The microbiome of children with short bowel syndrome

Infants who suffer from necrotizing enterocolitis, a condition we’ve written about on the blog, often must have the dead portion of their intestines surgically removed. Some children who undergo this procedure, as well as others with congenital malformations of the bowel, suffer from a condition called short bowel syndrome (SBS). SBS results when nutrients are unable to properly absorb in the intestines and intravenous feeding is often needed to ensure these children have the nutrients needed to survive. It is thought that the intestinal microbiome plays an important role in the ability to remove children from intravenous feeding, however the microbiome of these children had never previously been mapped.

Scientists in Sweden successfully mapped the microbiome of children with SBS that were diagnosed in the neonatal period. They collected fecal samples from 11 children with SBS and 7 healthy siblings who served as controls for the study. Children that were on parenteral nutrition (PN), or intravenous feeding, had significant intestinal dysbiosis compared to the children who had been weaned off of PN and suffered from a condition called small bowel bacterial overgrowth (SBBO), a condition that is known to prevent weaning off of PN.

In 6 of the 11 patients with SBS, and specifically those still on PN, Enterobacteriacae dominated the guts of these children. While those children who were off PN had more diverse microbiomes than those on PN, only one of those 5 children had diversity levels on the same level of the control individuals without SBS.

This microbial dysbiosis in children with SBS is in line with mappings of individuals with other bowel conditions such as Crohn’s disease and necrotizing enterocolitis. While this study was small in the number of children studied, it was the first to study the microbiome of children with this serious condition. Currently, children with SBS are often given probiotics but the results of this have been conflicting and there are often complications such as septicemia. Future studies will be important to look at how the microbiome can be altered to treat this dysbiosis so that children can be weaned off of parenteral nutrition.

Specific bacteria and overall diversity linked to severity of necrotizing enterocolitis

Necrotizing enterocolitis (NEC) is an inflammation of the gut that occurs due to bacterial infection in premature infants.  It has long been considered that a ‘healthy’ microbiome is important to preventing NEC in low birth weight infants, and, as we have written about before, there is a lot of science that supports this.  Still though, it is not known which bacteria are most responsible for causing NEC, and how overall diversity is associated with the disease.  Many studies have tried to nail this down, but there has been conflicting results.  Scientists at Louisiana State University thought that perhaps these conflicting results were from neglecting to consider the severity of the NEC as a variable in each study.  They hypothesized that the infants’ microbiomes would vary depending on the severity of the NEC, and that the most severe cases would show a characteristic microbiome that may be important to understanding the disease.  They published their results in the Journal Microbiome last week.  

The scientists studied the microbiomes of 74 healthy infants and 21 infants suffering from NEC.  They then categorized the NEC infants into three groups based on the severity of the disease.  The scientists learned that two bacterial genera, Veillonella and Streptococcus, were more abundant in all the NEC microbiomes compared to non-NEC controls.  They also discovered that overall microbiome diversity was decreased in NEC versus controls.  When the researchers looked microbiome differences that were a function of NEC severity they discovered that Clostridia were completely absent from the microbiomes of infants suffering from the most severe NEC and its increased with decreasing severity of NEC (15% in controls, 12% in mild NEC, 3% in moderate NEC, and 0% in severe NEC).  In addition, a similar trend was seen with diversity, it decreased with severity of NEC.

Many Clostridia species have been associated with a healthy microbiome, and they may be critically important to maintaining a homeostasis in the gut.  According to this study, their abundance appears to be of upmost importance in premature infants, and this should be considered moving forward.  Many countries administer probiotics to low birthweight infants who are at risk for NEC, but this is not yet down in the United States.  Fortunately, there are a number of clinical trials that are trying to nail down the science so that the FDA has enough evidence to make a recommendation.

