The gut microbiome: what it is, how it develops and what it acts through
The gut holds the largest community of microorganisms in the body, together with their genes and metabolites. It is seeded around birth and matures through infancy into a stable adult composition. Its diversity rises or falls with birth, feeding, diet, medicines and environment, and it interacts with other organs through biochemical axes.
Terms
The microbiome is an ecosystem: the microorganisms (bacteria, viruses, phages, fungi and archaea), their genes and their metabolites in a particular environment. The microbiome is also defined as the collective genomes of all the microorganisms in an environment. The microbiota is the microorganisms living in a particular environment, the community of microorganisms itself. The two terms are used interchangeably, but they name different things.
Alpha diversity is the intraspecies diversity in a particular environment in one individual. Vertical transmission is the direct transfer of bacteria and genes from mother to child.
Size and composition
Almost every animal carries microorganisms such as bacteria in its gut, forming the microbiota, a complex community of different species that influences health and fitness. The human microbiome consists of microbes that flourish in different parts of the body, and human cells live in a symbiotic relationship with this microbial community.
The body carries about 39 trillion microbial cells encoding nearly 20 million microbial genes, against about 30 trillion human cells with a little more than 20,000 human genes. This difference of a factor of 10² to 10³ in gene number has an impact on immunity, behaviour and health. The human digestive system carries more than three million genes from bacteria, viruses, fungi and protozoa, against a human genome of about 23,000 genes. Those genes code for thousands of metabolites that influence the host in many functions, from innate immunity to appetite and energy metabolism.
The gut, which with all its projections spans nearly 7 kilometres, holds the largest number of the body's microorganisms. The gut or intestinal microbiome accounts for 99% of the body's microbial flora, about 1,000 to 4,500 species, making it the densest organ of metabolism on the planet. The gut microbiota include bacteria of the phyla Proteobacteria, Firmicutes, Actinobacteria, Bacteroidetes and Verrucomicrobia; archaea such as Methanobrevibacter smithii and Methanosphaera stadtmanae; fungi of the phyla Basidiomycota and Ascomycota, with genera such as Aspergillus, Candida and Saccharomyces; and viruses and bacteriophages of families such as Myoviridae, Microviridae, Podoviridae, Circoviridae and Siphoviridae.
The Human Microbiome Project
Although studies of the microbiome's effects on health go back more than 50 years, the National Institutes of Health began a dedicated Human Microbiome Project in 2007 to understand the physical and genetic structure of the microbiome. Its first phase studied the composition of microbiomes at sites across the body, such as the skin, buccal mucosa, gut, faeces, vaginal wall, tongue and outer ear cavity. In 2023 a second, integrative project was studying how three conditions (prediabetes, inflammatory bowel disease and pregnancy) affect the dynamic interaction between microbiomes and the body.
Functions
Research has shown that the gut microbiome plays a significant part in immune system maturation, vitamin production, energy production from dietary components, the breakdown of complex sugars from plant-derived products and human milk, protection against pathogenic bacteria, the maturation and development of epithelial cells, and neurotransmitter production that facilitates communication with the brain. Its impact on health also includes cytokine production and iron absorption. Gut bacteria help maintain intestinal homeostasis by regulating biological functions such as immunity, protecting the intestine and regulating metabolism. Among the small molecules the bacteria produce, short-chain fatty acids are very important. The bacteria produce them by fermenting dietary fibre, and they have a positive effect on the gut, in particular on the intestinal mucosa.
Dysbiosis
Dysbiosis is a change in the composition of the gut microbiome, such as in its function and taxonomy, as seen in a disease state. Processed foods, high-fat diets, high-protein diets, low-fibre food, antibiotics, alcohol and diseases cause inflammation and an imbalance in the composition of the gut microbiome, or dysbiosis. Gut dysbiosis causes inflammation and immune reactions.
Development
The development of the gut microbiome is a dynamic process that begins either during gestation or at birth and evolves continuously with growth into adulthood.
