The gut microbiota compound that could become a drug for prevention and treatment of bronchiolitis

Experiments involving isolated and cultured cells as well as animals and babies suggest that short-chain fatty acid acetate produced in the gut can minimize the effects of infection by respiratory syncytial virus.

By Theo Ruprecht  |  Agência FAPESP – Brazilian researchers have discovered that human gut microbiota contains a compound with the potential to reduce the harm done to health by respiratory syncytial virus (RSV), an important cause of lower respiratory tract infections, especially bronchiolitis, in children aged 2 or less. Some 100,000 deaths worldwide are believed to be due to the virus each year.

The research was conducted under the aegis of four projects supported by FAPESP (18/15313-8, 20/04583-4, 17/06577-9 and 20/13689-0). The latest findings are reported in an article published in eBioMedicine.

According to the article, short-chain fatty acid acetate derived from gut microbiota protected mice against RSV and mitigated the severity of the disease in those already infected. “We confirmed the substance’s antiviral action in human cells and in animals. We also correlated its concentrations with a reduction in certain signs and symptoms caused by the virus in babies,” said Marco Aurélio Ramirez Vinolo, penultimate author of the article and a co-principal investigator for the study. Vinolo is a professor at the University of Campinas’s Institute of Biology (IB-UNICAMP) in São Paulo state, Brazil.

There are currently no specific treatments for RSV. The symptoms and consequences have to be managed as far as possible while the child’s organism struggles to overcome the infection. In certain cases, such as when a premature baby is infected, the monoclonal antibody palivizumab is recommended to prevent lung disease, but this prophylactic treatment is expensive.

According to the researchers, their findings support the idea that a low-cost natural product from gut microbiota could play a role in controlling severe RSV infection directly in the respiratory tract. The first author of the article is Krist H. Antunes, a postdoc in pediatrics and immunology at the Pontifical Catholic University of Rio Grande do Sul (PUC-RS) in Porto Alegre, Brazil.

During the COVID-19 pandemic, the number of cases of other viral respiratory infections temporarily declined, but RSV bronchiolitis cases have recently rebounded. Off-season outbreaks of such infections are a threat to susceptible babies, reinforcing the importance of affordable preventive interventions.

Laboratory tests

In previous experiments, the researchers used different strategies to alter gut microbiota in mice, such as administering antibiotics and increasing the amount of fiber in their diet, for example, after which they investigated how the organism responded to RSV. “Resistance to infection increased when the microbiota produced more short-chain fatty acids, especially acetate,” Vinolo said. Laboratory tests in which cells were treated with this acetate also produced promising results.

However, the tests used a laboratory-grown viral strain that differed from the one that circulates among humans. To address this limitation, for the latest study the researchers collected samples of the virus from two children treated at São Lucas Hospital, which is run by PUC-RS, and applied them to cultured cells previously treated with acetate. The results showed a lower level of cell death and an 88% reduction in viral load.

Analysis of these cells also showed that the acetate activated the production of antiviral molecules, among which RIG-I appeared to be especially effective against RSV. In cells without RIG-I, the acetate failed to prevent the advance of infections.

In the next step, viral samples from the children were inoculated into mice. Once infected, the mice received acetate intranasally. Once again, the acetate had positive effects, reducing viral load by 93% and mitigating airway inflammation. The mice also regained weight faster after the treatment.

Gut microbiota in infants with bronchiolitis

Thirty infants aged less than 12 months undergoing inpatient treatment for RSV bronchiolitis at São Lucas Hospital were then recruited in collaboration with Ana Paula Duarte de Souza and Renato Stein, both of whom are professors at PUC-RS. Stool samples were collected from 17 of the infants. “We analyzed the composition of their gut microbiota, and quantified the levels of short-chain fatty acids,” Vinolo said.

Cross-tabulation of this data with clinical information on the children’s bronchiolitis showed that higher levels of acetate were associated with less severe respiratory disease, especially higher oxygen saturation and fewer days with fever.

“This type of study points to a correlation but doesn’t guarantee that it’s one of cause and effect,” Vinolo said. “Nevertheless, it provides an additional argument for continuing to study gut acetate.”

To confirm their findings, the researchers collected cells from the upper airways of the same babies and treated them with acetate in the laboratory. As before, viral load fell and the activity of antiviral molecules increased.

With the advent of the COVID-19 pandemic, the team performed similar tests using the compound against SARS-CoV-2. Positive effects were not observed in this case. “This coronavirus is different from RSV. The pathways activated by the acetate may not inhibit its action,” Vinolo said.

Future implications

Vinolo believes enough evidence has been gleaned for the group to begin clinical trials designed to verify the safety and benefits of using acetate to prevent or control bronchiolitis. “We’ve been planning this for some years, but the pandemic has been an obstacle. We aim to complete the first trial in 2022, possibly with intranasal treatment,” he said.

The reason for focusing on the development of a drug based on acetate is that although other short-chain fatty acids produced by gut microbiota have similar effects, they do not reach the bloodstream in large amounts. “Acetate reaches high levels in various parts of the organism, such as the lungs,” Vinolo said. 

The article stresses the role of gut microbiota in the organism, and especially in the immune system. For Vinolo, this is a good reason for everyone to aim at a balanced diet with plenty of soluble fiber, including cereals such as oats, linseed and chia, legumes such as lentils and dry beans, and fruit such as apples and bananas.

“We don’t yet know whether eating habits can induce acetate production by gut microbiota sufficiently to protect human infants, but the possibility has been demonstrated in laboratory animals,” Vinolo said.

The article “Short-chain fatty acid acetate triggers antiviral response mediated by RIG-I in cells from infants with respiratory syncytial virus bronchiolitis” is at: www.thelancet.com/journals/ebiom/article/PIIS2352-3964(22)00075-5/fulltext.