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One of the puzzling aspects of our current epidemic of chronic non-communicable diseases is the continued increase in allergic and autoimmune disorders. While many factors may play a role in this phenomenon, recent research strongly implicates changes in interactions between the gut microbiota and the gut-associated immune system.

“… host-microbe interactions during the first three years of life starting in utero (the “first thousand days”) are particularly important for the development of the immune system.”

It has been known for some time, that host-microbe interactions during the first three years of life starting in utero (the “first thousand days”) are particularly important for the development of the immune system. Perturbations of the developing gut microbiota during this critical time (including C-section delivery, formula feedings, antibiotic exposure) can have long-lasting and often irreversible detrimental effects on health, including increasing the risk for allergic and autoimmune disorders. Until very recently, this microbe-mediated immune programming was thought to be initiated at birth when a newborn baby leaves the relatively sterile environment of the uterus and is exposed in the birth canal to the mother’s vaginal/rectal microbiota which begin to colonize the newborn’s gut.

“… it seems increasingly possible that our mothers’ microbiomes may, to some extent, shape our health and well-being long before we are born. One such mechanism is the transfer of maternal antibodies to the fetus.”

As discussed in an excellent review article by Drs. Carolyn Thomson and Kathy McCoy from the University of Calgary in The Scientist the maternal microbiome can exert its influence much earlier—on the developing fetus. Based on the accumulating science, it seems increasingly possible that our mothers’ microbiomes may, to some extent, shape our health and well-being long before we are born. One such mechanism is the transfer of maternal antibodies to the fetus. Antibodies generated by the pregnant mom’s immune system against her own microbiota as well as pathogenic microbes can cross the placenta to protect the fetus from infection. This remote control of the fetal microbiome via both bacteria-produced molecules and maternally derived antibodies appear to drive immune development in utero.

“… mouse studies have shown that perturbing the microbiota of pregnant mice, either with antibiotics or dietary intervention, can lead to a variety of physiological alterations in the offspring with implications not only for diabetes, but for susceptibility to asthma, obesity, and colitis, as well as the progression of autism-like behaviors.”

Less than a decade ago, as researchers began to question the role of the maternal microbiota during pregnancy several research groups performed epidemiological and preclinical studies to examine whether exposure of the fetus to antibiotics taken by the pregnant mother poses a risk to a child’s health. As fetuses don’t have their own microbiota, any microbe-mediated immune system modulation that may happen in the womb must be related to the gut microbes of the pregnant mother, and antibiotic exposure of the mother during pregnancy would disrupt this. As shown in mouse studies, prenatal antibiotic exposure influenced the development of type 1 diabetes, an autoimmune disease in the offspring. Subsequent mouse studies have shown that perturbing the microbiota of pregnant mice, either with antibiotics or dietary intervention, can lead to a variety of physiological alterations with implications not only for diabetes, but for susceptibility to asthma, obesity, and colitis, as well as the progression of autism-like behaviors.

In most circumstances, manipulating the maternal microbiota by chronic stress, antibiotics or diet are vertically passed from mother to offspring at birth, and subsequently alters both the infant’s microbiome and immune development. It has therefore proven challenging to attribute the immune system changes described in most of these studies to the maternal microbiota directly, as opposed to those mediated by the newly seeded microbiota of the neonate. However, recent research is beginning to demonstrate that the maternal microbiota can shape both the immune and nervous system development of the offspring remotely, via different communication channels.

“… the intestinal immune system must quickly learn to differentiate between innocuous and beneficial food components and benign microbes, and harmful molecules and pathogens which require the triggering of a successful defense against them.”

By adulthood, the intestine is home to the body’s largest collection of immune cells, about 70% of the entire immune system. Being located in such close connection to the intestinal contents transporting an enormous number of foreign antigens derived from both the microbiota our diet and ingested chemicals, the intestinal immune system must quickly learn to differentiate between innocuous and beneficial food components and harmful molecules, between benign microbes and pathogens which require the triggering of a successful defense against them. Moreover, even beneficial microbes can quickly become harmful if they come into contact with specific receptors (so called toll like receptors or TLRs) on gut-associated immune cells like dendritic cells, which extend into the intestinal mucus layer, or translocate into the bloodstream through a “leaky gut”. Such translocation of gut microbes from the gut into the bloodstream has been reported under conditions of chronic stress and when consuming a Western diet.

The immune system of a newborn infant is inexperienced. Despite some early reports to the contrary, the fetus is not thought to be colonized with its own microbial communities before birth. Traditionally, researchers thought that maternal antibodies transferred across the placenta were specific to infectious microbes that might infect the baby while its own immune system was still developing. We now know that maternally derived antibodies can also bind commensal bacteria—and that this helps to keep these nonpathogenic bacteria from crossing the epithelial barrier as a newborn’s gut is rapidly colonized by a vast array of unfamiliar microbes.

