Changes in Airway Metabolites May Predict Likelihood of NTM Infection

Marta Figueiredo, PhD avatar

by Marta Figueiredo, PhD |

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Cystic fibrosis (CF) patients with non-tuberculous mycobacteria (NTM) lung infection show significant changes in airway metabolites relative to those without such infections, a study shows.

Metabolites are intermediate or end products of cellular metabolism, and some of these altered metabolites play roles in immune responses and bacterial growth.

Combining metabolic and microbiota changes also allowed for an accurate distinction between patients with and without NTM infection, further suggesting that these may be risk factors of NTM infection in people with CF. Airway microbiota comprise the community of bacteria, fungi, and viruses that colonizes the lungs.

These findings support further research on host and bacterial community factors that may contribute to NTM infection risk in these patients, the researchers noted.

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Their study, “Sputum Metabolites Associated with Nontuberculous Mycobacterial Infection in Cystic Fibrosis,” was published in the journal mSphere.

The characteristic buildup of thick mucus in the lungs of people with CF increases patients’ vulnerability to lung infections, including those caused by opportunistic NTM — a set of more than 160 species of bacteria found naturally in the environment.

NTM are increasingly being recognized as common and worrisome infectious agents in people with CF, as they cause infections that are challenging to treat, associated with a poorer prognosis, and often become chronic.

Data, however, is limited on the risk factors of NTM infection for these patients.

A research team at the University of Michigan Medical School evaluated whether airway metabolites and microbiota — reflecting the lung environment — could potentially represent risk factors for NTM infection in people with CF.

Metabolites are products of cellular metabolism of amino acids (the building blocks of proteins), organic acids, sugars, or fatty molecules. Airway metabolites can be produced either by lung cells or by the bacteria that colonizes the lungs.

In this study, 42 sputum samples were collected from 32 patients with NTM infection — 14 collected before the infection and 28 after developing the infection — and 27 samples from 27 patients without NTM infection, used as controls. Sputum is the mix of saliva and mucus coughed up from the lungs.

Microbiota analysis was also performed on 43 samples from 41 of these 59 people.

The cause of nearly 60% of NTM cases was Mycobacterium avium complex, followed by Mycobacterium abscessus complex; both being the most common NTM types. The NTM cases and NTM-negative controls did not significantly differ in most clinical characteristics.

Several of the 902 total metabolites detected in these patients significantly differed between NTM cases and controls, the researchers found.

Notably, some of these alterations were present both before and after NTM infection, suggesting that they may represent risk factors of such infection.

Itaconate, a compound produced by immune cells upon infection that was previously shown to suppress the growth of certain mycobacteria, was reduced in NTM cases (both pre- and post-infection) relative to controls. These differences, however, did not reach statistical significance.

The levels of certain amino acid metabolites were also lower both pre- and post-NTM infection, while certain types of fatty molecules called ceramides were significantly higher.

Ceramides are known to be involved in the regulation of immune molecules and inflammation, but whether they have a protective or damaging role in CF remains to be clarified. Some studies suggest that they accumulate in CF, increasing inflammation and susceptibility to bacterial infections, while others report an anti-inflammatory effect in CF.

Similar to previous studies, certain anaerobic bacteria, those that can survive with no oxygen, were found to be “overrepresented in patients with NTM infection,” the researchers wrote.

Further analyses into differences in combinations of certain metabolites and bacteria present between the patient groups allowed for the correct identification of 12 of the 17 NTM cases and 21 of the 26 controls.

These findings highlight significant differences in metabolic patterns between CF patients with and without NTM infection, including “metabolites that play important roles in the host immune response and in bacterial [growth],” the researchers wrote.

Metabolites showing differences even before the infection may represent “risk factors and therapeutic targets for preventing and/or treating NTM infections in people with CF,” they added.

Larger studies that follow patients over time are needed to confirm these findings and to clarify the “mechanistic links between NTM, the CF airway microbial community, and the metabolome [all the metabolites in a biological sample],” the team wrote.

Such information will also help to guide the “development of novel biomarkers and therapeutic approaches,” the researchers noted.