Seeding
Two theories explain the first stage of development, seeding.
The sterile womb hypothesis holds that the uterus of a pregnant person is sterile and that microbial colonisation of the fetal gut begins at birth, during labour. When the amniotic sac ruptures in a vaginal birth, the fetus is exposed to and enveloped by the mother's vaginal microbiome on its way through the birth canal. Babies born by elective caesarean section have a gut microbiome that resembles the mother's skin microbiome. Infants born by emergency caesarean have gut microbiota that resemble both the mother's skin and her vaginal microbiomes.
The controversial in utero hypothesis holds that the fetal gut microbiome is seeded during gestation, when the fetus is exposed to the microbiota of the placenta or amniotic fluid. The placenta, the amniotic fluid and meconium, once considered sterile, are now being shown to hold microbial communities. Preterm babies are exposed to amniotic fluid microbiota during gestation through urinary infections (premature rupture of membranes) or through chorioamnionitis, infection within the amniotic sac and the surrounding fetal membrane. Critics argue against the presence of microbiota in these sites and suggest laboratory contamination as a potential source. These microbiota could also seed the neonatal gut by vertical transmission from mother to fetus, for example through breast milk.
Breast milk may play a part in seeding the infant microbiome. A quarter of the infant's gut microbiota is obtained from breast milk, which influences its development over the individual's lifetime and protects against potential allergies. The enteromammary hypothesis suggests that bacteria travel from the mother's gut to the lactating breast and create the breast milk microbiome, but it is based on a small sample size. Human breast milk contains bioactive compounds (secretory immunoglobulin A, growth factors, more than 200 human milk oligosaccharides, cytokines), immunological compounds, nutrients and maternal gut microflora. The bioactive compounds help develop a robust immune system in the infant. Human milk oligosaccharides are elaborate sugar complexes that act as prebiotics and a source of bioactive compounds. Microbiota such as Bifidobacteria digest them in the large intestine, because humans lack the enzymes to metabolise them in the small intestine. They are a major source of brain nourishment and prevent the growth of infectious pathogens. The components of breast milk change dynamically at each developmental stage of the infant.
Bacteria colonise the immature infant gut first, followed by viruses and fungi. In a term infant the gut is colonised at random at first by pioneer microbiota from sites across the mother's body, such as the skin, mouth, gut, vagina and breast milk. In the first week of life the infant gut is aerobic with a neutral pH, and facultative anaerobes, which grow with or without oxygen, act as the pioneers. The seeding facultative anaerobes in term infants include Prevotella melaninogenica, Haemophilus parainfluenzae, members of the Enterobacteriaceae, Alistipes putredinis, staphylococci and streptococci. In preterm infants they include Staphylococcus and Enterococcus, and colonisation by Enterobacteriaceae and Bifidobacterium is delayed. The pioneers then decline in number as obligate anaerobes begin to proliferate, and the pH of the gut changes as the infant grows. After six days of life there is a transition to Bifidobacteria species that use human milk oligosaccharides as a source of carbon.
Weaning
In the second stage, weaning, the infant gut microbiome changes significantly as solid food is introduced. The microbiome is compelled to mature and increase in diversity as the complexity of carbohydrate and starch components increases. Bifidobacterium and other obligate anaerobic species decrease, and the phylum Bacteroidetes and Clostridia species come to predominate. The gut flora is distinctly different in children aged 4 months, 12 months, 3 years and 5 years. As the infant grows through the first year, alpha diversity increases when solid foods are introduced.
The stable adult microbiome
In the third stage the gut microbiome stabilises in children after 5 years of age and appears to resemble an adult's, although information on the gut microbiomes of children and adolescents is limited. The five major phyla in an adult gut are Firmicutes, Proteobacteria, Bacteroidetes, Actinobacteria and Verrucomicrobia, but microbial content differs and is influenced by diet, geographical location and antibiotic use. The bacterial genera of the adult gut do not resemble those of children younger than 3 years. With the progress to adulthood, Bifidobacteria decline and Firmicutes and Bacteroidetes are enriched.
