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Necrotizing enterocolitis (NEC) is a leading cause of preterm infant morbidity and mortality. Treatment for NEC is limited and non-targeted, which makes new treatment and prevention strategies critical. Host defense peptides (HDPs) are essential components of the innate immune system and have multifactorial mechanisms in host defense. LL-37 and hBD2 are two HDPs that have been shown in prior literature to protect from neonatal sepsis-induced mortality or adult inflammatory bowel disease, respectively. Therefore, this article sought to understand if these two HDPs could influence NEC severity in murine preclinical models. NEC was induced in P14-16 C57Bl/6 mice and HDPs were provided as a pretreatment or treatment. Both LL-37 and hBD2 resulted in decreased NEC injury scores as a treatment and hBD2 as a pretreatment. Our data suggest LL-37 functions through antimicrobial properties, while hBD2 functions through decreases in inflammation and improvement of intestinal barrier integrity.
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Importance: Providing assisted ventilation during delayed umbilical cord clamping may improve outcomes for extremely preterm infants. Objective: To determine whether assisted ventilation in extremely preterm infants (23 0/7 to 28 6/7 weeks' gestational age [GA]) followed by cord clamping reduces intraventricular hemorrhage (IVH) or early death. Design, Setting, and Participants: This phase 3, 1:1, parallel-stratified randomized clinical trial conducted at 12 perinatal centers across the US and Canada from September 2, 2016, through February 21, 2023, assessed IVH and early death outcomes of extremely preterm infants randomized to receive 120 seconds of assisted ventilation followed by cord clamping vs delayed cord clamping for 30 to 60 seconds with ventilatory assistance afterward. Two analysis cohorts, not breathing well and breathing well, were specified a priori based on assessment of breathing 30 seconds after birth. Intervention: After birth, all infants received stimulation and suctioning if needed. From 30 to 120 seconds, infants randomized to the intervention received continuous positive airway pressure if breathing well or positive-pressure ventilation if not, with cord clamping at 120 seconds. Control infants received 30 to 60 seconds of delayed cord clamping followed by standard resuscitation. Main Outcomes and Measures: The primary outcome was any grade IVH on head ultrasonography or death before day 7. Interpretation by site radiologists was confirmed by independent radiologists, all masked to study group. To estimate the association between study group and outcome, data were analyzed using the stratified Cochran-Mantel-Haenszel test for relative risk (RR), with associations summarized by point estimates and 95% CIs. Results: Of 1110 women who consented to participate, 548 were randomized and delivered infants at GA less than 29 weeks. A total of 570 eligible infants were enrolled (median [IQR] GA, 26.6 [24.9-27.7] weeks; 297 male [52.1%]). Intraventricular hemorrhage or death occurred in 34.9% (97 of 278) of infants in the intervention group and 32.5% (95 of 292) in the control group (adjusted RR, 1.02; 95% CI, 0.81-1.27). In the prespecified not-breathing-well cohort (47.5% [271 of 570]; median [IQR] GA, 26.0 [24.7-27.4] weeks; 152 male [56.1%]), IVH or death occurred in 38.7% (58 of 150) of infants in the intervention group and 43.0% (52 of 121) in the control group (RR, 0.91; 95% CI, 0.68-1.21). There was no evidence of differences in death, severe brain injury, or major morbidities between the intervention and control groups in either breathing cohort. Conclusions and Relevance: This study did not show that providing assisted ventilation before cord clamping in extremely preterm infants reduces IVH or early death. Additional study around the feasibility, safety, and efficacy of assisted ventilation before cord clamping may provide additional insight. Trial Registration: ClinicalTrials.gov Identifier: NCT02742454.
