Maturation of the Human Intestinal Immune System Occurs Early in Fetal Development

Stras, Stephanie; Werner, Lael; Toothaker, Jessica; Olaloye, Oluwabunmi; Oldham, Austin; McCourt, Collin C.; Lee, Yu Nee; Rechavi, Erez; Shouval, Dror S.; Konnikova, Liza

doi:10.1016/j.devcel.2019.09.008

Cited by 88 publications

(102 citation statements)

References 65 publications

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“…The immune system of newborn animals is generally considered to be immature, which is closely related to a series of early diseases [1][2][3][4]. For instance, the immaturity of the intestinal immune system is regarded as one of the most important reasons for early-life diarrhea and early-weaning stress in mammals [5], and it has been confirmed that the development and maturation of the mammal intestinal immune system occur in infancy, even in the fetal period [6][7][8]. Hence, promoting the maturation of the intestinal immune system in the early-life period is of great significance for the improvement of growth, development, and disease resistance of neonatal mammals.…”

Section: Introductionmentioning

confidence: 99%

Early-Life Intervention Using Fecal Microbiota Combined with Probiotics Promotes Gut Microbiota Maturation, Regulates Immune System Development, and Alleviates Weaning Stress in Piglets

Xiang

Pan

et al. 2020

IJMS

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Previous studies have suggested that immune system development and weaning stress are closely related to the maturation of gut microbiota. The early-life period is a "window of opportunity" for microbial colonization, which potentially has a critical impact on the development of the immune system. Fecal microbiota transplantation (FMT) and probiotics are often used to regulate gut microbial colonization. This study aims to test whether early intervention with FMT using fecal microbiota from gestation sows combined with Clostridium butyricum and Saccharomyces boulardii (FMT-CS) administration could promote the maturation of gut microbiota and development of immune system in piglets. Piglets were assigned to control (n = 84) and FMT-CS treatment (n = 106), which were treated with placebo and bacterial suspension during the first three days after birth, respectively. By 16S rRNA gene sequencing, we found that FMT-CS increased the α-diversity and reduced the unweighted UniFrac distances of the OTU community. Besides, FMT-CS increased the relative abundance of beneficial bacteria, while decreasing that of opportunistic pathogens. FMT-CS also enhanced the relative abundance of genes related to cofactors and vitamin, energy, and amino acid metabolisms during the early-life period. ELISA analysis revealed that FMT-CS gave rise to the plasma concentrations of IL-23, IL-17, and IL-22, as well as the plasma levels of anti-M.hyo and anti-PCV2 antibodies. Furthermore, the FMT-CS-treated piglets showed decreases in inflammation levels and oxidative stress injury, and improvement of intestinal barrier function after weaning as well. Taken together, our results suggest that early-life intervention with FMT-CS could promote the development of innate and adaptive immune system and vaccine efficacy, and subsequently alleviate weaning stress through promoting the maturation of gut microbiota in piglets.

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Section: Introductionmentioning

confidence: 99%

Early-Life Intervention Using Fecal Microbiota Combined with Probiotics Promotes Gut Microbiota Maturation, Regulates Immune System Development, and Alleviates Weaning Stress in Piglets

Xiang

Pan

et al. 2020

IJMS

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“…In this, the experimental platform is similar to other examples of development of human tissues (lung, skin and liver) subcutaneously transplanted into SCID mice (Gaska and Ploss, 2015;Wahl et al, 2019). Furthermore, we have shown that many human innate and adaptive components of immune system, which have been shown to be already active in fetal gut at the time of transplantation (Rechavi et al, 2015;Li et al, 2018;Li et al, 2019;Schreurs et al, 2019;Stras et al, 2019), are present and active in the mature xenograft (Bruckner et al, 2019;Goldberg et al, 2019).…”

Section: Ibdmentioning

confidence: 74%

NF-kappa-B activation unveils the presence of inflammatory hotspots in human gut xenografts

