Biology subjects

Le Gall, G.

Publications and source records attributed to Le Gall, G..

11 recordsLinked to original sources

bioRxiv2026

Dietary fibre responses emerge through host-dietary regime interplay: Apple pectin modulates immune reactivity in adult zebrafish

Dietary fibres are rarely consumed independently. Instead, they form part of an overall diet that includes dietary fibres from different sources, in varying amounts and consumed under different feeding patterns. Here, we tested how dietary regimes containing apple pectin, oat {beta}-glucan, or cellulose shaped the host. We analysed gut microbiome composition by 16S rRNA sequencing, measured brain and intestinal SCFA profiles by targeted metabolomics, and assessed immunomodulation by measuring gene expression systemically in the blood and locally in the spleen, as well as intestinal enzyme activity. The dietary intervention was conducted for 12 weeks on adult female and male zebrafish (Danio rerio). Our results show that the gut microbial composition can be relatively stable across different dietary fibre exposure patterns yet still vary significantly between the sexes. Additionally, the effect of sex on the gut microbiome may become more evident when dietary fibres are administered at high dosages, but intermittently. Dietary fibre regimes can alter intestinal short-chain fatty acid profiles more readily than brain profiles, which show a stronger sexually dimorphic response. Interestingly, apple pectin modulated the zebrafish immune response through interactions dependent on the overall regime, tissue, sex, and host immune status. Notably, tissue il1b gene expression differed depending on how apple pectin was administered and the host's physiological state. Collectively, our study emphasises the highly context-specific effects of dietary fibres, shaped by the dynamic interplay between the overall dietary regime and intertwined host factors.

systems biology↗

bioRxiv2024

Gum Arabic (Acacia senegal) enhances reproduction and modulates the microbiota-gut-brain axis of zebrafish in a sex-specific and dosage-dependent manner

Dietary fibres (DFs) constitute a wide range of heterogeneous compounds that resist digestion and have beneficial effects on general health. Gum Arabic (GA) is a tree exudate consisting of 90% arabinogalactan, a polymer of arabinose and galactose sugars with prebiotic properties. As a dietary fibre, GA improves renal function, metabolism, and immune response in humans and animals. However, the underlying mechanisms leading to these health benefits are poorly understood. We supplemented female and male zebrafish (Danio rerio) with two concentrations of GA (6% and 60%) for two weeks. We assessed the effects of GA supplementation on the gut microbiome composition, intestinal and brain metabolic profiles, reproductive fitness, and brain gene expression. We found that GA supplementation resulted in changes to the gut microbiome with a relative increase in Fusobacteria and a relative decrease in Proteobacteria where the beneficial genus Cetobacterium was significantly more abundant after supplementation. GA supplementation increased acetate levels, particularly in the brain, causing a decreased expression of cart1 in the brain of female zebrafish. While GA supplementation increased overall activity in male and female fish, reproductive fitness was negatively affected by GA supplementation in females. Our results suggest that while GA supplementation may have positive effects on metabolic rate and overall activity, it may come at a trade-off with reproductive fitness. Significance StatementDietary fibres, found in plant-based food sources, can improve health. They include natural gums like gum Arabic, a highly sought-after food additive used as a homogeniser. Despite our better understanding of nutrition, a fibre gap is still prevalent in the Western world with efforts being made to incorporate new sources to close this gap and boost well-being. Here, we showed that when gum Arabic was supplemented into the zebrafish diet, it had a beneficial modulatory effect on the microbiota-gut-brain axis and reproductive fitness. Our findings support the benefits of dietary fibres but also link their impact to sexual dimorphism and dosage. This has implications for developing nutrition guidelines for both animals and humans.

systems biology↗

bioRxiv2024

Early life milk diets shape infant gut microbiota: evidence of microbial plasticity in response to breast and formula milk.

