Mother-to-Infant Transfer of Bacteriome, Fungome, Virome, and Metabolome in Health and Crohn's Disease

Study Overview
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Brief Summary
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Inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), are caused by the loss of mucosal tolerance towards the commensal microbiota resulting in inflammatory responses. Both CD and UC are difficult to manage clinically, and their incidences are increasing worldwide especially in newly industrialized countries. The etiology of these disorders is multifactorial, influenced by the complex interactions of genes, the immune system, intestinal microbiota, and the external environment. Studies have shown that there is a higher disease transmission rate from mothers with IBD than from fathers. It is well established that IBD is also associated with perturbations of gut microbiota composition. Early childhood is a golden age for microbiota manipulation to prevent disease. Studying microbiota at this golden age also allow us to dissect the development of a faulty microbiota and identify therapeutic targets to reverse it and cure diseases that are already developed. New evidence suggests that the gastrointestinal tract of new-borns becomes colonized with bacteria while in the womb, with the presence of different microbes. The source of these microbes is of continued interest because the initial intestinal colonization is believed to play a crucial role in the priming of the mucosal immune system and may predispose to the development of immune-mediated diseases, such as IBD, later in life. Overall, the microbiome structures in mother-babies across healthy and IBD populations are largely underexplored. A recent study discovered a novel mechanism of vertically transmitted protection of the new-born. The researchers found that bacteria in the mother's intestine during gestation can drive later innate maturation of the neonatal gut in the absence of colonization, through the transfer of specific bacterial metabolites to the foetus and via mother's milk. Study demonstrated that the effects of the gut microbiota on postnatal immune maturation are not simply due to colonization of the new-born after birth. Given the complexity of microbes present in the gestational gut, it will be exciting to learn whether there are other modules of priming induced by distinct microbes and their metabolites. Along these lines, it is tempting to speculate that this transgenerational effect represents a predictive adaptive response whereby mothers prepare the neonates for specific challenges that they are likely to encounter based on gestational environmental cues, not only by microbial colonisation but also by metabolite transfer. Meanwhile, it is unknown regarding whether there are abnormalities in the metabolome as well as its mother-to-infant transfer in IBD. Those results indicate that the metabolomic profiles are altered in IBD mother's breast milk, which may transfer to infants and influence their development and health.

Detailed Description
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Inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), are caused by the loss of mucosal tolerance towards the commensal microbiota resulting in inflammatory responses. Both CD and UC are difficult to manage clinically, and their incidences are increasing worldwide especially in newly industrialized countries. The etiology of these disorders is multifactorial, influenced by the complex interactions of genes, the immune system, intestinal microbiota, and the external environment. Studies have shown that there is a higher disease transmission rate from mothers with IBD than from fathers.[47] It is well established that IBD is also associated with perturbations of gut microbiota composition. Early childhood, when the microbiota is less mature and more malleable, is a golden age for microbiota manipulation to prevent disease. Studying microbiota at this golden age also allow us to dissect the development of a faulty microbiota and identify therapeutic targets to reverse it and cure diseases that are already developed. New evidence suggests that the gastrointestinal tract of new-borns becomes colonized with bacteria while in the womb[1], with the presence of different microbes reported in amniotic fluid[2, 3], umbilical cord blood[4], as well as placental and foetal membranes[5, 6]. The source of these microbes is of continued interest because the initial intestinal colonization is believed to play a crucial role in the priming of the mucosal immune system and may predispose to the development of immune-mediated diseases, such as IBD, later in life[7]. Our pilot study on several mother-baby samples showed that at the order level, Caudovirales predominated in the viral communities of breast milk and meconium with relative abundance above 95%. However, in the viral community of placenta, the Caudovirales only occupied approximately 50%, concomitant with the emergence of eukaryotic viruses such as Ortervirles (average 27.5%) and Herpesvirales (average 9.3%). Overall, the microbiome structures in mother-babies across healthy and IBD populations are largely underexplored. A recent study discovered a novel mechanism of vertically transmitted protection of the new-born. The researchers found that bacteria in the mother's intestine during gestation can drive later innate maturation of the neonatal gut in the absence of colonization, through the transfer of specific bacterial metabolites to the foetus and via mother's milk [8]. Gomez de Agu ero et al. (2016) clearly demonstrated that the effects of the gut microbiota on postnatal immune maturation are not simply due to colonization of the new-born after birth[9]. They show this in a simplified model of gestational monocolonization with E. coli whereby AhR ligands derived from this bacterium drive a distinct early postnatal intestinal developmental program[9]. Given the complexity of microbes present in the gestational gut, it will be exciting to learn whether there are other modules of priming induced by distinct microbes and their metabolites. Along these lines, it is tempting to speculate that this transgenerational effect represents a predictive adaptive response whereby mothers prepare the neonates for specific challenges that they are likely to encounter based on gestational environmental cues, not only by microbial colonisation but also by metabolite transfer. Meanwhile, it is unknown regarding whether there are abnormalities in the metabolome as well as its mother-to-infant transfer in IBD. To address this question, we began with a pilot study on breast milk metablome profiling, employing untargeted metabolomics approach by liquid chromatography-mass spectrometry (LC-MS). The results showed a total of 1,318 Negative-mode features and 1,418 Positive features discriminatory between IBD (4UC, 3 CD) mothers and healthy mothers, indicative of broad metabolic differences between them. Those significantly changed metabolites were involved in arginine and proline metabolism as well as tyrosine metabolism according to pathway enrichment analysis. Those results indicate that the metabolomic profiles are altered in IBD mother's breast milk, which may transfer to infants and influence their development and health.

Official Title
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Mother-to-Infant Transfer of Bacteriome, Fungome, Virome, and Metabolome in Health and Crohn's Disease

Conditions
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Crohn Disease

Intervention / Treatment
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* Other: No intervention procedure


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria for CD patients: To be pregnant in the 1st trimester or planning pregnancy. Diagnosis of Crohn's disease is confirmed by clinical, endoscopic, radiological and histological features All eligible should sign the consent form Inclusion Criteria for Healthy Control: To be pregnant in the 1st trimester or planning pregnancy Subjects without a diagnosis of IBD All eligible should sign the consent form Inclusion Criteria for non-pregnant CD patients Diagnosis of Crohn's disease is confirmed by clinical, endoscopic, radiological and histological features All eligible should sign the consent form Exclusion Criteria for all groups: Co-morbidities, such as type I or type II diabetes, autoimmune diseases, cancer, HIV Inability to give informed consent Probiotics. prebiotics and antibiotics use in the past 3 months
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Crohn's Disease<br>Pregnant CD patients Newborn of pregnant CD patients Father of the newborn Non-pregnant CD women | Other: No intervention procedure<br>* No intervention procedure<br>|
| Healthy Control<br>Pregnant women without CD Newborn of pregnant women without CD Father of the newborn | Other: No intervention procedure<br>* No intervention procedure<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The gut metagenomes at the bacteria species level the among different groups will be determined | Metagenomic sequencing will be used to evaluate the heterogeneities of the bacteria species among different groups. | across two years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The temporal dynamics of the development of the breast milk microbiota in mothers and infants will be determined | Metagenomic sequencing will be used to evaluate the heterogeneities of the bacteria species of breast milk in mothers and infants. | across two years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Crohn Disease, Gut Microbiota, Mother-baby Cohort