https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(05)71142-9.pdf

Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders.

Gut microbiota is an assortment of microorganisms inhabiting the length and width of the mammalian gastrointestinal tract. The composition of this microbial community is host specific, evolving throughout an individual's lifetime and susceptible to both exogenous and endogenous modifications. Recent renewed interest in the structure and function of this "organ" has illuminated its central position in health and disease. The microbiota is intimately involved in numerous aspects of normal host physiology, from nutritional status to behavior and stress response. Additionally, they can be a central or a contributing cause of many diseases, affecting both near and far organ systems. The overall balance in the composition of the gut microbial community, as well as the presence or absence of key species capable of effecting specific responses, is important in ensuring homeostasis or lack thereof at the intestinal mucosa and beyond. The mechanisms through which microbiota exerts its beneficial or detrimental influences remain largely undefined, but include elaboration of signaling molecules and recognition of bacterial epitopes by both intestinal epithelial and mucosal immune cells. The advances in modeling and analysis of gut microbiota will further our knowledge of their role in health and disease, allowing customization of existing and future therapeutic and prophylactic modalities.

Gut Microbiota in Health and Disease

https://www.cell.com/cell/pdf/S0092-8674(05)00451-4.pdf

An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system.

The hygiene hypothesis postulates that an environment with a high incidence of infectious diseases protects against allergic and autoimmune diseases, whereas hygienic surroundings increase the incidence of these disorders This review examines the evidence in support of the hygiene hypothesis and offers a number of mechanisms that could explain the relation between sanitary conditions and susceptibility to allergic and autoimmune diseases

https://www.nejm.org/doi/pdf/10.1056/NEJMra020100

The Effect of Infections on Susceptibility to Autoimmune and Allergic Diseases

An overview of mortality and sequelae of preterm birth from infancy to adulthood.

Background: Improved hygiene has altered early microbial exposure by reducing childhood infections, which has been suggested as a cause for the continuously rising prevalence of atopic diseases. On the basis of both intensity and timing of stimulus, it has been hypothesized that exposure to commensal microflora may represent another key protective modulator of immunity against atopy and subsequent atopic diseases. Objective: We sought to investigate whether differences in early gut microflora precede the later development of atopic sensitization. Methods: Intestinal microflora from 76 infants at high risk of atopic diseases were analyzed at 3 weeks and 3 months of age by using conventional bacterial cultivation and 2 culture-independent methods, gas-liquid chromatography of bacterial cellular fatty acids and quantitative fluorescence in situ hybridization of bacterial cells. Infants evincing at least one positive skin prick reaction at 12 months were grouped as atopic subjects, and those without positive reactions were grouped as nonatopic subjects. Results: Atopic sensitization was observed in 22 (29%) of 76 children. At 3 weeks, the bacterial cellular fatty acid profile in fecal samples differed significantly between infants in whom atopy was and was not developing ( P = .005). By using fluorescence in situ hydridization, atopic subjects had more clostridia (geometric mean [95% confidence interval]: 9.3 × 10 7 [3.8-22.9 × 10 7 ] vs 3.3 × 10 7 [1.8-6.1 × 10 7 ], P = .04) and tended to have fewer bifidobacteria (1.8 × 10 9 [0.4-7.6 × 10 9 ] vs 6.1 × 10 9 [2.5-14.6 × 10 9 ], P = .11) in their stools than nonatopic subjects, resulting in a reduced ratio of bifidobacteria to clostridia ( P = .03). The differences were not detected by bacterial cultivation. Conclusion: Differences in the neonatal gut microflora precede the development of atopy, suggesting a crucial role of the balance of indigenous intestinal bacteria for the maturation of human immunity to a nonatopic mode. (J Allergy Clin Immunol 2001;107:129-34.)

Distinct patterns of neonatal gut microflora in infants in whom atopy was and was not developing.

