What Impact Do Changes to a Newborn's Microbiota Have?

Marseille — There's a lot at stake in the first few months of life, and our gut microbiota are no exception. A newborn and infant's microbiota are especially vulnerable to environmental threats. A stable ecosystem does not develop until the age of 2 or 3 years. 

In toddlers, pathogenesis in the microbiota is linked to the microbiota's immaturity and to dysbiosis (or imbalance of the microbiota), explained Aurélie Morand, MD, PhD, infectious diseases pediatrician at the Timone Hospital in Marseille, France (part of Marseille Public Hospitals), at a conference held by the French Pediatric Society. 

This dysbiosis, depending on the number and nature of environmental threats, will either be rapidly corrected or become long-lasting and lead to short- or long-term disease. 

"The dysbiosis of the microbiota plays a real role in short-term pathogenesis, such as in acute necrotizing enterocolitis in newborns and premature babies, in diarrhea occurring after a bout of gastroenteritis or alongside antibiotic use, in multidrug-resistant bacteria colonization, in susceptibility to infection (B Streptococcus, etc.), in colitis caused by C. difficile, and so forth," said Morand. 

"On a long-term basis, it is difficult to figure out the role of the microbiota in the onset of dysbiosis after antibiotic use, for example, and that of a subsequent pathology, from likely intertwined roles, as in inflammatory bowel disease (IBD), celiac disease, insulin resistance, obesity, atopic disorders, autoimmune conditions, and neuropsychiatric disorders, including autism and Parkinson's disease," she added. 

Increased Infection Risk

This finding is common to studies published on the topic: Microbiota immaturity is associated with an increased risk for infection in newborns. 

An example of this phenomenon is group B streptococcal meningitis in newborns. This disease is encouraged by gut colonization, immature intestinal mucosa, and microbiota that are unable to compete with infectious agents they encounter, stimulate junction proteins in the epithelial barrier, or even sufficiently activate the immune system. These factors make newborns especially susceptible to bacterial meningitis. 

Due to these gaps in their defenses and protective barriers, bacteria cross the epithelial barrier, pass into the bloodstream, and cross the blood-brain barrier. 

Another textbook case is infant botulism, which is where the advice not to give honey to children under the age of 1 year comes in. The immaturity of an infant's gut microbiota allows colonization of the digestive tract with Clostridium botulinum after spores from the bacteria contained in honey, as well as from dust from our surroundings, are ingested. 

The germ then secretes toxins inside the digestive tract, which are spread via hematogenesis, potentially causing infant botulism.

Dysbiosis and Pathologies

Studies show links between dysbiosis and certain disease states. The latter, whether short- or long-term, are more prevalent in the case of dysbiosis. 

Childhood bronchiolitis is one example. The difference in bacterial growth in the respiratory tract is said to affect the severity of bronchiolitis, according to a study of 167 children, mostly under 6 months of age, requiring mechanical ventilation (the infectious agent was RSV in 78% of cases). 

"After analysis of their tracheal or bronchoalveolar aspirate, a not insignificant number of children were found to have a bacterial co-infection," said Morand. "The greater the colonization — not necessarily referring to a secondary bacterial infection — the longer time spent on mechanical ventilation and in intensive care."

The same is true in neonatology. "Children who develop necrotizing enterocolitis have a microbiota rich in certain bacteria that are not found in healthy subjects, specifically Clostridium butyricum. So, the question arises regarding its direct involvement in the pathogenesis of necrotizing enterocolitis, especially as the pro-oxidant nature — based on the oxidation reduction potential — is increased in this case, with a more acidic pH."

Another example concerns diarrhea acquired following antibiotic administration.

Dysbiosis after antibiotic use is associated with antibiotic-associated diarrhea (AAD). A study into this phenomenon, among many others, included 650 children, 11% of whom experienced AAD. 

