Seddon, J. A. | Search bioRxiv

bioRxiv2026

The impact of long-term levofloxacin on the bacterial gut microbiome of young South African children

Disruptions to gut microbial communities in early life can have lasting effects on metabolism, immune function, and resistance to infections. Antibiotics, including levofloxacin, can alter gut microbiota composition, potentially leading to long-term dysbiosis. The long-term impact of levofloxacin on the gut microbiota, especially in young children, remains poorly understood. This study investigated the effects of prolonged levofloxacin therapy over 6 months on gut microbiota in children and the stability of these changes after treatment cessation. This work used samples that were collected as part of a cluster-randomized, double-blind, placebo-controlled trial that investigated the efficacy and safety of levofloxacin for multidrug-resistant (MDR) tuberculosis (TB) preventive treatment in healthy children under the age of five years exposed to MDR-TB in the home. Levofloxacin or placebo were administered daily for 24 weeks following randomization, and stool samples were taken at baseline, and at 24- and 48-week follow-up visits. Bacterial 16S rRNA sequencing was performed on the Illumina MiSeq platform and the changes in bacterial gut microbiota composition and diversity were assessed at different time points and compared between the levofloxacin and placebo arms for different age group. Changes in the functional potential of the gut microbiome were predicted based on the observed taxonomy. Gut microbiota analysis was stratified into three age groups: 0 to <1 year, 1 to <2 years, and 2 to <5 years. The richness and evenness of microbiota were not significantly reduced following 24 weeks of levofloxacin therapy in any group. However, in infants (<1 year), the expected natural microbial diversification was significantly stunted at the end of treatment and remained impaired 24 weeks after treatment completion (48-week visit). Differential abundance testing supported this finding, revealing that a greater number of taxa were negatively impacted in the levofloxacin-treated group. Despite these shifts, beta-diversity analysis indicated no significant differences in overall microbial composition between baseline and follow-up visits after antibiotic treatment. This study showed that the natural diversification of the gut microbiota is stunted in infants and does not recover even at 24 weeks following cessation of treatment. The gut microbiota of 2 to <5-year-old children demonstrated more resilience to the influence of antibiotics.

microbiology↗

bioRxiv2022

Neutrophil degranulation, NETosis and platelet degranulation pathway genes are co-induced in whole blood up to six months before tuberculosis diagnosis

Mycobacterium tuberculosis (M.tb) causes tuberculosis (TB) and remains one of the leading causes of mortality due to an infectious pathogen. Host immune responses have been implicated in driving the progression from infection to severe lung disease. We analyzed longitudinal RNA sequencing (RNAseq) data from the whole blood of 74 TB progressors whose samples were grouped into four six-month intervals preceding diagnosis (the GC6-74 study). We additionally analyzed RNAseq data from an independent cohort of 90 TB patients with positron emission tomography-computed tomography (PET-CT) scan results which were used to categorize them into groups with high and low levels of lung damage (the Catalysis TB Biomarker study). These groups were compared to non-TB controls to obtain a complete whole blood transcriptional profile for individuals spanning from early stages of M.tb infection to TB diagnosis. The results revealed a steady increase in the number of genes that were differentially expressed in progressors at time points closer to diagnosis with 278 genes at 13-18 months, 742 at 7-12 months and 5,131 detected 1-6 months before diagnosis and 9,205 detected in TB patients. A total of 2,144 differentially expressed genes were detected when comparing TB patients with high and low levels of lung damage. There was a large overlap in the genes upregulated in progressors 1-6 months before diagnosis (86%) with those in TB patients. A comprehensive pathway analysis revealed a potent activation of neutrophil and platelet mediated defenses including neutrophil and platelet degranulation, and NET formation at both time points. These pathways were also enriched in TB patients with high levels of lung damage compared to those with low. These findings suggest that neutrophils and platelets play a critical role in TB pathogenesis, and provide details of the timing of specific effector mechanisms that may contribute to TB lung pathology. Author summaryMycobacterium tuberculosis (M.tb) causes tuberculosis (TB) and remains one of the leading causes of mortality due to an infectious pathogen. Human immune responses must be balanced to inhibit disease progression while limiting self-damage, however in defense against M.tb host responses have been implicated in lung damage and in driving progression of M.tb infection to severe lung disease. The identification of immune responses that are activated during the development of TB could provide potential targets for interventions that might suppress disease progression, and possibly limit tissue damage. Here we identify a subset of genes that function in several biological processes that are strongly activated in the late stages of TB development and in TB patients. The proteins encoded by these genes are known to degrade lung tissue and contribute to severe lung disease.

genomics↗