Human microbiota: how bacteria affect body weight

All the bacteria that inhabit the human body – good and bad – are called the microbiota. Up to 100 trillion microbes live in the intestine alone, which are in a symbiotic, mutually beneficial relationship with their host. Thanks to worldwide research (and the Human Microbiome Project ), we now know that their collective genome is at least 100-150 times larger than ours ( 1, 2, 8 ). 

The link between gut microflora and health has been known for over a century ( 3 ), but scientists have long been unable to isolate and describe the entire population of gut bacteria. Only recently have direct microbiome sequencing methods been developed, and we have learned that bacteria can influence various processes in the body, including energy consumption and expenditure ( 4 ).

The gut microflora can vary greatly in size and composition both between individuals and within an individual over a lifetime: age, nutrition, medications, weight changes, and general metabolic health can all influence this. Different gut microflora subpopulations produce signaling molecules influencing energy balance, metabolism, and body weight ( 5, 6 ). There is already a wealth of rodent research showing that the gut microbiota is a sensitive enteroendocrine ‘organ’ that may be involved in developing obesity and comorbidities like diabetes and could someday be used therapeutically.

The intestinal microflora is very diverse, not all yet studied, but the main bacteria, expressed as a percentage of the total population, are:

• Bacteroidetes (20–25%)
• Firmicutes (60–65%)
• Proteobacteria (5–10%)
• Actinobacteria (3%)

Together, these types comprise over 97% of the gut microbial population.

Previously, it was believed that the intrauterine environment is sterile, and colonization of the newborn with bacteria begins only at the time of his birth. But today, it is known that the creation of a microbial population of the intestine in a newborn is a complex process of interaction between the genotypes of the mother and fetus, its intrauterine life, the mother’s nutrition, the presence of allergies, the use of antibiotics, the type of birth (natural or via cesarean section), the nutrition of the mother and child. After childbirth ( 12 ).

For example, antibiotic use by a woman during the second and third trimesters of pregnancy is associated with reduced bacterial diversity in neonatal stools, reduced numbers of lactobacilli and bifidobacteria in the gut, and, according to observational studies, even an increased risk of future obesity ( 13, 14, 15 ).

Children born naturally are colonized by the mother’s vaginal and intestinal bacteria, while children born by cesarean section are initially colonized by bacteria from the mother’s skin ( 16, 14 ).

Preterm infants initially develop a less diverse microbiota, with Proteobacteria and Firmicutes predominating compared to Bacteroidetes ( 17, 18 ). And regardless of the time of birth, cesarean-born babies have a less diverse microflora that contains absolutely and relatively smaller populations of Bacteroides and Bifidobacteria ( 19 ) that persist for months to years ( 20 ). Obese adults have a similar microbial pattern ( 21 ), so scientists suggest that the microflora of children born via cesarean section may be responsible for an increased risk of obesity by ±40% ( 14, 22, 23). But we must remember that these results from observational studies show the relationship between two variables without cause and effect.

Although genetics can influence the human microbiota, especially in the first years of life (twin studies show this), then it plays a very small role compared to how the environment influences the microflora – nutrition, climate, geography, and other factors ( 22, 23, 24 ). For example, some studies use multivariate analysis to compare industrial societies such as the United States or Europe with traditional societies such as the Hadza hunter-gatherers of Tanzania ( 25 ) or the aborigines of Papua New Guinea ( 26 ). They show that industrialization is associated with less diversity of fecal bacteria within individuals and more diversity between individuals.

Energy homeostasis

Under normal conditions, energy intake from food and its expenditure during the day adjust to each other – this allows you to maintain a relatively constant level of energy stored in fat ( 27, 28 ). Undernourishment/starvation and maintaining a reduced body weight force the body to turn on the mechanisms of adaptation and economy. First, energy expenditure during the day is reduced: the parasympathetic nervous system becomes more active, which is manifested by a slowing of the heart rate, a decrease in blood pressure, and resting energy expenditure due to a decrease in the production of thyroid hormones ( 29, 30 ).

