Antibiotic and antifungal use in pediatric leukemia and lymphoma patients are associated with increasing opportunistic pathogens and decreasing bacteria responsible for activities that enhance colonic defense

Abstract

Due to decreased immunity, both antibiotics and antifungals are regularly used in pediatric hematologic-cancer patients as a means to prevent severe infections and febrile neutropenia. The general effect of antibiotics on the human gut microbiome is profound, yielding decreased diversity and changes in community structure. However, the specific effect on pediatric oncology patients is not well-studied. The effect of antifungal use is even less understood, having been studied only in mouse models. Because the composition of the gut microbiome is associated with regulation of hematopoiesis, immune function and gastrointestinal integrity, changes within the patient gut can have implications for the clinical management of hematologic malignancies. The pediatric population is particularly challenging because the composition of the microbiome is age dependent, with some of the most pronounced changes occurring in the first three years of life. We investigated how antibiotic and antifungal use shapes the taxonomic composition of the stool microbiome in pediatric patients with leukemia and lymphoma, as inferred from both 16S rRNA and metagenome data. Associations with age, antibiotic use and antifungal use were investigated using multiple analysis methods. In addition, multivariable differential abundance was used to identify and assess specific taxa that were associated with multiple variables. Both antibiotics and antifungals were linked to a general decline in diversity in stool samples, which included a decrease in relative abundance in butyrate producers that play a critical role in host gut physiology (e.g., Faecalibacterium, Anaerostipes, Dorea, Blautia),. Furthermore, antifungal use was associated with a significant increase in relative abundance of opportunistic pathogens. Collectively, these findings have important implications for the treatment of leukemia and lymphoma patients. Butyrate is important for gastrointestinal integrity; it inhibits inflammation, reinforces colonic defense, mucosal immunity. and decreases oxidative stress. The routine use of broad-spectrum anti-infectives in pediatric oncology patients could simultaneously contribute to a decline in gastrointestinal integrity and colonic defense while promoting increases in opportunistic pathogens within the patient gut. Because the gut microbiome has been linked to both short-term clinical outcomes, and longer-lasting health effects, systematic characterization of the gut microbiome in pediatric patients during, and beyond, treatment is warranted.

Faecalibacterium: a bacterial genus with promising human health applications

“…In vaginal-delivered infants, Faecalibacterium levels were lower at the 1-year mark for babies that had received postnatal antibiotics at any point compared to babies that had not (Ainonen et al 2022 ). Another study reported that antibiotic and antifungal treatments diminished Faecalibacterium abundance in children with leukemia (Dunn et al 2022 ); the same result was seen in response to intraveinously administered antibiotics in individuals with multiple myeloma (D’Angelo et al 2022 ).…”

Gut microbiome immaturity and childhood acute lymphoblastic leukaemia

“…For example, the chronological age of participants is a major determinant of gut microbiome maturation and could account for significant discrepancies in the relative abundance of different bacterial taxa between study groups 49 . Similarly, recent antibiotic exposure (depending on the class of the antibacterial agent, duration of exposure and its precise timing relative to specimen collection) can cause transient disturbances in the composition of the gut microbiome 69 , 74 , 79 and has the potential to obfuscate study group differences in the relative abundance of a subset of implicated taxa. However, given that antibiotic-induced dysbiosis and reduction in SCFA-producing taxa in mice and humans are usually reversible within a few weeks of exposure 64 , 65 , antibiotic exposure is unlikely to account for the consistent differences observed across all included studies.…”

Role of the gut microbiota in hematologic cancer

“…One critical factor are medications, such as antibiotics, which can disrupt the balance of the gut microbiota, leading to dysbiosis that may affect cancer treatment outcomes. For example, although antibiotics are commonly administered in hematologic cancer treatment to prevent infections, they can affect bacteria such as Faecalibacterium, Anaerostipes, and Blautia, potentially disrupting the overall gut microbial ecosystem (Dunn et al, 2022;Sochacka-ćwikła et al, 2022).…”