Gut microbiome sequencing opens new possibilities for predicting infection in leukemia patients

Infectious diseases researchers at St. Jude Children’s Research Hospital have isolated three types of bacteria commonly found among intestinal microbiota, or gut microbiome, that may help physicians predict the risk of infections during chemotherapy for children with acute lymphoblastic leukemia (ALL).

The study was led by Hana Hakim, MD, and Jason Rosch, PhD, of the St. Jude Department of Infectious Diseases.

“We sought to better understand the impact of chemotherapy and antibiotics on the gut microbiome, along with many other therapies that ALL patients receive during the treatment phase,” Hakim explained.

Predictors of infection risk

Leukemia patients live under the threat of several infections related to decreased immunity and bone marrow activity (myelosuppression). Previously, physicians lacked the biomarkers, or clues, to help them identify the infections for which each newly diagnosed leukemia patient is at risk. To find these clues, infectious diseases researchers at St. Jude studied the patients’ stool.

Hakim, Rosch and their research team found that an abundance of Proteobacteria species in the intestines, before chemotherapy, predicts the development of fever when leukemia patients become neutropenic. Febrile neutropenia might be the first sign of a serious infection. Study results indicate that high levels of the bacterial group Enterococcaceae in a patient’s gut during chemotherapy also predicts febrile neutropenia as well as diarrheal infection. Patients whose intestines are rich with Streptococcaceae were more likely to develop diarrheal infections in subsequent phases of chemotherapy.

None of the three bacteria types are known to actually cause the diseases or conditions that they helped to predict.

The study, published in the journal Clinical Infectious Diseases, is the first to evaluate changes to the gut microbiome in such a large group of children with ALL, analyzing the subtle relationship between microorganisms found in the intestines and infections throughout the body.

Gut microbiota and the gut microbiome

Hundreds of microbial species form a delicately balanced ecosystem in the intestines collectively known as the gut microbiota. Most of these bacteria, fungi and other microorganisms are not harmful and many of them are essential for everyday health, prompting some scientists to describe the microbiota as a type of organ. Microbiota produce vitamins that our bodies need along with anti-inflammatory compounds that fight off harmful microbes. They also extract energy from otherwise indigestible fiber and show the immune system how to recognize threats.

“The more diverse the microbiome, the healthier the microbiome,” Hakim said.

The gut microbiome is the collective genome of all the microorganisms making up the gut microbiota. This term is especially relevant to this study because the researchers sequenced a bacterial gene (16S ribosomal RNA, collected via fecal samples), to estimate populations for each species. Gut is a short word for a long series of connected organs, the gastrointestinal tract, often referring specifically to the intestines.

Tipping the scale on a healthy microbiome

Leukemia and its treatments, including chemotherapy and antibiotics, tend to upset the balance of the gut microbiome.  So-called “good” or mutualistic bacteria such as Bacteroidetes, Ruminococcaceae and Faecalibacterium species are believed to protect intestinal lining, maintaining a barrier between blood vessels and billions of microbes. If chemotherapy kills most of these bacteria, there is an increased risk that other types of bacteria will make it into the bloodstream. Of the 199 children in this study, 26 patients had 31 bloodstream infections.

“If you disturb any sort of ecosystem, like burning or bulldozing a forest, you don't know exactly how it's going to grow back,” Rosch said. “Both chemotherapy and antibiotics disrupt the ‘forest.’ It takes some of the players out.”

“And the ones that remain are not the good bacteria,” Hakim said.

“Yes, the last ones standing are often the worst ones,” Rosch agreed.

Clinical implications for the findings

The clinical significance of the study’s findings lies in predicting risk levels for infections rather than determining the root causes of the infections. This ability to predict infections means clinicians may be able to proactively reduce them by manipulating the gut microbiota composition with customized probiotics, fecal microbiota transplant, modified diet, or other innovative approaches.

Read the study’s report in Clinical Infectious Diseases:  Gut Microbiome Composition Predicts Infection Risk During Chemotherapy in Children with Acute Lymphoblastic Leukemia

Co-authors included Ronald Dallas, Joshua Wolf, Li Tang, Stacey Schultz-Cherry, Victoria Darling, Cydney Johnson, Erik A Karlsson, Ti-Cheng Chang, Sima Jeha, Ching-Hon Pui, Yilun Sun, Stanley Pounds, Randall T Hayden and Elaine Tuomanen.