Factors that shape diversity
Normal development of the gut microbiome, with species diversity increasing from birth, is essential to the future health of the individual. Several factors enhance or impede the microbial balance in the gut. The quality of microbial diversity in the gut is crucial and depends on the interplay of different factors.
In infancy
In a term neonate, vaginal birth, good maternal health, breast milk and probiotics enhance the diversity of the gut flora. Antibiotics, hospitalisation and smoking give rise to antimicrobial resistance genes and facilitate the growth of facultative anaerobic pathogenic bacteria. The mother's diet, caesarean birth, formula feeds, bovine-milk-fortified human milk and the environment, such as living with family members, day care, pets, a rural or urban lifestyle or an industrialised setting, influence the maturation of the gut flora in different ways. The gut microbiota of infants born by caesarean section or fed formula are very diverse and closely resemble the mature microbiota of adults. Chemical factors (pH, bile acid, mucus), microbial factors (adhesion capability, metabolic pathways, bacterial enzymes) and bacteriophages also influence gut microbiome diversity.
Preterm infants show delayed development of microbial diversity and a distinctly different species composition from age-matched term infants before 6 months. Microbial colonisation may occur before birth because of complications during gestation. Gestational age plays a major part in the initial colonisation and microbial diversity of the preterm infant's gut. Other factors include genetics, sex, the mode of feeding (enteral, parenteral, breastfeeding), the type of milk (breast milk, formula, donor milk), the pumping and storage of milk, and the environment (hospital, intensive care unit, medical interventions, antibiotics, family members).
In term infants, vaginal birth is associated with bacteria such as Escherichia coli, Lactobacillus, Bifidobacterium species and Bacteroides, and caesarean birth with Klebsiella, Clostridium, Staphylococcus and Enterococcus, with Bifidobacterium and Bacteroidaceae reduced. In preterm infants, caesarean birth is associated with bacteria such as enterococci, Enterobacteriaceae, staphylococci and Klebsiella, with Mycoplasmataceae raised in chorioamnionitis and Bacteroidetes, Bifidobacteria, lactobacilli, Clostridia and Atopobium reduced. In preterm infants, formula is associated with Bifidobacteria and Clostridiales, and antibiotics with Firmicutes and Proteobacteria. Hospital-associated bacteria in preterm infants include Klebsiella pneumoniae, enterococci and Escherichia coli, and butyrate producers include Eubacterium hallii, Anaerostipes caccae and Coprococcus eutactus.
In childhood
The gut microbiomes of children are more susceptible than those of adults to changes in diet, environment and antibiotics. Babies born by caesarean section appear to be predisposed to obesity and coeliac disease. Antibiotic treatment reduces microbiota diversity, leading to antibiotic-related obesity, multidrug resistance and asthma. Gut health could be restored by treatment with beneficial bacteria. Despite breastfeeding, malnutrition reduces alpha diversity, with an increased prevalence of Proteobacteria, and slows growth in children.
Diet and place
A Western diet of low-fibre, high-fat processed foods increases Bacteroides and reduces overall alpha diversity. Numerous health conditions, such as obesity, inflammatory bowel disease and cancer, appear to be associated with reduced alpha diversity. By contrast, high-fibre diets increase microbial diversity and overall health in rural populations in Asia and Africa. Geographical location appears to influence microbial diversity: people in industrialised urban areas have lower gut microbial diversity than people in rural areas.
Eating habits can affect the composition of the microbiota and so the amount and type of metabolites it releases. Sugar, excessive protein, saturated fatty acids, drugs such as proton pump inhibitors and antibiotics, and many of the substances in processed foods, such as additives, preservatives and sweeteners, have negative effects on the microbiota, resulting in less production of beneficial substances and an increased risk of disease and inflammation. A good and varied intake of fibre, or probiotics, leads to better health. Such an intake is more than taking a supplement, and whole and varied foods are better. Diet and lifestyle are important factors in achieving overall health, preventing gut disorders and reducing the predisposition to more serious diseases. Eating more fibre-rich foods, vegetables and fruits, and avoiding antibiotics when they are not needed, can help keep a healthy gut.