Secondly, a person feels hunger more acutely, gets more pleasure from food, does not feel full longer, and evaluates the amount of food eaten worse. All this pushes us to eat more to restore energy reserves – both short-term and long-term in the form of fat. Studies show that these signals do not decline over time, even in people who once lost weight and are trying to maintain the new weight. As a result, many dial it back ( 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 ).

All of these adaptations are controlled by the hormone leptin, produced by fat cells and acts directly on receptors in the brain through the autonomic nervous and neuroendocrine systems.

RESEARCH ON RODENTS

We have a lot of research into the effect of gut microflora on energy balance, but almost all controlled studies have been done on rodents.

The two most common gut bacteria types are Bacteroidetes and Firmicutes. In genetically obese mice, the relative proportion of Bacteroidetes is reduced, and Firmicutes is increased ( 7 ), in contrast to slender mice. This shows that obesity itself changes the composition of bacteria. Weight loss also affects the diversity and ratio of bacteria in the gut.

Diet affects both the composition and diversity of bacteria in the gut. Thus, a diet high in polysaccharides leads to a greater diversity of bacteria ( 8 ). And a high-fat diet in normal mice, as well as those genetically engineered to be resistant to obesity, results in a significant reduction in Bacteroidetes, regardless of the rate of weight gain ( 9 ).

Changes in microflora also affect energy homeostasis in rodents. For example, laboratory mice deprived of birth of bacteria in the intestines absorb food worse and get energy from it worse. The colonization of their intestines with bacteria from “normal” mice (combined with a normal mouse diet without overfeeding or underfeeding) leads to body weight gain to the same level as that of donor mice ( 10 ).

And mice that received microflora from obese donors containing higher absolute and relative amounts of Firmicutes gained twice as much fat as mice that received bacteria from “normal” donors. Interestingly, both mice ate about the same, and there was no significant difference in energy consumption between them, so the scientists suggest that the reason is an increase in the efficiency of extracting energy from food ( 11 ).

Other studies show that the composition of the diet also plays a role. Sterile mice that received bacteria from obese mice gained more weight than those that received bacteria from obesity-resistant donors, but this effect was only when fed a high-fat diet.

Before transferring the research results to humans, it is important to understand that the systems of energy homeostasis in humans and mice are fundamentally different at some points.

First, the typical diet is different: mice have more carbohydrates and less fat. Secondly, night and daily biorhythms associated with energy consumption and its consumption differ. Third, the most significant differences are in the amount of brown and white (normal) body fat: mice have much more brown fat, accounting for >50% of their metabolism, while humans have less than 5% ( 41, 42 ). In mice, the amount of brown fat and its metabolism is influenced by dietary composition and gut bacteria ( 43, 44 ), which is why microflora influences mouse energy homeostasis much more. Before transferring the results of research on bacteria directly to humans, this must be kept in mind.

What about people?

Today we know that the composition of the intestinal microflora and its diversity respond to:

• body weight and body fat;
• a history of weight changes (the person was obese and lost weight or was never obese);
• diet composition and energy intake—calorie deficit or weight maintenance ( 45, 46, 47, 48, 49 ).

But it is not yet clear which influences the most ( 50 ). Future studies of changes in the intestinal microflora after liposuction will answer the question more precisely because, with this operation, a person loses weight without dieting and without a negative energy balance.

How does the gut microflora affect weight?

Scientists propose several mechanisms by which bacteria can potentially influence body weight.

1. ASSIMILATION OF ENERGY FROM FOOD (ENERGY HARVEST)

Intestinal colonization of sterile mice with common murine bacteria leads to weight gain, even though these mice begin to eat less and move more ( 51, 52, 53 ). It is assumed that the point is to increase energy assimilation efficiency from food.

It is not yet clear exactly what allows sterile mice to maintain a lower weight (and lower energy stores) than the body will “protect” after colonizing the intestines with bacteria and gaining weight. Interestingly, colonization of obese mice with bacteria from lean donors not only leads to weight loss but also does not appear to include an adaptation of the body to the loss of energy reserves.