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Lactente Extremamente Prematuro , Clampeamento do Cordão Umbilical , Humanos , Recém-Nascido , Feminino , Masculino , Clampeamento do Cordão Umbilical/métodos , Canadá , Respiração Artificial/métodos , Hemorragia Cerebral Intraventricular/prevenção & controle , Cordão Umbilical , Pressão Positiva Contínua nas Vias Aéreas/métodos , Idade Gestacional , Fatores de Tempo , Estados UnidosRESUMO
Introduction: Paneth cells are critically important to intestinal health, including protecting intestinal stem cells, shaping the intestinal microbiome, and regulating host immunity. Understanding Paneth cell biology in the immature intestine is often modeled in rodents with little information in larger mammals such as sheep. Previous studies have only established the distribution pattern of Paneth cells in healthy adult sheep. Our study aimed to examine the ontogeny, quantification, and localization of Paneth cells in fetal and newborn lambs at different gestational ages and with perinatal transient asphyxia. We hypothesized that ovine Paneth cell distribution at birth resembles the pattern seen in humans (highest concentrations in the ileum) and that ovine Paneth cell density is gestation-dependent. Methods: Intestinal samples were obtained from 126-127 (preterm, with and without perinatal transient asphyxia) and 140-141 (term) days gestation sheep. Samples were quantified per crypt in at least 100 crypts per animal and confirmed as Paneth cells through in immunohistochemistry. Results: Paneth cells had significantly higher density in the ileum compared to the jejunum and were absent in the colon. Discussion: Exposure to perinatal transient asphyxia acutely decreased Paneth cell numbers. These novel data support the possibility of utilizing ovine models for understanding Paneth cell biology in the fetus and neonate.
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For over a century, physicians have witnessed a common enrichment of bifidobacteria in the feces of breast-fed infants that was readily associated with infant health status. Recent advances in bacterial genomics, metagenomics, and glycomics have helped explain the nature of this unique enrichment and enabled the tailored use of probiotic supplementation to restore missing bifidobacterial functions in at-risk infants. This review documents a 20-year span of discoveries that set the stage for the current use of human milk oligosaccharide-consuming bifidobacteria to beneficially colonize, modulate, and protect the intestines of at-risk, human milk-fed, neonates. This review also presents a model for probiotic applications wherein bifidobacterial functions, in the form of colonization and HMO-related catabolic activity in situ, represent measurable metabolic outcomes by which probiotic efficacy can be scored toward improving infant health.
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Microbioma Gastrointestinal , Microbiota , Probióticos , Recém-Nascido , Feminino , Lactente , Humanos , Leite Humano/metabolismo , Bifidobacterium/metabolismo , Fezes/microbiologia , Oligossacarídeos/metabolismoRESUMO
A key aspect of postnatal intestinal adaptation is the establishment of symbiotic relationships with co-evolved gut microbiota. Necrotizing enterocolitis (NEC) is the most severe disease arising from failure in postnatal gut adaptation in premature infants. Although pathological activation of intestinal Toll-like receptors (TLRs) is believed to underpin NEC pathogenesis, the mechanisms are incompletely understood. We postulate that unregulated aberrant TLR activation in NEC arises from a failure in intestinal-specific mechanisms that tamponade TLR signaling (the brakes). In this review, we discussed the human and animal studies that elucidate the developmental mechanisms inhibiting TLR signaling in the postnatal intestine (establishing the brakes). We then evaluate evidence from preclinical models and human studies that point to a defect in the inhibition of TLR signaling underlying NEC. Finally, we provided a framework for the assessment of NEC risk by screening for signatures of TLR signaling and for NEC prevention by TLR-targeted therapy in premature infants.