Background Selective serotonin reuptake inhibitors (SSRIs) have gained wide acceptance in the treatment of mental disorders in pregnant women, but there seems to be an increased risk for neonatal adaptation problems after exposure to SSRIs in late pregnancy. We aimed to investigate the perinatal sequelae of infants exposed to SSRIs during their fetal life and the relationship of these symptoms to the cord blood monoamine and prolactin concentrations. Methods We conducted a prospective, controlled, follow-up study with 20 mothers taking 20 to 40 mg/d of either citalopram or fluoxetine for depression (n= 10) or panic disorder (n = 10) and their infants and 20 matched controls not receiving psychotropic medication for confounding obstetric characteristics. Maternal cord blood and infant citalopram, fluoxetine, and norfluoxetine, cord blood monoamine and metabolite, and prolactin concentrations were measured. The newborns underwent standard clinical examination and specific assessment of serotonergic symptoms during the first 4 days of life and at the ages of 2 weeks and 2 months. Results There was a statistically significant ( P =.008, V = 15, n = 20 for both groups), 4-fold difference in the serotonergic symptom score during the first 4 days of life between the SSRI group and the control group. The SSRI-exposed infants had significantly lower cord blood 5-hydroxyindoleacetic acid (5-HIAA) concentrations ( P =.02, t 31 = 2.57) compared with the control group. A significant inverse correlation ( r s = −0.66, P = .007, n = 15) was seen between the serotonergic symptom score and the umbilical vein 5-HIAA concentrations in the SSRI-exposed but not the control infants. Conclusions Infants exposed to SSRIs during late pregnancy are at increased risk for serotonergic central nervous system adverse effects, and the severity of these symptoms is significantly related to cord blood 5-HIAA levels.

https://jamanetwork.com/journals/jamapsychiatry/articlepdf/207591/YOA20572.pdf

Effects of exposure to selective serotonin reuptake inhibitors during pregnancy on serotonergic symptoms in newborns and cord blood monoamine and prolactin concentrations.

AIM—To evaluate the role of intestinal microflora and early formula feeding in the maturation of humoral immunity in healthy newborn infants.
STUDY DESIGN—Sixty four healthy infants were studied. Faecal colonisation with Bacteroides fragilis group, Bifidobacterium-like, and Lactobacillus-like bacteria was examined at 1, 2, and 6 months of age, and also the number of IgA-secreting, IgM-secreting, and IgG-secreting cells (detected by ELISPOT) at 0, 2, and 6 months of age.
RESULTS—Intestinal colonisation with bacteria from the B fragilis group was more closely associated with maturation of IgA-secreting and IgM-secreting cells than colonisation with the other bacterial genera studied or diet. Infants colonised with B fragilis at 1month of age had more IgA-secreting and IgM-secreting cells/106 mononuclear cells at 2 months of age (geometric mean (95% confidence interval) 1393 (962 to 2018) and 754 (427 to 1332) respectively) than infants not colonised (1015 (826 to 1247) and 394 (304 to 511) respectively); p = 0.04 and p = 0.009 respectively.
CONCLUSIONS—The type of bacteria colonising the intestine of newborns and the timing may determine the immunomodulation of the naive immune system.

https://fn.bmj.com/content/fetalneonatal/83/3/F186.full.pdf

Importance of intestinal colonisation in the maturation of humoral immunity in early infancy: a prospective follow up study of healthy infants aged 0–6 months

Background: According to data from animal and in vitro studies, transforming growth factor-β (TGF-β) has a crucial effect on 2 essential parts of the mucosal immune system: IgA production and oral tolerance induction. Objective: We sought to ascertain whether TGF-β in breast milk is associated with specific IgA production and atopic disease in human subjects. Methods: Forty-seven infants with several atopic family members were followed during their first year of life. The concentrations of TGF-β1 and TGF-β2 in maternal colostrum, mature milk, and the infants' sera were determined. The enzyme-linked immunospot assay was used to assess the infants' specific IgA production in response to β-lactoglobulin, casein, gliadin, and ovalbumin. Results: At 12 months, atopic dermatitis was confirmed in 29 of 47 infants; in 11, atopic disease had begun during exclusive breast-feeding (preweaning onset), whereas in 18 the disease manifested itself after weaning (postweaning onset). The concentrations of both TGF-β1 and TGF-β2 were higher in maternal colostrum, but not in mature milk and infants' serum, in infants with postweaning-onset atopic disease compared with those with preweaning-onset disease ( P = .0008 and P = .015, respectively). The concentration of TGF-β2 was, and that of TGF-β1 tended to be, higher in the colostrum of mothers whose infants had specific IgA-secreting cells at 3 months in response to at least one of the dietary antigens tested compared with those who did not have such cells ( P = .048 and P = .076, respectively). Conclusion: TGF-β in colostrum may prevent the development of atopic disease during exclusive breast-feeding and promote specific IgA production in human subjects. (J Allergy Clin Immunol 1999;1251-7.)

