Brazilian researchers have identified in the intestinal microbiota a compound with the potential to reduce the health impacts caused by RSV (respiratory syncytial virus) — the main agent involved in lower respiratory tract infections, especially bronchiolitis, in children up to two years old. It is estimated that the pathogen is responsible for about 100,000 deaths per year worldwide.
The work is the result of four projects supported by Fapesp (18/15313-8, 20/04583-4, 17/06577-9 and 20/13689-0). The most recent results were published in the journal eBioMedicine.
According to the article, acetate — a short-chain fatty acid produced by bacteria in the gut — would have potential both as a prophylactic treatment and to minimize the consequences of RSV infection.
“We pointed out the antiviral action of this substance in human cells and in animals. In addition, we correlated its concentrations with the reduction of some signs and symptoms caused by the virus in babies”, says pharmacist Marco Aurélio Ramirez Vinolo, one of the coordinators of the study and professor of Immunology at the Institute of Biology at the State University of Campinas (IB-Unicamp).
Currently, there is no specific treatment against RSV. Professionals manage symptoms and consequences while waiting for the child’s body to recover. In specific cases (prematurity, for example), the monoclonal antibody Palivizumab is recommended as a way to avoid infection. This prophylactic treatment, however, is expensive.
“Our findings support the concept that a low-cost microbiota product may have a role in controlling RSV infection in the respiratory tract,” the authors write in the paper.
The Covid-19 pandemic has changed the landscape of almost all other viral respiratory infections, transiently leading to a large decrease in cases. This has caused an outbreak of RSV bronchiolitis today. These off-season spikes in infections pose a threat to susceptible babies, reinforcing the need for new and affordable preventive interventions.
In the lab
In previous experiments, researchers used different strategies to change the gut microbiota of mice — they administered antibiotics or offered dietary fiber, for example — and then assessed how the organism responded to RSV.
“Under conditions in which the microbiota produced a greater amount of short-chain fatty acids, especially acetate, there was greater resistance to infection”, says Vinolo.
Tests applying acetate to isolated cells also revealed promising results.
But until then, researchers had been using a laboratory strain of RSV, which is not the same as the one that circulates among humans. To circumvent this limitation, in the current study, virus samples were collected from two children treated at Hospital São Lucas, Pontifical Catholic University of Rio Grande do Sul (PUC-RS). These pathogens were then applied to cell cultures previously treated with acetate. Result: This pretreatment reduced cell death and decreased viral load by more than 88%.
The evaluation of these cells also signaled that acetate activates the production of antiviral molecules. Among them, RIG-I appears to be especially relevant against VSR. In cells grown without RIG-I, acetate failed to prevent the progression of infection.
The next stage of the research used those same strains taken from the children and inoculated them into mice. Once infected, they were given acetate intranasally. Once again, this short-chain fatty acid had positive effects, such as a more than 93% decrease in viral load and airway inflammation. The animals also regained their weight more quickly after treatment.
The microbiota of children with bronchiolitis
With these data in hand, 30 children younger than 12 months admitted to Hospital São Lucas because of RSV were recruited. This was an effort in collaboration with professors Ana Paula Duarte de Souza and Renato Stein, from PUC-RS. Of the children, 17 had their feces collected. “We evaluated the composition of the intestinal microbiota and quantified the concentrations of short-chain fatty acids”, says Vinolo.
When crossing this information with the evolution of bronchiolitis, it was found that a higher concentration of acetate was associated with a lower severity of the condition. The babies had higher oxygen saturation — a marker of preservation of respiratory capacity — and fewer days with fever.
“This type of study traces a relationship, but does not guarantee that it is one of cause and effect”, ponders Vinolo. “Still, it is one more argument for us to advance in the studies with acetate”, he adds.
To consolidate their findings, the team collected cells from the upper respiratory tracts of children examined at this stage, who were already infected. In the laboratory, these cells were treated with acetate. And, again, there was a reduction in viral load and greater activity of antiviral molecules.
With the arrival of the Covid-19 pandemic, the team carried out similar tests in the laboratory, but using the compound against Sars-CoV-2. In this case, positive effects were not observed. “Coronavirus is different from RSV. Possibly, the pathways activated by acetate do not prevent its action”, explains Vinolo.
future implications
Vinolo believes that, with the accumulated evidence, it is possible to start clinical studies to verify the safety and eventual benefits of acetate as a preventive drug or for the control of bronchiolitis.
“We had been planning this for the last few years, but the pandemic made the project difficult,” he says. “The goal is to start a first trial in 2022, possibly with an intranasal treatment,” he adds.
The choice of acetate has a reason to be: although other short-chain fatty acids produced by the microbiota have similar effects, they end up not reaching the bloodstream in large quantities.
“Acetate can reach different regions of the body in considerable concentrations, such as the lungs”, explains Vinolo. Hence why the idea would be to develop a drug based on this substance specifically.
In addition, the article reinforces the role of the intestinal microbiota in the body and in the immune system. According to Vinolo, it is an important message for people to value healthy habits, such as a balanced diet rich in soluble fiber. Among the sources of this substance are: cereals (oats, flaxseed, chia), legumes (lentils, beans) and fruits (apple and banana).
“We still don’t know if food is capable of modifying the intestinal microbiota to the point of producing acetate in concentrations that would protect children. However, in laboratory animals this was possible”, he concludes.
The article’s first author is Krist H. Antunes, from the Postgraduate Program in Pediatrics and Child Health at PUC-RS. It can be read here.
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