesity, but from the beginning of our relationship she lost weight noticeably. Even as a student, she joked that I infected her with my worms, but as soon as I got a job in the laboratory, I checked everything and found nothing of the kind. Then, for the first time, I suggested that the matter might be in the peculiarities of my microbiota, which my wife gradually adopted. Unfortunately, it is impossible to study these features in our laboratory, so I sent a sample of my "inner world" to Atlas for analysis. I will write about the results of the analysis in the next article, in which I will talk in detail about the methods of correcting the microbiota in order to reduce body weight (upd: a story about the results).