In early life, diet plays a key role in shaping the infant microbiota, yet the impact of breast milk and formula on microbial ecosystems at different stages of infant development remains poorly understood. Here, we performed static batch culture experiments using infant faecal samples at ages 1, 12 and 18 months of age, supplemented with either breast milk or formula for 48 hours. We further removed small metabolites (e.g. small carbohydrates, proteins and lipids) from breast and formula milk through dialysis and also added this to the static batch cultures with faecal samples from each infant. Our results show that the one-month-old faecal microbiota exhibited the greatest sensitivity to dietary intervention, with significant changes in microbial composition, metabolites and lipids, particularly in response to formula supplementation. In contrast, the microbiota at 12 months displayed increased stability, while the 18-month-old infant samples were the most resilient to different dietary supplementation. We also observed that triglyceride (TG46:1) was produced in the youngest infant samples but consumed by the older infant microbiota, suggesting a shift in metabolic interactions as the gut microbiota diversifies with age. Metabolite profiles linked to KEGG pathways further indicated the older infants diverse microbiotas had greater functional capacity in comparison to the one-month-old infant, particularly in response to breast milk. Fewer overall metabolic pathways were affected when the infant samples were grown in formula. Collectively, our data underscores the importance of early life diet in shaping microbiota profiles, with more stable microbial dynamics in more mature gut ecosystems, in response to dietary changes which are also associated with downstream functional (i.e. metabolite/lipid) readouts. Notably, the removal of small metabolites from breast milk by dialysis highlighted the potential role of milk lipids in promoting growth of foundational microbiota members like Bifidobacterium. Our data, along with further studies, are required to probe the mechanisms by which specific nutrients, particularly lipids, modulate microbial composition and support infant health during the first 2 years of life.

microbiology↗

bioRxiv2024

Maternal gut Bifidobacterium breve modifies fetal brain metabolism in mice

In recent years, our understanding of the gut microbiomes impact on host physiology and metabolism has grown exponentially. Yet, the specific role of certain microorganisms in regulating gestational health and fetal development remains largely unexplored. During pregnancy, Bifidobacterium represents a key beneficial microbiota genus that provides multiple benefits, including changes in placental development and fetal glycaemia. In this study, using germ-free mice colonized with or without Bifidobacterium breve UCC2003 during pregnancy, we demonstrated that this bacterium is important for controlling fetal brain metabolism. In particular, presence of maternal Bifidobacterium led to reduced levels of ten metabolites (including citrate, 3-hydroxyisobutyrate, and carnitine) in the fetal brain, with concurrent elevated abundance of transporters involved in glucose and branched-chain amino acid uptake. B. breve supplementation was also associated with increased expression of critical metabolic and cellular pathways, including the PI3K-AKT, AMPK, STAT5 and Wnt-{beta}-catenin (including its receptor Frizzled-7) in the fetal brain. Furthermore, maternal-associated Bifidobacterium resulted in HIF-2 protein stabilization and altered a number of https://pubmed.ncbi.nlm.nih.gov/38269505/ genes and proteins involved in cellular growth, axogenesis, and mitochondrial function. These findings highlight that Bifidobacterium breve colonisation of the maternal gut is important for the metabolism and growth of the fetal brain.

developmental biology↗

bioRxiv2022

Cerebrovascular damage caused by the gut microbe-derived uraemic toxin p-cresol sulfate isprevented by blockade of the epidermal growth factor receptor

Circulating levels of the gut microbe/host co-metabolite p-cresol sulfate (pCS) correlate with cerebrovascular event risk in individuals with chronic kidney disease, but whether this relationship is mechanistic is unclear. We hypothesised that pCS would impair function of the blood-brain barrier (BBB), the primary brain-vasculature interface. We report that pCS exposure impairs BBB integrity in human cells in vitro and both acutely and chronically in mice, enhancing tracer extravasation, disrupting barrier-regulating tight junction components and ultimately affecting whole-brain transcriptomic activity. In vitro and in vivo mechanistic studies showed that pCS activated epidermal growth factor receptor (EGFR) signalling, resulting in matrix metalloproteinase mobilisation and BBB damage. Furthermore, blockade of EGFR prevented the permeabilising effects of serum from haemodialysis patients upon cerebromicrovascular endothelia in vitro. Our results define a pathway linking the co- metabolite pCS with BBB damage and suggest targeting the EGFR may mitigate against cerebrovascular damage in CKD.