https://www.jacionline.org/article/S0091-6749(99)70021-7/pdf

Transforming growth factor-β in breast milk: A potential regulator of atopic disease at an early age

Objectives. The aims of this prospective nationwide investigation were to establish the birth rate, mortality, and morbidity of extremely low birth weight (ELBW) infants in Finland in 1996 -1997, and to analyze risk factors associated with poor outcome. Participants and Methods. The study population in- cluded all stillborn and live-born ELBW infants (birth weight: 12 hours, the overall incidence of respiratory distress syndrome (RDS) was 76%; of blood culture-positive septicemia, 22%; of IVH grades II through IV, 20%; and of necrotizing enterocolitis (NEC) with bowel perforation, 9%. The rate of IVH grades II through IV and NEC with bowel perforation decreased with increasing gestational age, but the incidence of RDS did not differ significantly between GWs 24 to 29. A total of 5 infants (2%) needed a shunt operation because of posthemorrhagic ventricular dilatation. Two hundred eleven ELBW infants (40% of all and 60% of live-born infants) survived until discharge or to the age corre- sponding with 40 GWs. The oxygen dependency rate at the age corresponding to 36 GWs was 39%, and 9% had ROP stage III-V. Neurological status was considered completely normal in 74% of the surviving infants. The proportions of infants born at 22 to 23, 24 to 25, 26 to 27, and 28 to 29 GWs with at least one disability (ROP, oxygen dependency, or abnormal neurological status) at the age corresponding to 36 GWs were 100%, 62%, 51%, and 45%, respectively. Birth weight <600 g and gesta- tional age <25 GWs were the independent risks for death and short-term disability. The primary risk factor for IVH grades II through IV was RDS. Low 5-minute Apgar scores predicted poor prognosis, ie, death or IVH, and antenatal steroid treatment to mothers with threatening premature labor seemed to protect infants against these. Some differences were found in the mortality rates be- tween the 5 university hospital districts: neonatal mor- tality was significantly lower (25% vs 44%) in one uni- versity hospital area and notably higher (53% vs 34%) in another area. Furthermore, significant differences were also found in morbidity, ie, oxygen dependency and ROP rates. Differences in perinatal (79% vs 45%) and neonatal (59% vs 32%) mortality rates were found between second- ary and tertiary level hospitals. Conclusion. Our study shows that even with modern perinatal technology and care, intrauterine and early deaths of ELBW infants are common. The outcome of infants born at 22 to 23 GWs was unfavorable, but the prognosis improved rapidly with increasing maturity. The clear regional and hospital level differences detected in survival rates and in short-term outcome of ELBW infants emphasizes that the mortality and morbidity rates should be continuously followed and that differ- ences should be evaluated in perinatal audit procedures. However, before the overall outcome of ELBW infants can be evaluated, the results of long-term follow-up and the effects of a premature birth on the family should be taken into consideration. Pediatrics 2001;107(1). URL: http://www.pediatrics.org/cgi/content/full/107/1/e2; pre- maturity, perinatal mortality, neonatal morbidity, ex- tremely low birth weight infants.

https://pediatrics.aappublications.org/content/pediatrics/107/1/e2.full.pdf

Pentti Kero

Papers

Distinct patterns of neonatal gut microflora in infants in whom atopy was and was not developing.

Effects of exposure to selective serotonin reuptake inhibitors during pregnancy on serotonergic symptoms in newborns and cord blood monoamine and prolactin concentrations.

Importance of intestinal colonisation in the maturation of humoral immunity in early infancy: a prospective follow up study of healthy infants aged 0–6 months

Transforming growth factor-β in breast milk: A potential regulator of atopic disease at an early age

A National Short-Term Follow-Up Study of Extremely Low Birth Weight Infants Born in Finland in 1996–1997