With normal weight loss, as was written above, this is exactly what happens, but when fat mice are colonized with bacteria from thin ones and weight loss as a result of this, it does not. Once we understand the mechanisms precisely, this could be used to manipulate nutrition, drugs, and other interventions that will affect the microbiome and reduce the absorption of energy from food in humans ( 54, 55 ).

So far, it is known that more efficient energy extraction from food is associated with an increase in Firmicutes and a decrease in Bacteroidetes ( 53 ). One study examined the effects of a calorie deficit diet (2400 kcal/day) and overeating (3400 kcal/day) on the microflora of 12 lean and nine obese people.

In both overeating and obesity, there were more Firmicutes and fewer Bacteroidetes in the gut. With malnutrition, as well as in slender people, the opposite is true ( 50 ). The same study showed that a 20% increase in Firmicutes and a corresponding decrease in Bacteroidetes was associated with an increase in energy absorption from food of ~150 kcal/day or ~5% of calories consumed.

The mechanisms by which the microflora can influence energy absorption from food remain hypothetical. It is known from rodent studies that this is influenced by the duration of food exposure to the intestinal mucosa: a decrease or increase in the time of passage of food through the intestines led, respectively, to an increase in the abundance of Bacteroidaceae and Porphyromonadaceae ( 56 ).

ABOUT BACTERIAL TRANSPLANT

Given that fat mice can be made lean and lean mice fat by changing their microbiota, it has been hypothesized that transplanting slender human bacteria into obese humans could aid in weight loss, as occurs in mice. Previous studies of human transplants have shown an improvement in insulin resistance in the liver in patients with metabolic syndrome (this disease is a frequent companion of obesity). But recently, the first controlled study of obese people who do not have obesity-related diseases has appeared. It was presented at Digestive Disease Week in 2019. 

“In our clinic, we see patients who do not have any other medical problems and cannot lose weight. This is a very important population that we wanted to focus on and try to help understand the causes,” said Jessica Allegretti, MD, lead author of the study and director of the fecal microbiota transplant program.

This study included 22 obese patients without diabetes, liver problems, or other comorbidities associated with obesity. During the 12-week study, half took capsules containing the feces of a slim donor, and the other half received a placebo (dummy) in the form of identical capsules. In addition to weight loss, the researchers looked for changes in glucagon-like peptide 1 (GLP1), a hormone produced in the gut that is associated with satiety and, through that, with weight gain or loss.

At the end of the study, there was no difference in GLP1 hormone and weight loss in both groups. But the scientists found other changes in the microbiota of the participants who received the feces in the capsules. Among them is a decrease in specific bile acid and bacterial changes in stool samples that have become more similar to slender donors.

And although, formally, a study on transplanting the microflora of slender people did not show any significant results, scientists are not discouraged. “Our study takes an encouraging first step in understanding the role of the gut microflora in obesity in metabolically healthy people. We hope this will help more targeted therapy in the future.”

Next, the scientists plan to make more sensitive measurements of GLP1, conduct additional studies with different doses of fecal material, and look for other mechanisms to better understand the microbiota’s role in obesity. “The bile acid data is intriguing and shows that there may be several different pathways because obesity is a complex, multifactorial disease,” says Dr. Allegretti.

2. IMPROVED LEPTIN SENSITIVITY

Leptin is an important hormone that controls body weight and long-term energy balance. Fat cells produce it and tell the brain how much energy is stored in the body. When there is a lot of leptin, the brain understands that the body has enough fat (energy). As a result, there is no severe hunger, and the metabolic rate is at a good level ( 5 ). When leptin is low, fat reserves (energy) are low, which means starvation and possible death. As a result, metabolism decreases, and hunger increases so that energy reserves are increased. Thus, the main role of leptin is the long-term management of energy balance ( 6 ).

