The early life microbiota protects neonatal mice from pathological small intestinal epithelial cell shedding

Abstract

<jats:title>Abstract</jats:title><jats:p>The gut microbiota plays a crucial role in regulating and maintaining the epithelial barrier, particularly during early life. Notably, patients with chronic intestinal inflammation have a dysregulated process of renewal and replenishment of the intestinal epithelial cell (IEC) barrier, which is linked to disturbances in the gut microbiota. To date, there are no studies focussed on understanding the impact of inflammatory cell shedding events during the early life developmental window, and which host and microbial factors mediate these responses. Here we sought to determine pathological cell shedding outcomes throughout the postnatal developmental period (day 14, 21, 29 and week 8). Surprisingly neonatal mice (day 14 and 21) were highly refractory to induction of cell shedding after intraperitoneal administration of LPS, with day 29 mice showing strong pathological responses, more similar to those observed in adult mice. These differential responses were not linked to defects in the cellular mechanisms and pathways known to regulate cell shedding responses, although we did observe that neonatal mice had elevated anti-inflammatory (IL-10) responses. Notably, when we profiled microbiota and metabolites from these mice, we observed significant alterations. Neonatal mice had high relative abundances of <jats:italic>Streptococcus</jats:italic>, <jats:italic>Escherichia</jats:italic> and <jats:italic>Enterococcus</jats:italic> and increased primary bile acids. In contrast, older mice were dominated by <jats:italic>Candidatus</jats:italic> Arthromitus, <jats:italic>Alistipes</jats:italic> and <jats:italic>Lachnoclostridium</jats:italic>, and had increased concentrations of SCFAs and methyamines. Faecal microbiota transplant (FMT) and antibiotic studies confirmed the importance of early life gut microbiota in cell shedding responses. In these studies, neonates treated with antibiotics restored LPS-induced small intestinal cell shedding, whereas adult FMT alone had no effect. Our findings further support the importance of the early life window for microbiota-epithelial interactions in the presence of inflammatory stimuli and highlight areas for further investigation to probe underlying mechanisms to drive therapeutic development within the context of chronic inflammatory intestinal diseases.</jats:p>

Host-age prediction from fecal microbiome composition in laboratory mice

“…It has been well established that the microbiomes of humans and animals change significantly in early life phases, e.g. after the weaning transition from milk to solid foods (12,16,17), but the longitudinal changes of the gut microbiome throughout adulthood are less well characterized. In this study, we characterized the gut microbiome of conventionally raised adult male C57BL/6J mice at regular fine-scale intervals for two years, which corresponds to the approximate lifespan of this species (10).…”

“…Longitudinal studies are rarely performed compared to cross-sectional studies, partly due to the convenience of obtaining mice of different ages and accumulative cost of mice maintenance. Cross-sectional studies of the murine gut microbiome are generally focused on the early or later years of the murine life (2,12,13). One such study examined the gut microbiomes of 'young' (24 weeks old), 'middle age' (84 weeks old) (which was not certified by peer review) is the author/funder.…”

Bifidobacterium breve UCC2003 Induces a Distinct Global Transcriptomic Program in Neonatal Murine Intestinal Epithelial Cells

“…However, we did not observe associated global transcriptional inflammatory immune changes that would be expected if this was the case, but rather global changes in barrier function transcripts and pathways. Furthermore, Bifidobacterium has previously been isolated from C57BL/6 mice (including from our mouse colony), and therefore appears to be a resident rodent gut microbiota member, although it is found at varying abundances in different animal units and suppliers ( Grimm et al., 2015 ; Hughes et al., 2020 ). Indeed, one particular study has shown that high levels of resident Bifidobacterium in mice directly correlated with improved immune responses to cancer immunotherapies ( Sivan et al., 2015 ).…”

Maternal gut microbiota Bifidobacterium promotes placental morphogenesis, nutrient transport and fetal growth in mice

“…Colony forming units were counted using a click counter. In SPF animals housed in the same animal facility we have previously shown that Bifidobacterium represents ∼1% of the total gut microbiota [19].…”