The composition of the gut microbiome may make a difference in height gain in infants with cystic fibrosis during their first year of life, according to a new study.
Many babies with cystic fibrosis have difficulty in putting on weight and getting taller. Improvements in detecting and treating cystic fibrosis in newborns means many now achieve weight goals by the time they are 1 year old. However, increases in remain slower than normal on average in babies with cystic fibrosis.
Stunted growth in the early months of life has been associated with long-term respiratory problems and lower survival rates in babies with cystic fibrosis.
Little is known about why treatment of infants with cystic fibrosis can improve their average weight, but not their height, measurements. Research led by scientists and pediatricians at the University of Washington School of Medicine sought to determine what distinguishes these babies from other babies with cystic fibrosis of normal height for their age.
Cystic fibrosis causes gut inflammation, poor digestion and malabsorption of nutrients. The scientists wondered if any of these gastrointestinal conditions held sway over the microbial environment of the babies’ guts. The scientists wanted to see whether the bacterial communities residing in the infant intestinal tract might play a role in the babies’ growth.
Their research on this topic was published recently in Nature Medicine. Participants came from the Baby Observational and Nutrition Study (BONUS), which periodically collected clinical data on cystic fibrosis patients under a year old, and from the concurrent Healthy Baby Study. Both studies also collected fecal samples throughout the babies’ first year. This allowed the researchers to characterize changes in the composition of the babies’ gut microbiome.
Lucas Hoffman, professor of pediatrics and microbiology and a children’s lung specialist at UW Medicine; Elhanan Borenstein, associate professor of computer science and of medicine at Tel Aviv University who does computational microbiome research; and Samuel Miller, UW professor of medicine, microbiology, immunology and genome sciences, oversaw the study. Hillary Hayden, a research scientist in Miller’s lab, and Alex Eng, a graduate student in Borenstein’s lab, ran the project.
The team found that, like healthy newborns, babies with cystic fibrosis started life without much diversity in the bacteria present in their stools.
Until they are four months olds, babies usually have relatively few gut microbial species, mainly Bifidobacterium longum, Bifidobacterium breve, and Escherichia coli. As they got older, healthy babies, as expected, had a greater variety of bacteria in their stools. However, while samples from the cystic fibrosis babies also started showing more bacterial diversity, this did not develop at the same rate as healthy babies.
These, and other data on the bacterial composition of specimens taken over several months, suggest that maturation of the gut microbiome in infants with cystic fibrosis is delayed. To demonstrate and quantify this delayed maturation, the scientists trained a computational machine-learning model to predict the age of healthy infants based on their gut microbiome data. When this model was then applied to microbiome data from babies with CF, the predicted age was younger than the actual age of the babies with cystic fibrosis. This difference in accuracy in predicting age indicates that the microbiome developmental stage in babies with cystic fibrosis is delayed compared to healthy babies.
The researchers also found that infants with cystic fibrosis whose bodies were shorter than normal-length infants with this genetic disorder had a much more extreme imbalance in the kinds of bacteria in their stools.
Further investigation supports the possibility that malabsorption of fat, not inflammation of the intestine, is causing the abnormal constitution of the microbiome in the guts of infants with cystic fibrosis. The findings suggest
that the bacteria composition of these babies’ gut microbiome is influenced by the nutrient content in the gastrointestinal tract.
The results indicate, the researchers noted, that “malabsorption is a recalcitrant risk factor” for the bacterial imbalance in the gut of infants with cystic fibrosis, and, “as an apparent consequence, for impaired growth in early cystic fibrosis childhood.”
In what ways might the gut microbiome of babies with cystic fibrosis alter their ability to achieve a satisfactory growth in height during their first year? The researchers had earlier found that the fecal microbiota of children with cystic fibrosis had a lower overall capacity for building two short-chain fatty acids. These chemicals are known to modulate bone and body growth. The researchers’ analysis showed that the bacterial species that produce these two short-chain fatty acids were less prevalent in the samples from infants with cystic fibrosis than in infants without this genetic disorder. Other studies have shown that short-chain fatty acids can affect growth hormone levels.
Put together, these studies raise the possibility that lack of the right kind of bacterial species may be affecting babies’ body length growth by impairing endocrine functions. However, further studies would be needed to better identify aspects of the gut microbiota that modulate hormonal signaling. It is also possible, the researchers point out,
that cystic fibrosis gene mutations directly disrupt normal growth through other, non-microbial mechanisms not uncovered in this study. However, they added that there are a wide variety of outcomes in children with the same cystic fibrosis mutation. This variation in outcomes suggests a role for factors, such as microbiota activities, that may be amenable to clinical interventions.
Early therapies that address the fecal bacteria imbalance identified in this project in young infants with cystic fibrosis may become a topic for future studies. For example, probiotics, prebiotics, or even supplements of short-chain fatty acids themselves might possibly improve early growth in infants with cystic fibrosis and, possibly, in other diseases that cause infant growth stunting. According to the researchers, these efforts might be directed at “more effective strategies to improve growth and, as a consequence, long term outcomes in infants with cystic fibrosis.”
The project reported in Nature Medicine was funded by the National Institutes of Health (grants RO1DK095869, K24HL141669, and SP30DK089507) and the Cystic Fibrosis Foundation.