systems biology↗

bioRxiv2021

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

The gut microbiota plays a central role in regulating host metabolism. While substantial progress has been made in discerning how the microbiota influences host functions post birth and beyond, little is known about how key members of the maternal gut microbiota can influence feto-placental growth. Notably, in pregnant women, Bifidobacterium represents a key beneficial microbiota genus, with levels observed to increase across pregnancy. Here, using germ-free and specific-pathogen-free mice, we demonstrate that the bacterium Bifidobacterium breve UCC2003 modulates maternal body adaptations, placental structure and nutrient transporter capacity, with implications for fetal metabolism and growth. Maternal and placental metabolome were affected by maternal gut microbiota (i.e. acetate, formate and carnitine). Histological analysis of the placenta confirmed that Bifidobacterium modifies placental structure via changes in Igf2P0, Dlk1, Mapk1 and Mapk14 expression. Additionally, B. breve UCC2003, acting through Slc2a1 and Fatp1-4 transporters, was shown to restore fetal glycaemia and fetal growth in association with changes in the fetal hepatic transcriptome. Our work emphasizes the importance of the maternal gut microbiota on feto-placental development and sets a foundation for future research towards the use of probiotics during pregnancy.

physiology↗

bioRxiv2020

Antibiotic-induced disturbances of the gut microbiota result in accelerated breast tumour growth via a mast cell-dependent pathway

The diverse community of commensal microbes that comprise the gut microbiota is known to play an integral role in human health, not least through its ability to regulate host immune responses and metabolic pathways. Alterations to the homeostasis of this community, including through the use of broad-spectrum antibiotics, have already been associated with the progression of several cancers, namely melanoma and liver. The aggressive nature of breast cancer (BrCa), largely due to its ability to metastasize early, has ranked the disease with the second highest mortality rate of all cancers globally. Yet the body of research into the complex relationship between the microbiota and BrCa is still limited. This study found that a depletion of the microbiota, through the administration of antibiotics, significantly increased the rate of primary tumour progression in mouse BrCa models. We show that antibiotic-induced microbiota disturbances lead to changes in behaviour of a relatively obscure tumour-immune cell population: mast cells. We observed increases in tumour stroma-associated mast cells in antibiotic treated animals. Moreover, inhibition of mast cell degranulation, via cromolyn, slowed tumour progression in antibiotic treated animals but not in control animals. Thus, it appears that a perturbed microbiota drives stroma-associated mast cell recruitment and activation, which in turn promotes primary tumour growth through an as yet unknown mechanism. One Sentence Summary: We show that breast cancer progression is accelerated through a unique/novel immune response involving mast cells as a result of an antibiotic induced perturbation of the gut microbiota in a mouse model.

cancer biology↗

bioRxiv2019

Faecal microbiota transplant from aged donor mice into young recipients affects spatial learning and memory

BackgroundThe gut-brain axis and the intestinal microbiota are emerging as key players in health and disease. Shifts in intestinal microbiota composition affect a variety of systems, however, evidence of their direct impact on cognitive functions is still lacking. We tested whether faecal microbiota transplant (FMT) from aged donor mice into young adult recipients affected the hippocampus, an area of the central nervous system (CNS) known to be affected by the ageing process, and related functions. Methods and FindingsYoung adult mice were transplanted with the microbiota from either aged or age-matched donor mice. Following transplantation, characterization of the microbiotas and metabolomics profiles along with a battery of cognitive and behavioural tests were performed. Label-free quantitative proteomics was employed to monitor protein expression in the hippocampus of the recipients. Gut permeability, levels of circulating cytokines and expression of markers of microglia cells were also assessed. FMT from aged donors led to impaired spatial learning and memory in young adult recipients, whereas anxiety, explorative behaviour and locomotor activity remained unaffected. This was paralleled by altered expression of proteins involved in synaptic plasticity and neurotransmission in the hippocampus. Also, a strong reduction of bacteria associated with short-chain fatty acids (SCFAs) production (Lachnospiraceae, Faecalibaculum, and Ruminococcaceae) and disorders of the CNS (Prevotellaceae and Ruminococcaceae) was observed. Finally, microglia cells of the hippocampus fimbria, acquired an ageing-like phenotype, while gut permeability and levels of circulating cytokines remained unaffected. ConclusionsThese results demonstrate a direct effect of the age-associated shifts of the microbiota on protein expression and key functions of the central nervous system. Furthermore, these results additionally highlight the paramount importance of the gut-brain axis in ageing and provide a strong rationale to devise therapies aiming to restore a young-like microbiota to improve cognitive functions in the elderly.