Axes to other organs
The gut microbiome is part of an intricate metabolic and signalling network in the body, and it communicates through biochemical pathways or axes with the skin, brain, lungs, kidneys, breast and liver. It does not act in isolation: microbiota or their metabolites travel to other sites of the body and interact with the microbiomes there through bidirectional or multidirectional pathways. This network explains the gut microbiome's influence on immunity, health and even emotions. The gut-organ axes include the gut-liver, gut-lung, gut-brain, gut-skin, gut-liver-kidney, gut-brain-liver, gut-brain-skin and gut-liver-heart axes.
Gut-skin axis
The biochemical interactions between the skin and gut microbiomes are bidirectional. A dysbiotic gut microbiome may induce changes in the skin microbiome through the release of proinflammatory cytokines. This lets gut bacteria or their metabolic byproducts and toxins enter the systemic circulation. The gut bacteria reach the skin and affect the integrity of the skin barrier. The resulting inflammation has been linked to chronic skin disorders such as psoriasis, acne and alopecia.
Gut-brain axis
According to preclinical research, the gut, the brain and the gut microbiome interact bidirectionally. The gut-brain axis comprises the autonomic nervous system, the gut microbiota with their metabolic products, the enteric neuroendocrine system, the hypothalamic-pituitary-adrenal system, the enteric nervous system and the gut-associated immune system. Research has shown that bacteria, their metabolites and immune cells have access to the brain through the blood-brain barrier. Gut bacteria of the genera Bifidobacteria, streptococci, Escherichia, lactobacilli and enterococci regulate the production of neurotransmitters such as GABA, serotonin and acetylcholine, which pass through the blood-brain barrier and modulate brain signalling directly or indirectly. Interactions between the nervous system and the immune system are also affected. People with neurological, psychiatric and degenerative conditions such as depression and anxiety also show perturbations in the diversity of their gut microbiome.
The gut and the brain communicate in two ways: the nerves around the intestine, the enteric system, receive and send signals to and from the brain, and the microbiota themselves send messages to the brain. The microbiota release small molecules called neuropeptides, as well as hormones. These are absorbed in the intestine and reach the blood, and through the circulation they reach the brain, where they bind to receptors and set off physiological or behavioural changes. Because the gut communicates with the brain through the gut-brain axis, signals from the microbiota can affect behaviour. More studies show that tracking changes in mood, sleep or eating habits can let people modify their lifestyle to improve their gut and overall health.
What happens in the gut microbiota is deeply connected with changes in sleep patterns. The bacteria in the intestines can influence sleep by communicating with the brain through the gut-brain axis. In studies of mice depleted of microbiota, impaired sleep was associated with a drastic reduction in serotonin, an important regulator of sleep. So an imbalance of the microbiota can affect sleep by altering the intestinal balance of neurotransmitters.
Gut-brain-skin axis
The gut-brain-skin axis is gaining relevance in relation to the consistent link between skin conditions such as psoriasis and acne and mental health conditions such as depression. The central nervous system is regulated by neurotransmitters transmitted from the gut microbiota through the vagus nerve. Neurotransmitters facilitate the interactions between the nervous system and immune responses to skin inflammation. Mental health conditions such as depression and skin conditions such as psoriasis generate cytokines such as interleukin 6 from the brain and the skin, and these cytokines cause inflammation. At the same time, central nervous system conditions such as depression or anxiety appear to cause gut dysbiosis and increase the permeability of the gut epithelial cells (a leaky gut). Gut microbiota and their metabolites then enter the bloodstream and trigger inflammation in the skin and the brain.