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Enterocolite Necrosante , Doenças do Recém-Nascido , Lactente , Animais , Recém-Nascido , Humanos , Enterocolite Necrosante/etiologia , Recém-Nascido Prematuro , Receptores Toll-Like , Transdução de SinaisRESUMO
The severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) pandemic has impacted all patient populations including pregnant mothers. There is an incomplete understanding of SARS-CoV-2 pathogenesis and transmission potential at this time and the resultant anxiety has led to variable breastfeeding recommendations for suspected or confirmed mothers with novel coronavirus disease 2019 (COVID-19). Due to the potential concern for transmission of infection from maternal respiratory secretions to the newborn, temporary separation of the maternal-baby dyad, allowing for expressed breast milk to be fed to the infant, was initially recommended but later revised to include breastfeeding by the American Academy of Pediatrics in contrast to international societies, which recommend direct breastfeeding. This separation can have negative health and emotional implications for both mother and baby. Only two publications have reported SARS-CoV-2 in human breast milk but the role of breast milk as a vehicle of transmission of COVID-19 to the newborns still remains unclear and may indeed be providing protective antibodies against SARS-CoV-2 infection even in infected neonates. Other modes of transmission of infection to neonates from infected mothers or any care providers cannot be overemphasized. Symptomatic mothers on hydroxychloroquine can safely breastfeed and no adverse effects were reported in a baby treated with remdesivir in another drug trial. The excretion of sarilumab in human breast milk is unknown at this time. Hence, given the overall safety of breast milk and both short-term and long-term nutritional, immunological, and developmental advantages of breast milk to newborn, breast milk should not be withheld from baby. The setting of maternal care, severity of maternal infection and availability of resources can impact the decision of breastfeeding, the role of shared decision making on breastfeeding between mother and physician needs to be emphasized. We strongly recommend direct breastfeeding with appropriate hygiene precautions unless the maternal or neonatal health condition warrants separation of this dyad. KEY POINTS: · Breastmilk does not appear to play a significant role in transmission of SARS-CoV-2.. · Mother-baby separation has negative health and emotional consequences.. · Mothers with suspected or confirmed COVID-19 can directly breastfeed with appropriate precautions..
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COVID-19 , Complicações Infecciosas na Gravidez , Lactente , Feminino , Gravidez , Recém-Nascido , Humanos , Criança , Aleitamento Materno , SARS-CoV-2 , Pandemias/prevenção & controle , Leite Humano , Mães/psicologia , Transmissão Vertical de Doenças Infecciosas/prevenção & controle , Complicações Infecciosas na Gravidez/prevenção & controle , Complicações Infecciosas na Gravidez/epidemiologiaRESUMO
Antibiotics are administered near-universally to very low birth weight (VLBW) infants after birth for suspected early-onset sepsis (EOS). We previously identified a phenotypic group of VLBW infants, referred to as low-risk for EOS (LRE), whose risk of EOS is low enough to avoid routine antibiotic initiation. In this cohort study, we compared 18 such infants with 30 infants categorized as non-LRE to determine if the lower risk of pathogen transmission at birth is accompanied by differences in microbiome acquisition and development. We did shotgun metagenomic sequencing of 361 fecal samples obtained serially. LRE infants had a higher human-to-bacterial DNA ratio than non-LRE infants in fecal samples on days 1-3 after birth, confirming lower bacterial acquisition among LRE infants. The microbial diversity and composition in samples from days 4-7 differed between the groups with a predominance of Staphylococcus epidermidis in LRE infants and Enterobacteriaceae sp. in non-LRE infants. Compositional differences were congruent with the distribution of virulence factors and antibiotic resistant genes. After the first week, the overall composition was similar, but changes in relative abundance for several taxa with increasing age differed between groups. Of the nine late-onset bacteremia episodes, eight occurred in non-LRE infants. Species isolated from the blood culture was detected in the pre-antibiotic fecal samples of the infant for all episodes, though these species were also found in infants without bacteremia. In conclusion, LRE infants present a distinct pattern of microbiome development that is aligned with their low risk for EOS. Further investigation to determine the impact of these differences on later outcomes such as late-onset bacteremia is warranted.