"The effect of antibiotics — the initial source of infection doesn't really matter — is greater in someone whose microbiome is less resilient and who is young," said Morand. "Indeed, 18% with AAD were aged between 1 month and 2 years, vs 4% of 2- to 7-year-olds and 2% of over-7-year-olds." 

Another example, that of the "malnutrition" phenotype, is linked to changes to the microbiota. 

"Cause or consequence, unblurring the lines is still very complicated, even today," said Morand. "The proinflammatory status induced by malnutrition disturbs the microbiota, with more aerobic and less anaerobic bacteria, an increased redox potential, and an element of scarcity of certain beneficial bacteria. Even so, correcting malnutrition does not correct dysbiosis, which reinforces the idea that an abnormal microbiota could be a cause of malnutrition. This would result in a sort of self-powered vicious circle."

Obesity, IBD, Diabetes

The "obese" phenotype in children between the ages of 2 and 5 years is linked to changes to the microbiota caused by antibiotic use before the age of 2 years. This observation was notably made in a cohort of nearly 56,000 children. The investigators asked whether antibiotics or dysbiosis create obesity? The second hypothesis seems to be supported in multiple studies.

Antibiotics are said to play a probiotic role for some obesity-promoting bacteria and, conversely, deplete the microbiota of certain bacteria that protect against obesity, thus leading to an increased risk of the condition. It should be noted that the impact is even greater when the antibiotics prescribed are broad-spectrum.

Indirect evidence has been obtained pertaining to the role of the microbiota in the occurrence of IBD, due to a difference in bacterial microbiota between patients with IBD and healthy subjects. 

"Cause or consequence?" asked Morand. "Once again, it is difficult to come to a solid conclusion, since patients with IBD have specific immunity, and therefore specific immunity-microbiota interactions, as well as inflammation of the digestive tract. Nevertheless, studies show that dysbiosis guides the immune system towards the Th17 and Th1 pathways, which promotes the synthesis of proinflammatory cytokines, reduces the synthesis of short-chain fatty acids (which play a part in making up the gut barrier), and establishes proinflammatory conditions, potentially resulting in the development of IBD." 

The role of the microbiota in type 1 diabetes is also in question. Several studies have highlighted the fact that dysbiosis precedes the appearance of specific antibodies (GAD antibodies, etc.). One study demonstrated this in 33 infants who were genetically predisposed to develop type 1 diabetes. 

"The most likely explanation, per the relevant literature, is that gradually developing immunity modifies the microbiota," said Morand. "This mechanism is probably intertwined with that of stimulation by dysbiosis of predisposed immunity."

Similarly, atopic conditions are much more common in people with dysbiosis after antibiotic use. When bacterial diversity goes down, the risk of asthma goes up. This correlation was observed in several studies, with the issue of cause vs consequence once again remaining unresolved.

This statistically significant link is found with the secretion of immunoglobulin E (IgE), having positive prick tests, hypereosinophilic syndrome, allergic rhinitis, and atopic dermatitis. By favoring the Th1 and Th2 pathways, dysbiosis could be involved in the onset of certain atopic conditions, or even, at a more pronounced stage, in the onset of allergies. 

Neuropsychiatric Disorders

The question is identical as regards the link between dysbiosis and neurological, neurodevelopmental, or psychiatric disorders. The potential link with autism, for example, is hotly debated. 

"A patient diagnosed with autism spectrum disorder will often have a stereotypical diet, resulting in changes to their microbiota," said Morand. "Nevertheless, the evidence of interaction via the gut-brain axis is increasingly robust. Changes to the microbiota lead to reduced secretion of much-needed metabolites, in particular short-chain fatty acids that have an essential role in neurotransmission and immunity. Secondly, these disturbances affect signaling linked to the CNS, reduced secretion of gamma-aminobutyric acid neurotransmitters, serotonin, dopamine, and so on. This system of dysfunctional neurotransmitters could potentially be involved in the onset of these conditions. 

"We are in the early stages of research on the microbiota, and the reliability of our strategies for investigation is still low," Morand concluded. 

This article was translated from Medscape's French edition.