More evidence that probiotics help to prevent necrotizing enterocolitis

In an article published by Nature Pediatric Research, researchers investigated the effectiveness of the bacteria Bifidobacterious longum subsp. infantis as a probiotic used to decrease the risk of necrotizing enterocolitis (NEC). NEC, as we have discussed previously in this blog, is a type of bacterial infection in premature babies, which can often be fatal. To study the effectiveness of B. infantis, researchers assigned 50 rat pups into three groups, which were delivered one day premature of term, to be fed by their mothers, fed with formula, or fed with formula supplemented with B. infantis. The pups were also exposed to hypoxia and cold stress. Intestinal tissue was tested for response.

The results of this experiment reinforced the importance of maternal milk, and showed the importance of a probiotic, B. infantis, if formula must be used.  None of the mother fed mice were diagnosed with NEC, while ~80% of formula fed pups were.  By supplementing the probiotic though, less than 40% of the rat pups were diagnosed with NEC, and the severity of NEC was lower in these instances.  Results also suggested that the probiotic decreased the inflammatory immune response of the underdeveloped intestinal mucus layer. The second part of the experiment, involving putting stress on the rat to observe responses, resulted in data that was inconclusive but suggested that stresses such as hypoxia and cold may not significantly alter the microbiome of the intestines.

While the results of the above experiment did not conclude whether outside stress effects the response of the microbiome in premature rat pups, they still show that certain bacteria such as B. infantis can be useful as a probiotic in preventing NEC.

Hospitals influence infants' intestinal microbiomes

Pig Ileum with and without NEC.  Figure taken from different study.

As we have previously discussed, necrotizing enterocolitis (NEC) is a bacterial infection that often occurs in low weight, premature infants, that can lead to death.  The rates of NEC vary between neonatal intensive care units (NICUs), meaning that individual NICUs may play a role in causing NEC.  A new study published in the journal Microbiome sought to discover if different NICUs had any influence on a premature infants' gut microbiome.

Around 60 preterm babies had their microbiome studied during their first week of life.  Two hospitals were chosen for the study, one in Cincinnati, Ohio, the other in Birmingham, Alabama, over the course of two years.  The researchers discovered that while many of the infants' microbiomes showed similar characteristics, such as an abundance of Proteobacteria, there were nevertheless statistically significant differences in the microbiomes between hospitals, and temporally within hospitals.  For example, one hospital's infants had a higher level of Firmicutes than the other hospital.  

Understanding the risk factors for NEC will ultimately help prevent the disease, so while this study does not show any direct association between hospital and NEC, it shows the need for a large scale epidemiological study that spans many geographic areas over long periods of time.  

Let's talk about necrotizing enterocolitis

Radiograph of infant with necrotizing enterocolitis.

A rather contentious issue at the recent Harvard Probiotics Symposium, which AMI was fortunate enough to attend, was the use of probiotics in treating necrotizing enterocolitis (NEC).  NEC occurs in 7% of very low birth weight babies, and is caused by a bacterial infection in the gut.  The mortality rate of children who suffer from NEC is around 25%.  Many studies have shown that using human milk, rather than formula, to feed low birth weight infants, reduces risk of NEC, presumably by encouraging commensal bacterial growth, and this is now common practice in NICUs in the United States.

Several countries, including Australia and New Zealand, but not the United States, give a prophylactic probiotic to low birth weight infants immediately following birth to prevent NEC.  Double blind randomized clinical trials demonstrate that using probiotics in these infants decreases both risk of NEC and mortality from NEC by half in each case.

Reviews of all the clinical data on using probiotics have shown that the studies have not been robust enough for US regulators to develop clinical guidelines regarding probiotics.  These trials have occurred outside the US, so are under even more scrutiny. Adding more complexity to the issue is the fact that many of the studies used different probiotics, so how can they be compared?  Now however, many of the countries providing probiotics to low birth weight infants require the probiotic administration as a course of treatment, thereby making controlled randomized trials unethical. Withholding probiotics would place these infants at a greater risk for NEC.  

A recent commentary on the subject in the Journal Pediatrics points to the need for a robust randomized clinical trial to occur in the United States, to truly determine whether probiotics are useful in treating NEC.  The AMI has not yet adopted a formal position on the subject, but we agree more work is needed.