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Microbioma Gastrointestinal , Recém-Nascido Prematuro , Recém-Nascido , Humanos , Estudos de Coortes , Metagenômica , Antibacterianos/farmacologiaRESUMO
Background and aims: Plasmin in human milk partially hydrolyzes milk proteins within the mammary gland and may enhance the hydrolysis of milk proteins within the infant's stomach. This study examined the effects of extremely preterm (EP)-, very preterm (VP)-, and term-delivery on plasmin activity and the concentrations of plasminogen activators [urokinase-type plasminogen activator (uPA) and tissue-type plasminogen activator (tPA)], plasminogen activator inhibitor type 1 (PAI-1) and the complexes of PAI-1/uPA and PAI-1/tPA in human milk. Materials and methods: Human milk samples were collected from mothers who delivered extremely preterm infants [24-27 weeks gestational age (GA), n = 20], very preterm infants (28-32 weeks GA, n = 12), and term infants (38-39 weeks GA, n = 8) during 2-72 days postnatally. Plasmin activity was determined using fluorometric substrate assay, whereas concentrations of uPA, tPA, PAI-1, the PAI-1/uPA complex and the PAI-1/tPA complex were quantified by ELISA. Results: Plasmin activity, uPA and tPA were detected in all human milk samples, PAI-1 and the PAI-1/uPA complex were present in 42.5 and 32.5% of milk samples, respectively, and the PAI-1/tPA complex was not detected. Plasmin activity was correlated negatively with postnatal age and postmenstrual age (PMA) in the VP group and positively with postnatal age in the term group. uPA and tPA concentrations decreased with increasing postnatal age in both EP and VP groups but did not correlate in the term group. uPA concentration was correlated positively with GA in the VP group and tended to be elevated with increasing GA in the combined three groups. In contrast, tPA concentrations were correlated negatively with GA and PMA in the combined three groups (P < 0.008) and with PMA in the EP and VP groups. PAI-1 concentration tended to be correlated positively with postnatal age in the combined three groups. No correlation was detected with the PAI-1/uPA complex. Conclusion: Premature delivery impacted the plasmin activity and the concentrations of uPA, tPA, and PAI-1 in human milk. Whether these changes in milk plasminogen activators and inhibitors have a role in balancing the proteolytic digestion of premature infants remains to be investigated.
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OBJECTIVES: To compare the impact of two probiotic supplements on fecal microbiota and metabolites, as well as on gut inflammation in human milk-fed preterm infants. METHODS: In this single-center observational cohort study, we assessed the effects of Bifidobacterium longum subsp. infantis or Lactobacillus reuteri supplementation on the infant gut microbiota by 16S rRNA gene sequencing and fecal metabolome by 1 H nuclear magnetic resonance spectroscopy. Fecal calprotectin was measured as a marker of enteric inflammation. Aliquots of human or donor milk provided to each infant were also assessed to determine human milk oligosaccharide (HMO) content. RESULTS: As expected, each probiotic treatment was associated with increased proportions of the respective bacterial taxon. Fecal HMOs were significantly higher in L. reuteri fed babies despite similar HMO content in the milk consumed. Fecal metabolites associated with bifidobacteria fermentation products were significantly increased in B. infantis supplemented infants. Fecal calprotectin was lower in infants receiving B. infantis relative to L. reuteri ( P < 0.01, Wilcoxon rank-sum test) and was negatively associated with the microbial metabolite indole-3-lactate (ILA). CONCLUSIONS: This study demonstrates that supplementing an HMO-catabolizing Bifidobacterium probiotic results in increased microbial metabolism of milk oligosaccharides and reduced intestinal inflammation relative to a noncatabolizing Lactobacillus probiotic in human milk-fed preterm infants. In this context, Bifidobacterium may provide greater benefit in human milk-fed infants via activation of the microbiota-metabolite-immune axis.
