Early-life use of antibiotics disrupts gut microbiota in a rat model of multiple sclerosis (MS) and provokes nervous system autoimmunity, ultimately aggravating disease severity, new research shows.
Results also indicate early-life antibiotic use may have unfavorable consequences on regulation of the immune system.
The research article, “Oral neonatal antibiotic treatment perturbs gut microbiota and aggravates central nervous system autoimmunity in Dark Agouti rats,” was published in the journal Nature Scientific Reports.
Increasing evidence shows that a stable gut microbiota — the microbes living in our guts — is required for a properly functioning immune system. For example, changes in intestinal microbiota have been shown to throw off a carefully regulated balance of two types of immune cells: effector T-cells and regulatory T-cells.
Importantly, an imbalance in these immune cell populations has been linked to an increased risk for autoimmune diseases, such as MS and its similar disease in animal models — the experimental autoimmune encephalomyelitis (EAE) model.
Similarly, dysbiosis — gut microbiota imbalances — has been suggested to have a disease-causing role in autoimmune diseases. It is known that patients with autoimmune neuroinflammatory diseases, like MS, have a different make-up of microbes in the gut compared to healthy individuals.
However, it is unclear if gut dysbiosis increases the risk of MS, or is the result of the disease. Also, the relationship between gut dysbiosis and T-cell imbalance is unclear.
Although antibiotics are generally considered safe, their use is known to negatively affect and potentially change the gut microbiota.
To address this question, researchers from the University of Belgrade, Serbia, studied the effects of gut microbiota dysbiosis in an EAE rat model of MS.
The pregnant animals were given oral antibiotics starting two weeks before birth) to disturb their gut microbiota. The treatment continued for an additional four weeks after birth. As such, the infants were exposed to antibiotics transferred to milk during nursing and directly through drinking water.
EAE was then induced in eight-week-old rats. Results were compared with those of EAE rats not subjected to antibiotic treatment.
Results showed that by the time the autoimmune response was triggered at eight weeks, differences were already seen in rats treated with antibiotics. After the autoimmune response was triggered, rats treated with antibiotics experienced more severe EAE than control rats.
Specifically, EAE rats treated with antibiotics had higher levels of inflammation and infiltrating immune cells in the nervous system; higher levels of IFN-γ and IL-17 in the spinal cords (indicative of T-cell imbalance); and an overall stronger immune response and longer disease duration.
“This implies that intestinal microbiota dysbiosis occurring early in the lifetime, and not the direct effect of antibiotics or gut microbiota dysbiosis at the time of central nervous system autoimmunity initiation, was a contributing factor to EAE pathogenesis,” researchers wrote.
The team also found that early-life treatment with antibiotics caused a decrease in major bacterial groups important for early gut colonization, such as lactobacilli and bifidobacteria. They showed that these bacteria were replaced by other types, primarily by Proteobacteria and Bacteroidetes.
Antibiotic-treated rats also experienced a decrease in Turicibacteriaceae, which has been suggested to play a role in the prevention of EAE development and alleviating the disease’s symptoms.
A balanced intestinal microbiota is linked to the production and release of various compounds that regulate the immune system response, including short-chain fatty acids. The results also showed a major decrease in fecal short-chain fatty acids concentration in antibiotic-treated rats, compared to non-treated rats, which potentially could lead to a dysregulated immune response.
Overall, the team concluded that “the alteration of gut microbiota leads to an escalation of CNS [central nervous system]-directed autoimmunity,” and that the results “indicate that antibiotic use in early life may have subsequent unfavorable effects on the regulation of the immune system,” they wrote.
“Although simultaneous application of different antibiotics in high doses and for an extremely long period is not likely to be used in humans, our results suggest caution in antibiotic use,” the researchers added.