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Infant bronchiolitis risk linked to gut flora composition

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Microbiota modification may hold promise for respiratory treatment

This cross-sectional, case-control study raises multiple hypotheses about the relationship between different gut microbiota compositions and the presence of bronchiolitis while also exposing limitations in the study. For instance, polysaccharide A of Bacteroides suppresses T-cell responses to inflammatory stimuli. Inappropriate suppression of “cellular learning” in infancy may alter subsequent mucosal immunity upon infection, resulting in exacerbated inflammatory responses to environmental challenges. Thus, an increased abundance of enteric Bacteroides before a viral challenge may be hypothesized to increase the likelihood of reduced viral immunity and an inappropriate response to an infection.

However, in the study by Hasegawa et al., the gut microbiota was sampled only at the time of hospitalization for infection and once in age-matched controls. Any of the observed microbiota profiles may not reflect earlier states of the microbiota and critical windows of early immune priming. Therefore, prospective longitudinal studies will be essential to determine whether the observed microbiota profiles at the time of bronchiolitis preceded symptoms, were concurrent with the disease onset, or occurred after the disease was well under way. Only through these types of studies, coupled with preclinical mechanistic models of bronchiolitis, can causality be established.

The associations identified by Hasegawa et al., if upheld by the necessary prospective and causal studies, may yield new insights into the failures of antibiotic therapy and suggest alternative approaches to therapeutically modify the microbiota and thus reduce the risk and severity of viral bronchiolitis in infants.

Respiratory tract research has entered a new era. Through a combination of clinical and preclinical models, genomics, immunology, and metabolomics, investigations into the gut-lung axis are expected to drive a paradigm shift in which pulmonary health is viewed through a wider lens of multisystem interactions that includes the microbiota, and through which new preventive strategies, diagnostics and therapeutics may be envisioned for common respiratory diseases.

These comments were condensed from an editorial by Dr. Patrick C. Seed that was published in Pediatrics (doi: 10.1542/peds.2016-1377) alongside the original research. Dr. Seed is supported by the National Institutes of Health, and he reported having no disclosures.


 

PEDIATRICS

References

Infants with gut flora dominated by the genus Bacteroides have more than four times greater odds of developing bronchiolitis than those with microbiota dominated by Enterobacter and Veillonella combined, according to results of a recent study. Two other bacterial profiles, one dominated by Bifidobacterium and another by Escherichia, were not associated with any higher or lower risk of bronchiolitis.

“Our observations, in conjunction with earlier studies, suggest a causal pathway linking the gut microbiota in early infancy to the respiratory tract immune response against viral infection,” wrote Dr. Kohei Hasegawa of Harvard Medical School in Boston, and his associates (Pediatrics. 2016 June 27. doi: 10.1542/peds.2016-0218). “That is, the Bacteroides-dominant gut microbiota in early infancy attenuates the development of immune function in the respiratory tract and thereby leads to an increased susceptibility to bronchiolitis.”

The researchers collected stool samples from 115 healthy infants from a Massachusetts General Hospital primary care group practice, and from 40 infants who were hospitalized with bronchiolitis from November 2013 through April 2014 at one of three children’s hospitals in Wilmington, Del.; Boston; and Louisville, Ky. The groups were age matched, and the infants overall were a median 3 months old. Just over half were male, and just over half were white. Of those with bronchiolitis, 65% had respiratory syncytial virus and 23% had rhinovirus.

Further, “compared with healthy controls, infants with bronchiolitis were [significantly] more likely to have a parental history of asthma, maternal antibiotic use during pregnancy, a history of premature birth, a sibling at home, and corticosteroid use before the enrollment, but they were less likely to be breastfed,” the authors reported.

The researchers used a 16S rRNA gene-sequencing method similar to the one used by the Human Microbiome Project to identify the composition of the fecal samples’ microbiota. Four different bacterial profiles emerged. The most common was an Escherichia-dominant profile, occurring in 30% of the infants overall. Microbiota dominated by Bacteroides followed next, occurring in 28% of infants, while 22% of infants had a Enterobacter/Veillonella–dominant profile, and 21% had a Bifidobacterium-dominant profile. Those with a Bacteroides-dominant profile were older, more likely to be born vaginally, and more likely to be prenatally exposed to maternal smoking.

In infants with bronchiolitis, however, flora dominated by Bacteroides was most common, occurring in 44% of the ill infants. Enterobacter/Veillonella–dominant microbiota occurred in only 15% of the infants with bronchiolitis. Infants’ risk of bronchiolitis was not significantly different among those with Bifidobacterium-dominant or Escherichia-dominant profiles, compared with the Enterobacter/Veillonella–dominant profile.

Patients with Bacteroides-dominant microflora had 4.59 greater odds of severe bronchiolitis than those with Enterobacter/Veillonella–dominant microbiota (P = .008). These odds dropped only to 3.89 after adjustments for age, sex, prematurity, mode of birth, and a history of systemic antibiotic use (P = .03). Similarly, adjusting for age, sex, parental history of asthma, maternal antibiotic use during pregnancy, and systemic corticosteroid use before enrollment resulted in 4.12 greater odds of bronchiolitis in those with a Bacteroides-dominant profile (P = .02).

The research was funded by the National Institutes of Health. Dr. Hasegawa reported having no disclosures. Two authors reported owning shares at the microbiome research company Diversigen, and one had consulted on bronchiolitis for Regeneron. The other authors reported having no disclosures.

pediatricnews@frontlinemedcom.com

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