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Microbiota , Probióticos , Bifidobacterium , Bifidobacterium longum subspecies infantis/metabolismo , Humanos , Lactente , Recém-Nascido , Recém-Nascido Prematuro , Inflamação , Complexo Antígeno L1 Leucocitário/metabolismo , Oligossacarídeos/metabolismo , RNA Ribossômico 16SRESUMO
OBJECTIVE: Feeding tubes harbor microbial contaminants; studies to date have not explored differences between orogastric (OG) and nasogastric (NG) tube biofilms. We sought to extend a previous analysis by comparing bacterial colonization by location (OG v NG) and by evaluating clinical factors that may affect tube bacterial populations. STUDY DESIGN: The pharyngeal segments of 41 infant feeding tubes (14 OG and 27 NG) from 41 infants were analyzed by next generation 16 S rRNA sequencing on the MiSeq platform. RESULTS: At the phylum level, Proteobacteria had the highest relative abundance of both OG and NG tubes. At the genus/species level, nine taxa differed significantly between OG and NG tubes. Alpha and beta diversity analyses showed significant differences between OG and NG tubes with relatively little contribution from clinical factors. CONCLUSION: The route of feeding tube insertion (oral vs nasal) had a greater impact on bacterial colonization than the assessed clinical factors.
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Nutrição Enteral , Unidades de Terapia Intensiva Neonatal , Lactente , Recém-Nascido , Humanos , Intubação Gastrointestinal , Bactérias/genética , NarizAssuntos
Enterocolite Necrosante , Doenças Fetais , Doenças do Recém-Nascido , Probióticos , Bifidobacterium , Bifidobacterium longum subspecies infantis , Enterocolite Necrosante/epidemiologia , Enterocolite Necrosante/microbiologia , Enterocolite Necrosante/terapia , Feminino , Humanos , Recém-Nascido , Unidades de Terapia Intensiva Neonatal , Pais , Probióticos/uso terapêuticoRESUMO
BACKGROUND: Human milk oligosaccharides (HMOs) are an abundant class of compounds found in human milk and have been linked to the development of the infant, and specifically the brain, immune system, and gut microbiome. OBJECTIVES: Advanced analytical methods were used to obtain relative quantitation of many structures in approximately 2000 samples from over 1000 mothers in urban, semirural, and rural sites across geographically diverse countries. METHODS: LC-MS-based analytical methods were used to profile the compounds with broad structural coverage and quantitative information. The profiles revealed their structural heterogeneity and their potential biological roles. Comparisons of HMO compositions were made between mothers of different age groups, lactation periods, infant sexes, and residing geographical locations. RESULTS: A common behavior found among all sites was a decrease in HMO abundances during lactation until approximately postnatal month 6, where they remained relatively constant. The greatest variations in structural abundances were associated with the presence of α(1,2)-fucosylated species. Genomic analyses of the mothers were not performed; instead, milk was phenotyped according to the abundances of α(1,2)-fucosylated structures. Mothers from the South American sites tended to have higher proportions of phenotypic secretors [mothers with relatively high concentrations of α(1,2)-fucosylated structures] in their populations compared to the rest of the globe, with Bolivia at â¼100% secretors, Peru at â¼97%, Brazil at â¼90%, and Argentina at â¼85%. Conversely, the cohort sampled in Africa manifested the lowest proportion of secretors (South Africa â¼ 63%, the Gambia â¼ 64%, and Malawi â¼ 75%). Furthermore, we compared total abundances of HMOs in secretors compared with nonsecretors and found that nonsecretors have lower abundances of HMOs compared to secretors, regardless of geographical location. We also observed compositional differences of the 50+ most abundant HMOs between milk types and geographical locations. CONCLUSIONS: This study represents the largest structural HMO study to date and reveals the general behavior of HMOs during lactation among different populations.
