Anti-TB drugs affect intestinal bacteria and increase the risk of reinfection

Study shows that the effects of anti-tuberculosis drugs on intestinal bacteria may explain the risk of reinfection of patients

Current treatments for tuberculosis (TB) are very effective in controlling tuberculosis infection caused by Mycobacterium tuberculosis (Mtb). However, they do not always prevent reinfection. The reason this happens is one of the recurring issues in tuberculosis research.

So, why is our body incapable of generating permanent immunity against tuberculosis, the leading killer of infectious diseases in the world?

A team of scientists from the Research Institute of the McGill University Health Center (RI-MUHC) and McGill University may have found the answer … in the intestine.

In a study published recently in Mucosal immunology, they showed that antituberculous drugs altered the gut microbiota – the diverse community of microbes living in our intestines – and increased vulnerability to Mtb infection.

The intestinal microbiota is essential for keeping us healthy; they help digest food, fight pathogens and strengthen our immune system. Recent research has shown that the chronic use of antibiotics causes a disturbance of this community, which can in turn lead to a dysregulation of the immune system. However, it is unclear whether changes in the composition of microbes living in our intestine have an influence on TB infection.

By transplanting feces from mice treated with antituberculous drugs (particularly isoniazid and pyrazinamide) into untreated mice prior to infection, they were able to demonstrate for the first time that fecal transplantation was sufficient to compromise immunity against Mtb.

Impact of anti-tuberculosis drugs on the microbiome

To find out, Drs. Irah King and Maziar Divangahi of the Meakins-Christie Laboratories of the RI-MUHC, along with colleagues from McGill's Macdonald Campus, treated mice with the most commonly used anti-TB drugs – isoniazid, rifampicin and pyrazinamide – for a period of eight weeks. They found that while all three drugs significantly altered the composition of the mouse intestinal microbiome, only mice treated with pyrazinamide-badociated isoniazid showed increased susceptibility to Mtb infection.

To make sure that the vulnerability of the host to Mtb infection was due to a compromised intestinal microbiota, the researchers looked at … the feces. By grafting feces of mice treated with anti-TB drugs (particularly isoniazid and pyrazinamide) into untreated mice prior to infection, they were able to demonstrate for the first time that fecal transplantation was sufficient to jeopardize immunity at Mtb.

Relationship between the intestinal microbiome and the lungs

King and his colleagues also wanted to better understand the gut-lung axis – a two-way communication system between the microorganisms residing in the gastrointestinal tract and the lungs – to determine how this could be involved in the treatment. 39, infection and immunity at Mtb.

To do this, they evaluated a number of lung cell types recognized as being important for resistance to Mtb infection. As a result of anti-tuberculosis treatment, alveolar macrophages, a type of immune cell located in the respiratory tract of mice and humans and the first cell to be infected with Mtb after infection, have been compromised in their ability to kill Mtb .

"We need to do more research to understand how the microbiome affects alveolar macrophages, as these cells are essential for controlling early infection with tuberculosis. We must also identify the molecular pathways involved in the gut-lung axis, "says King.

"TB treatments have been incredibly effective in controlling the TB epidemic by reducing the morbidity and mortality badociated with Mtb," says King. "Now, this work provides a foundation for new therapeutic strategies exploiting the intestinal-lung axis in Mtb infection."

Researchers are already considering monitoring patients treated with these drugs to see how their gut microbiota evolves over time and after treatment is complete. The idea will be to control the changes of the microbiome in combination with effective drugs to kill Mtb.