Nissim-Eliraz

Nir

Marsiano

et al. 2020

Preprint

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The single-epithelial cell layer of the gut mucosa serves as an essential barrier between the host and luminal microflora and plays a major role in innate immunity against invading pathogens. Nuclear factor kB (NF-κB), a central component of the cellular signaling machinery, regulates immune response and inflammation. NF-κB proteins are activated by signaling pathways downstream to microbial recognition receptors and cytokines receptors. Highly regulated NF-κB activity in intestinal epithelial cells (IEC) is essential for normal gut homeostasis; dysregulated activity has been linked to a number of disease states, including inflammatory bowel diseases (IBD) such as Crohn’s Disease (CD). Our aim was to visualize and quantify spatial and temporal dynamics of NF-κB activity in steady state and inflamed human gut. Lentivirus technology was used to transduce the IEC of human gut xenografts in SCID mice with a NF-κB luminescence reporter system. NF-κB signaling was visualized and quantified using low resolution, intravital imaging of the whole body and high resolution, immunofluorescence microscopic imaging of the tissues. We show that NF-κB is activated in select subset of IEC with low “leaky” NF-κB activity. These unique inflammatory epithelial cells are clustered in the gut into discrete hotspots of NF-κB activity that are visible in steady state and selectively activated by systemic LPS and human TNFα or luminal bacteria. The presence of inflammatory hotspots in the normal and inflamed gut might explain the patchy mucosal lesions characterizing CD and thus could have important implications for diagnosis and therapy.

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“…Britanova et al reported a decrease in TCR repertoire diversity with age; nevertheless, the youngest subject in that study was 6 years of age, and most participants were adult (45). We have recently reported that the intestinal B and T cell receptor repertoire among infants is diverse, similar to pediatric adolescent subjects (46). Although we did not assess repertoire of circulating blood-borne lymphocytes, we can speculate it is also diverse in the first year of life.…”

Section: Discussionmentioning

confidence: 87%

Alterations in T and B Cell Receptor Repertoires Patterns in Patients With IL10 Signaling Defects and History of Infantile-Onset IBD

et al. 2020

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Patients with loss-of-function mutations in IL10 or IL10 receptor (IL10R) genes develop severe, medical-refractory, infantile-onset inflammatory bowel disease (IBD). We have previously reported significant alterations in innate and adaptive immune responses in these patients. Next generation sequencing platforms enable a comprehensive assessment of T cell receptor (TCR) and B cell receptor (BCR) repertoire patterns. We aimed to characterize TCR and BCR features in peripheral blood of patients with deleterious IL10 signaling defects. DNA was isolated from blood of seven patients with IL10R mutations and one with an IL10 mutation, along with eight controls, and subjected to next generation sequencing of TRB and IgH loci. A significant increase in clonality was observed in both TCR and BCR repertoires in circulating lymphocytes of IL10/IL10R-deficient patients, but to a much greater extent in T cells. Furthermore, short CDR3β length and altered hydrophobicity were demonstrated in T cells of patients, but not in B cells, secondary to lower rates of insertions of nucleotides, but not deletions, at the V-, D-, or J-junctions. We were unable to observe specific T or B clones that were limited only to the patients or among controls. Moreover, the expanded T cells clones were unique to each patient. In conclusion, next generation sequencing of the TCR and BCR is a powerful tool for characterizing the adaptive immune cell phenotype and function in immune-mediated disorders. The oligoclonality observed among IL10/IL10R-deficient patients may suggest specialization of unique clones that

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Maturation of the Human Intestinal Immune System Occurs Early in Fetal Development

Cited by 88 publications

References 65 publications

Early-Life Intervention Using Fecal Microbiota Combined with Probiotics Promotes Gut Microbiota Maturation, Regulates Immune System Development, and Alleviates Weaning Stress in Piglets

Early-Life Intervention Using Fecal Microbiota Combined with Probiotics Promotes Gut Microbiota Maturation, Regulates Immune System Development, and Alleviates Weaning Stress in Piglets

NF-kappa-B activation unveils the presence of inflammatory hotspots in human gut xenografts

Alterations in T and B Cell Receptor Repertoires Patterns in Patients With IL10 Signaling Defects and History of Infantile-Onset IBD

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