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Leite Humano , Oligossacarídeos , Aleitamento Materno , Feminino , Humanos , Lactente , Lactação , Malaui , Leite Humano/química , Oligossacarídeos/químicaRESUMO
PURPOSE: The goal of this study was to review the role of human milk in shaping the infant intestinal microbiota and the potential of human milk bioactive molecules to reverse trends of increasing intestinal dysbiosis and dysbiosis-associated diseases. METHODS: This narrative review was based on recent and historic literature. FINDINGS: Human milk immunoglobulins, oligosaccharides, lactoferrin, lysozyme, milk fat globule membranes, and bile salt-stimulating lipase are complex multifunctional bioactive molecules that, among other important functions, shape the composition of the infant intestinal microbiota. IMPLICATIONS: The co-evolution of human milk components and human milk-consuming commensal anaerobes many thousands of years ago resulted in a stable low-diversity infant microbiota. Over the past century, the introduction of antibiotics and modern hygiene practices plus changes in the care of newborns have led to significant alterations in the intestinal microbiota, with associated increases in risk of dysbiosis-associated disease. A better understanding of mechanisms by which human milk shapes the intestinal microbiota of the infant during a vulnerable period of development of the immune system is needed to alter the current trajectory and decrease intestinal dysbiosis and associated diseases.
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Microbioma Gastrointestinal , Microbiota , Disbiose , Humanos , Lactente , Recém-Nascido , Leite Humano , OligossacarídeosRESUMO
BACKGROUND: Recent studies have reported a dysfunctional gut microbiome in breastfed infants. Probiotics have been used in an attempt to restore the gut microbiome; however, colonization has been transient, inconsistent among individuals, or has not positively impacted the host's gut. METHODS: This is a 2-year follow-up study to a randomized controlled trial wherein 7-day-old infants received 1.8 × 1010 colony-forming unit Bifidobacterium longum subsp. infantis (B. infantis) EVC001 (EVC) daily for 21 days or breast milk alone (unsupplemented (UNS)). In the follow-up study, mothers (n = 48) collected infant stool at 4, 6, 8, 10, and 12 months postnatal and completed the health-diet questionnaires. RESULTS: Fecal B. infantis was 2.5-3.5 log units higher at 6-12 months in the EVC group compared with the UNS group (P < 0.01) and this relationship strengthened with the exclusion of infants who consumed infant formula and antibiotics. Infants in the EVC group had significantly higher Bifidobacteriaceae and lower Bacteroidaceae and Lachnospiraceae (P < 0.05). There were no differences in any health conditions between the two groups. CONCLUSIONS: Probiotic supplementation with B. infantis within the first month postnatal, in combination with breast milk, resulted in stable colonization that persisted until at least 1 year postnatal. IMPACT: A dysfunctional gut microbiome in breastfed infants is common in resource-rich nations and associated with an increased risk of immune diseases. Probiotics only transiently exist in the gut without persistent colonization or altering the gut microbiome. This is the first study to show that early probiotic supplementation with B. infantis with breast milk results in stable colonization of B. infantis and improvements to the gut microbiome 1 year postnatal. This study addresses a key gap in the literature whereby probiotics can restore the gut microbiome if biologically selected microorganisms are matched with their specific food in an open ecological niche.
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Microbioma Gastrointestinal , Probióticos , Bifidobacterium longum subspecies infantis , Aleitamento Materno , Fezes/microbiologia , Feminino , Seguimentos , Humanos , Lactente , Leite HumanoRESUMO
Streptococcus salivarius (S. salivarius) K12 supplementation has been found to reduce the risk of recurrent upper respiratory tract infections. Yet, studies have not reported the effect of supplementation on oral S. salivarius K12 levels or the salivary microbiome. This clinical trial was designed to determine how supplementation with S. salivarius K12 influences the oral microbiome. In a randomized, double-blind, placebo-controlled trial, 13 healthy adults received a probiotic powder (PRO) containing Lactobacillus acidophilus, Bifidobacterium lactis, and S. salivarius K12 and 12 healthy adults received a placebo-control powder (CON) (n = 12) for 14 consecutive days. Oral S. salivarius K12 and total bacteria were quantified by qPCR and the overall oral microbiome was measured using 16S rRNA amplicon sequencing. Supplementation significantly increased mean salivary S. salivarius K12 levels by 5 logs compared to baseline for the PRO group (p < 0.0005), which returned to baseline 2 weeks post-supplementation. Compared with the CON group, salivary S. salivarius K12 was 5 logs higher in the PRO group at the end of the supplementation period (p < 0.001). Neither time nor supplementation influenced the overall oral microbiome. Supplementation with a probiotic cocktail containing S. salivarius K12 for two weeks significantly increased levels of salivary S. salivarius K12.