Leptin-deficient rodents were given probiotics to decrease Firmicutes and increase Bacteroidetes, resulting in increased brain sensitivity to leptin ( 57 ). This suggests that the gut microflora may influence leptin signaling to the hypothalamus. At the same time, the situation may be reversed: signaling molecules produced by bacteria can suppress the pathways by which the brain responds to leptin. Leptin deficiency or poor sensitivity of brain receptors leads to weight gain because a person begins to feel constant hunger, is poorly satiated, and becomes less physically active.

3. REDUCING SYSTEMIC INFLAMMATION

Increased circulating inflammatory cytokines have been proposed as a mechanism by which a high-fat diet leads to obesity ( 58,59 ). This may be due to increased lipopolysaccharides’ expression in the colon and ileum, which can also be secreted by intestinal bacteria ( NF-kB and TNFa ) ( 60, 61 ).

Scientists also suggest that the production of endotoxins by intestinal bacteria and cells of the ileum and colon leads to metabolic endotoxemia, which acts on the hypothalamus, causes overeating, and increases intestinal permeability to nutrients ( 62, 63 ). The situation has been found to improve with antibiotic treatment.

4. PRODUCTION OF SHORT CHAIN FATTY ACIDS

Dietary fiber from vegetables, fruits, grains, and legumes are prebiotics—food for beneficial bacteria to keep them growing and active ( 64 ). For example, small amounts of inulin-type fructooligosaccharides administered to humans stimulate the growth of Bifidobacterium, Lactobacillus, Roseburia, and Faecalibacterium, which are particularly beneficial to health ( 65 ).

Bacteria metabolize (ferment) the fibers supplied with carbohydrates into short-chain fatty acids (SCFA, short chain fatty acids) – acetate, butyrate, and propionate. They serve as an energy source for the colonic epithelium (butyrate), hepatocytes (propionate), and other peripheral tissues ( 67 ) and may influence energy balance. For example, with the participation of SCFA, the release of inflammatory cytokines is reduced ( 68 ), which may indirectly increase the sensitivity of the hypothalamus to leptin ( 69, 70 ).

Different SFCAs affect weight differently. For example, butyrate improves satiety, associated with increased levels of “satiation hormones” — glucagon-like peptide one and peptide YY, which are produced in the intestine and act on the satiety center in the hypothalamus and are also involved in glucose homeostasis ( 66 ). Propionate also affects glucose metabolism, and in mice, it reduces food intake and increases locomotor activity ( 72 ). Administration of acetate increases the release of leptin from fat cells and has an anorexigenic (appetite-reducing) effect, which can be seen on a high carbohydrate diet.

In addition, SCFAs can cross the blood-brain barrier and enter the brain by interacting directly with the satiety center in the hypothalamus. Scientists have found that they increase the synthesis and release of glutamate, gamma-aminobutyric acid, and pro-opiomelanocortin and reduce the production of appetite-enhancing peptides in the hypothalamus ( 71 ).

Conclusions

Rodent studies show that gut bacteria affect energy intake, absorption from food, and energy expenditure. It is speculated that something similar could be in humans and that manipulating the microflora could be a potential therapeutic intervention for treating obesity. But data is scarce so far, and further human studies are needed with the manipulation of prebiotics (fiber), probiotics (bacteria themselves), and dietary composition. It is still too soon to suggest “microbial therapy” for overweight people.

We also need to study changes in microflora through direct transplantation, nutrition, and taking pro- or prebiotics in people with different somatotypes (obese, thinner, or never overweight). This will help to find specific behavioral, microbial, and metabolic phenotypes that can predict people’s response to different approaches to weight loss – behavioral, drug, pro-, and prebiotic or surgical.

To complicate matters further, the gut microflora influences other systems involved in obesity, including glucose and lipid homeostasis, systemic inflammation, and others ( 74 ), so again, more human studies are needed.

So far, all hypotheses about the effect of bacteria on human weight are based on:

• Animal research. But these results are for scientists; they serve as a starting point for building various hypotheses and future studies in humans, and not for a plan of action and not for high-profile headlines on the Internet.
• Indirect measurements: Scientists change the intestinal flora and study its influence on individual molecules that affect energy production and consumption without directly measuring all variables in a single system.