neuroscience↗

bioRxiv2019

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

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 Streptococcus, Escherichia and Enterococcus and increased primary bile acids. In contrast, older mice were dominated by Candidatus Arthromitus, Alistipes and Lachnoclostridium, 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.

microbiology↗

bioRxiv2019

Perturbation of the gut microbiota by antibiotics results in accelerated breast tumour growth and metabolic dysregulation

BackgroundBreast cancer is the second most prevalent cancer worldwide with around 1.7 million new cases diagnosed every year. Whilst prognosis is generally favourable in early stages, this worsens significantly in advanced disease. Therefore, it is pertinent to focus on mitigating factors that may slow growth or progression. Recently, the gut microbiome has been implicated in a wide-range of roles in tumour biology. Through modulation of immunity, the gut microbiota can improve the efficacy of several immunotherapies. However, despite the prevalence of breast cancer, there is still a lack of microbiota studies in this field, including exploring the influence of external microbiome-modulating factors such as antibiotics. We describe herein how disruption of the gut microbiota via antibiotics may be detrimental to patient outcomes through acceleration of tumour growth. ResultsSupplementing animals with a cocktail of antibiotics leads to gut microbiota alterations and is accompanied by significant acceleration of tumour growth. Surprisingly, and distinct from previous microbiome-tumour studies, the mechanism driving these effects do not appear to be due to gross immunological changes. Analysis of intratumoural immune cell populations and cytokine production are not affected by antibiotic administration. Through global tumour transcriptomics, we have uncovered dysregulated gene expression networks relating to protein and lipid metabolism that are correlated with accelerated tumour growth. Fecal metabolomics revealed a reduction of the microbial-derived short-chain fatty acid butyrate that may contribute to accelerated tumour growth. Finally, through use of a routinely administered antibiotic in breast cancer patients, Cephalexin, we have shown that tumour growth is also significantly affected. Metataxanomic sequencing and analysis highlighted significant antibiotic-associated reductions in the butyrate producing genera Odoribacter and Anaeotruncus, and increased abundance of Bacteroides. ConclusionsOur data indicate that perturbation of the microbiota by antibiotics may have negative impacts on breast cancer patient outcomes. This is of importance as antibiotics are regularly prescribed to breast cancer patients undergoing mastectomy or breast reconstruction. We have also shown that the metabolic impact of disruption to the microbiome should be considered alongside the potent immunological effects. We believe our work lays the foundation for improving the use of antibiotics in patients, and with further investigation could potentially inform clinical practice.

cancer biology↗

bioRxiv2018

Association between Apolipoprotein E genotype and the gut microbiome composition in humans and mice

Apolipoprotein E (APOE) genotype is the strongest prevalent genetic risk factor for Alzheimers disease. Numerous studies have provided insights into the pathological mechanisms. However, a comprehensive understanding of the impact of APOE genotype on microflora speciation and metabolism is completely lacking. The aim of this study was to investigate the association between APOE genotype and the gut microbiome composition in human and APOE-targeted replacement (TR, APOE3 and APOE4) transgenic mice. Faecal microbiota amplicon sequencing from matched individuals with different APOE genotypes revealed no significant differences in overall microbiota diversity (alpha or beta diversity) in group-aggregated human APOE genotypes. However, several bacterial taxa showed significantly different relative abundance between APOE genotypes. Notably, we detected an association of Prevotellaceae and Ruminococcaceae and several butyrate-producing genera abundances with APOE genotypes. These findings were confirmed by comparing the gut microbiota of APOE-TR mice. Furthermore, metabolomic analysis of faecal water from murine samples detected significant differences in microbe-associated amino acids and short-chain fatty acids between APOE genotypes. Together, the findings indicate that APOE genotype associated with specific gut microbiome profiles in both humans and in APOE-TR mice. This suggests that the gut microbiome is worth further investigation as a potential therapeutic target to mitigate the deleterious impact of the APOE4 allele on cognitive decline and the prevention and treatment of AD.

genomics↗