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Suplementos Nutricionais , Voluntários Saudáveis , Probióticos/administração & dosagem , Probióticos/farmacologia , Saliva/microbiologia , Streptococcus salivarius , Adulto , Método Duplo-Cego , Feminino , Humanos , Masculino , Recidiva , Infecções Respiratórias/prevenção & controleRESUMO
This paper describes IEEE P7001, a new draft standard on transparency of autonomous systems. In the paper, we outline the development and structure of the draft standard. We present the rationale for transparency as a measurable, testable property. We outline five stakeholder groups: users, the general public and bystanders, safety certification agencies, incident/accident investigators and lawyers/expert witnesses, and explain the thinking behind the normative definitions of "levels" of transparency for each stakeholder group in P7001. The paper illustrates the application of P7001 through worked examples of both specification and assessment of fictional autonomous systems.
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Intelectins are ancient carbohydrate binding proteins, spanning chordate evolution and implicated in multiple human diseases. Previous GWAS have linked SNPs in ITLN1 (also known as omentin) with susceptibility to Crohn's disease (CD); however, analysis of possible functional significance of SNPs at this locus is lacking. Using the Ensembl database, pairwise linkage disequilibrium (LD) analyses indicated that several disease-associated SNPs at the ITLN1 locus, including SNPs in CD244 and Ly9, were in LD. The alleles comprising the risk haplotype are the major alleles in European (67%), but minor alleles in African superpopulations. Neither ITLN1 mRNA nor protein abundance in intestinal tissue, which we confirm as goblet-cell derived, was altered in the CD samples overall nor when samples were analyzed according to genotype. Moreover, the missense variant V109D does not influence ITLN1 glycan binding to the glycan ß-D-galactofuranose or protein-protein oligomerization. Taken together, our data are an important step in defining the role(s) of the CD-risk haplotype by determining that risk is unlikely to be due to changes in ITLN1 carbohydrate recognition, protein oligomerization, or expression levels in intestinal mucosa. Our findings suggest that the relationship between the genomic data and disease arises from changes in CD244 or Ly9 biology, differences in ITLN1 expression in other tissues, or an alteration in ITLN1 interaction with other proteins.
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Citocinas/genética , Trato Gastrointestinal/metabolismo , Regulação da Expressão Gênica , Variação Genética , Lectinas/genética , Alelos , Doença de Crohn/genética , Citocinas/química , Suscetibilidade a Doenças , Proteínas Ligadas por GPI/química , Proteínas Ligadas por GPI/genética , Loci Gênicos , Humanos , Lectinas/química , Especificidade de Órgãos/genéticaRESUMO
Immune-microbe interactions early in life influence the risk of allergies, asthma, and other inflammatory diseases. Breastfeeding guides healthier immune-microbe relationships by providing nutrients to specialized microbes that in turn benefit the host's immune system. Such bacteria have co-evolved with humans but are now increasingly rare in modern societies. Here we show that a lack of bifidobacteria, and in particular depletion of genes required for human milk oligosaccharide (HMO) utilization from the metagenome, is associated with systemic inflammation and immune dysregulation early in life. In breastfed infants given Bifidobacterium infantis EVC001, which expresses all HMO-utilization genes, intestinal T helper 2 (Th2) and Th17 cytokines were silenced and interferon ß (IFNß) was induced. Fecal water from EVC001-supplemented infants contains abundant indolelactate and B. infantis-derived indole-3-lactic acid (ILA) upregulated immunoregulatory galectin-1 in Th2 and Th17 cells during polarization, providing a functional link between beneficial microbes and immunoregulation during the first months of life.