Rat microbial biogeography and age-dependent lactic acid bacteria in healthy lungs

lab animal Article https://doi.org/10.1038/s41684-023-01322-x Rat microbial biogeography and age-dependent lactic acid bacteria in healthy lungs Check for updates 1,2,3 1,2,3 1,3 1,3 Lan Zhao    , Christine M. Cunningham , Adam M. Andruska , Katharina Schimmel    , Md Khadem Ali1,3, Dongeon Kim1,2,3, Shenbiao Gu1,2,3, Jason L. Chang    1,2,3, Edda Spiekerkoetter1,3 & Mark R. Nicolls    1,2,3 The laboratory rat emerges as a useful tool for studying the interaction between the host and its microbiome. To advance principles relevant to the human microbiome, we systematically investigated and defined the multitissue microbial biogeography of healthy Fischer 344 rats across their lifespan. Microbial community profiling data were extracted and integrated with host transcriptomic data from the Sequencing Quality Control consortium. Unsupervised machine learning, correlation, taxonomic diversity and abundance analyses were performed to determine and characterize the rat microbial biogeography and identify four intertissue microbial heterogeneity patterns (P1–P4). We found that the 11 body habitats harbored a greater diversity of microbes than previously suspected. Lactic acid bacteria (LAB) abundance progressively declined in lungs from breastfed newborn to adolescence/adult, and was below detectable levels in elderly rats. Bioinformatics analyses indicate that the abundance of LAB may be modulated by the lung–immune axis. The presence and levels of LAB in lungs were further evaluated by PCR in two validation datasets. The lung, testes, thymus, kidney, adrenal and muscle niches were found to have age-dependent alterations in microbial abundance. The 357 microbial signatures were positively correlated with host genes in cell proliferation (P1), DNA damage repair (P2) and DNA transcription (P3). Our study established a link between the metabolic properties of LAB with lung microbiota maturation and development. Breastfeeding and environmental exposure influence microbiome composition and host health and longevity. The inferred rat microbial biogeography and pattern-specific microbial signatures could be useful for microbiome therapeutic approaches to human health and life quality enhancement. The laboratory rat has been widely used and well examined as a model in a variety of biomedical fields, from cardiovascular diseases to cancer1. Recent evidence from the Human Microbiome Project2 and The Cancer Genome Atlas pan-cancer microbiome projects3,4 suggests that different body sites and disease status feature distinct microbial communities, which have essential roles in human physiology, health and disease. In this Article, we examine the spatial and longitudinal structures of the microbial community in various body compartments and across different life-history stages, to characterize the microbiota landscape of Fischer 344 (F344) rats, with a view to help advance human microbiome research. The F344 is an inbred laboratory strain of rats that is frequently used in aging, cancer and toxicity studies5. Throughout the natural lifespan of F344 rats, 2–104 weeks would be equivalent to 1–3 months to 70–80 years in humans6. In F344 male and female rats, weaning normally occurs at week 3 of age, with sexual maturity by week 7 of age. Thus, our microbial discovery cohort, which was based on the Sequencing Quality Control (SEQC) data7, consecutively constitutes four major life-history stages of rats: newborns (2 weeks old), adolescents (6 weeks old), adults (21 weeks old) and seniors (104 weeks old). The Biology of Aging Program from the National Institutes of Health has used multiple mammalian and nonmammalian model systems, including F344 rats, to investigate genetics and 1 Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, Stanford, CA, USA. 2VA Palo Alto Health Care System, Palo Alto, CA, USA. 3Vera Moulton Wall Center for Pulmonary Vascular Disease, Stanford, CA, USA. e-mail: ; Lab Animal | Volume 53 | February 2024 | 43–55 43 Article https://doi.org/10.1038/s41684-023-01322-x other aging-related degenerative changes; however, the contribution of microbes in these processes in F344 rats is still unknown. In mammals, microbial colonization starts in utero and extends throughout the lifespan, particularly in newborn infants who experience rapid microbial community changes. Human placenta harbors a unique low-abundance microbiome composed of commensal bacteria such as Escherichia coli, Prevotella tannerae and Neisseria spp8. Maternal– fetal transmission of microbes has taken place long before birth9. Newborns are then exposed to microbes from birth, during breastfeeding and through interactions with their surrounding environments that colonize the newborn’s skin10, oral cavity11, gut12, respiratory tract13 and other mucosal surfaces14. For example, the neonatal skin microbiome is dynamic, site specific and varies from individual to individual10. Neonatal oral microbiota is dominated by Streptococcus within the Firmicutes phylum11. Bifidobacterium and Lactobacillus spp. are among the first colonizers of the gastrointestinal (GI) tract, representing the pioneer microbial communities in the newborn’s gut12. The replacement of breast milk or infant formula with solid foods greatly changes the infant’s microbial composition to resemble an adult-like gut microbiota15. Each microbial niche in the body tends to develop and mature both independently and cooperatively, beginning in the first stages of life13. Human microbiomes, particularly gut microbiomes, remain stable once established during adulthood16. Later in life, elderly individuals are characterized by decreased microbial diversity and shifts in community structure17. For laboratory neonatal rodent models, which are more exposed to fecal and environmental contaminants than humans18, limited studies have shown that Enterobacteriaceae and Lactobacillus are among the most dominant bacteria in newborn mice and rats gut microbiota19,20. Similar to studies carried out in humans, adult rodents are typically selected because their body microbial community is more stable. Translocation of indigenous microbes, such as Enterobacteriaceae, Lactobacillus and Staphylococcus19, from the GI tract to other distant organs via systemic circulation is common in humans and rats19,21. Furthermore, microbial bidirectional interactions across multiple organs, including (but not limited to) the gut–brain, lung–brain, gut–liver and gut–lung axes, are important for shaping immune responses and cross-niche microbial interactions22–26. The axes can be disrupted by dietary components and the host’s health conditions. For example, in a rat maternal separation model, Donoso et al.22 found that maternal separation-induced behavioral despair substantially correlated with gut microbiota changes. A dietary intervention with polyphenols can not only alter gut microbiota composition, but also reverse depressive-like behavior (...truncated)