“Different components of breast milk also play an important role in mediating the maternal influence on the developing infant microbiome…”

According to the American Academy of Pediatrics, babies should be breastfed until they are 1 or older, and the Centers for Disease Control and Prevention states that breast milk is the best source of nutrition in those early months. In addition to providing optimal nutrition for the baby, different components of breast milk play an important role in mediating the maternal influence on the developing infant microbiome, including the Human Milk Oligosaccharides (HMOs) and maternal antibodies which can interact directly with the microbial inhabitants of the infant’s gastrointestinal tract.

The medical and economic realities of new parenthood in America can make that one-year finish line an impossible goal for many mothers. By six months, the majority of new mothers give their babies some formula, for reasons ranging from problems with latching and milk supply to the demands of work outside the home. Aggravating this problem, there is now a nationwide formula shortage, driven by supply chain problems and exacerbated by the closure of a major production plant in February and the recall of select infant formulas.

Both HMOs and antibodies are unique to human breast milk, and not provided by baby formula. While the HMOs, which are influenced both by maternal genes and diet, are large, non-absorbable molecules essential for the initial organization and development of the microbial ecosystem, the antibodies contained in breast milk keep populations of beneficial microbes in check and ensure that they stay in the gut lumen, preventing the inappropriate activation of the gut-associated immune system.

The role of the maternal diet

Another important component of the maternal influence on the infant’s microbiome and immune system are short-chain fatty acids (SCFAs), derived from the fermentation of dietary fiber by the mother’s intestinal microbes. The amounts and types of SCFAs that are produced in the mother’s gut and transferred to her baby depend on the maternal microbiome, which is in turn shaped by her diet. As discussed in detail in The Gut Immune Connection, when pregnant women eat a largely plant-based diet rich in fiber (Microbe Accessible Carbohydrates, or MACs), SCFA-producing microbes thrive, and increased amounts of SCFAs not only have an anti-inflammatory effect on the mother’s gut and body but are transferred to the developing fetus as well. Recent research suggests that SCFAs not only exert their anti-inflammatory effects but influence the maturation of the fetal immune system. Specifically, they stimulate the development of a population of immune cells (regulatory T cells, or Tregs), which produce anti-inflammatory molecules (in particular the cytokine IL-10) crucial for the prevention of immune activation in the gut.

“Considering the extent of inflammatory diseases that can be controlled and suppressed by these anti-inflammatory immune cells simply through maternal dietary changes, these findings are likely to have far-reaching effects on a better understanding of developmental diseases…”

These IL-10 producing cells are crucial for protecting our bodies from attacking our own tissues in the form of autoimmune diseases, as well as from allergies and asthma. They also teach our immune systems to tolerate food and friendly bacteria. These abilities make these cells a key factor in differential immune response to what is good or bad for our bodies. These immune cells are long-lived, and their “offspring” is assumed to be present throughout the life of the host. It is easy to see, how the influence of maternal microbiome, shaped by the mother’s diet can influence the development or maturation of these cells, could have far-reaching implications for the health of the offspring. This crucial effect of maternal diet on the anti-inflammatory ability of the offspring’s microbiome was demonstrated in a study from the Juntendo University in Tokyo which showed that pregnant dams that ate more fiber not only had increased amounts of several SCFAs in their feces, as well as increased butyrate in their blood, but that their pups had increased SCFAs in their blood at day 11 of life as well. Considering the extent of inflammatory diseases that can be controlled and suppressed by these anti-inflammatory immune cells simply through maternal dietary changes, these findings are likely to have far-reaching effects on a better understanding of developmental diseases like autism spectrum disorders. For example, a recent mouse study reported that a high fat diet in pregnant mothers induced a shift in the gut microbiome that negatively impacted social behavior in the offspring.

As pointed out by the authors of this The Scientist article, implications of these new insights into the role of maternal diet, and its influence on the microbiome and immune system are extensive. For one, they could provide evidence for guidance about maintaining a healthy microbiota throughout gestation—for example, by eating a microbiome targeted diet (largely plant-based diet without ultra-processed foods and high amounts of sugar), avoiding unnecessary antibiotic use, and practicing simple stress reduction techniques.

In addition, as the current baby formula crisis has brought to public attention, greater public health efforts should be made to enable mothers to nurse their babies during the first year, and not become fully or partially dependent on alternatives that lack some crucial components necessary for the development of a healthy gut microbiome.