Natural Pig Plasma Immunoglobulins Have Anti-Bacterial Effects: Potential for Use as Feed Supplement for Treatment of Intestinal Infections in Pigs

There is an increasing demand for non-antibiotics solutions to control infectious disease in intensive pig production. Here, one such alternative, namely pig antibodies purified from slaughterhouse blood was investigated in order to elucidate its potential usability to control post-weaning diarrhoea (PWD), which is one of the top indications for antibiotics usage in the pig production. A very cost-efficient and rapid one-step expanded bed adsorption (EBA) chromatography procedure was used to purify pig immunoglobulin G from slaughterhouse pig plasma (more than 100 litres), resulting in >85% pure pig IgG (ppIgG). The ppIgG thus comprised natural pig immunoglobulins and was subsequently shown to contain activity towards four pig-relevant bacterial strains (three different types of Escherichia coli and one type of Salmonella enterica) but not towards a fish pathogen (Yersinia ruckeri), and was demonstrated to inhibit the binding of the four pig relevant bacteria to a pig intestinal cell line (IPEC-J2). Finally it was demonstrated in an in vivo weaning piglet model for intestinal colonization with an E. coli F4+ challenge strain that ppIgG given in the feed significantly reduced shedding of the challenge strain, reduced the proportion of the bacterial family Enterobacteriaceae, increased the proportion of families Enterococcoceae and Streptococcaceae and generally increased ileal microbiota diversity. Conclusively, our data support the idea that natural IgG directly purified from pig plasma and given as a feed supplement can be used in modern swine production as an efficient and cost-effective means for reducing both occurrence of PWD and antibiotics usage and with a potential for the prevention and treatment of other intestinal infectious diseases even if the causative agent might not be known

Enabling Passive Immunization as an Alternative to Antibiotics for Controlling Enteric Infections in Production Animals

Enteric infections cause major problems in most intensive animal production sectors, including poultry, pigs and cattle, leading to disease, reduced production and compromised welfare. In addition some of these infections are zoonotic, and they are to a large extent responsible for the continued massive use of antibiotics in food animals. Thus there is a pressing need for economically feasible, efficient, non-antibiotics based means for controlling the problem. Passive immunization has been known for decades as an efficient way of endowing humans or animals with short-term (weeks) immunity. To control enteric infections by passive immunization a bolus of immunoglobulin may simply be administered orally. For this to work, large amounts of active immunoglobulins are needed. To be a real alternative to antibiotics the price of the immunoglobulin product needs to be low. We combined an efficient and mild high-capacity method for extracting immunoglobulins directly from raw materials like milk, whey and blood plasma with a novel method for stabilizing activity. In a first experiment a total of 15 kg unstabilized bovine immunoglobulin was purified from whey (35.000 liters) and administered to colostrum-deprived calves (225-300 g pr calf during the first 24 hours after birth). No difference in resulting immunoglobulin serum concentration, weight gain or disease frequency were seen in this group of calves compared to a control group given full access to high-quality colostrum. The effect of orally administered bovine immunoglobulin is currently being tested in a calf herd with persistent diarrhea problems. Furthermore, it was shown in a Campylobacter challenge model in chickens that caecal and faecal counts of Campylobacter were between 0.5 and 1.0 logs lower in birds when given 200 mg avian immunoglobulins orally together with the challenge (at day 21 of age) compared to a placebo group receiving immunoglobulin with no reactivity against Campylobacter. While clearly preliminary, these results show that immunoglobulin can be produced from renewable sources at a price enabling passive immunization as a viable strategy for control of infectious diseases in the intensive animal production, with the potential to significantly reduce antibiotics consumption

A nationwide register-based cohort study examined the association between preeclampsia in mothers and the risk of kidney disease in their offspring

Introduction: Women with preeclampsia often deliver preterm (under 37 weeks of gestation). Preterm birth is associated with an increased risk of offspring kidney disease, but whether preeclampsia is independently associated with kidney disease risk is unknown. Here, we conducted a register-based cohort study to explore associations between maternal preeclampsia and offspring kidney disease after accounting for preterm birth. Methods: Using Cox regression, we estimated hazard ratios (HRs) comparing kidney disease rates, overall and by subtype, in offspring with and without exposure to maternal preeclampsia. Results: The study included 2,288,589 persons born in Denmark 1978-2017 of whom 63,191 were exposed to preeclampsia; 37,782 individuals developed kidney disease during 43,137,193 person-years of follow-up. Offspring exposed to preeclampsia and born at term (37 or more weeks’ gestation) were 26% more likely than offspring born at term but not exposed to preeclampsia to develop kidney disease in infancy (HR 1.26, 95% confidence interval [1.09-1.46]), and had increased rates of all kidney disease subtypes except acute kidney disease after one year of age (HR range 1.11 to 1.88). Associations between term preeclampsia and offspring chronic, unspecified, and diabetic kidney disease were strongest after 25 years of age (HRs 1.36, 1.70 and 2.85, respectively). Conversely, there was little evidence that exposure to preeclampsia with preterm delivery was associated with increased rates of offspring kidney disease beyond the first year of life (under 1 year: 1.41, [1.05-1.90]; one year or more: 0.94, [ 0.79- 1.11]). Conclusions: Associations of maternal term preeclampsia with offspring kidney disease hint at underlying mechanisms different from those potentially explaining established associations with preterm birth.</p

Patterns of Antihypertensive Medication Use in the First 2 Years Post Partum.

IMPORTANCE: Women who had a hypertensive disorder of pregnancy (HDP) have a well-documented risk of chronic hypertension within a few years of delivery, but management of postpartum hypertension among these women remains inconsistent. OBJECTIVE: To assess the incidence of initiation of antihypertensive medication use in the first 2 years after delivery by HDP status and antenatal antihypertensive medication use. DESIGN, SETTING, AND PARTICIPANTS: This Danish register-based cohort study used data from women with at least 1 pregnancy lasting 20 or more gestational weeks (only the first pregnancy in the period was considered) who delivered from January 1, 1995, to December 31, 2018. Statistical analysis was conducted from October 2022 to September 2023. EXPOSURE: Hypertensive disorders of pregnancy. MAIN OUTCOMES AND MEASURES: Cumulative incidences and hazard ratios of initiating antihypertensive medication use within 2 years post partum (5 postpartum time intervals) by HDP status and antenatal medication use. RESULTS: The cohort included 784 782 women, of whom 36 900 (4.7% [95% CI, 4.7%-4.8%]) had an HDP (HDP: median age at delivery, 29.1 years [IQR, 26.1-32.7 years]; no HDP: median age at delivery, 29.0 years [IQR, 25.9-32.3 years]). The 2-year cumulative incidence of initiating postpartum antihypertensive treatment ranged from 1.8% (95% CI, 1.8%-1.8%) among women who had not had HDPs to 44.1% (95% CI, 40.0%-48.2%) among women with severe preeclampsia who required antihypertensive medication during pregnancy. Most women who required postpartum antihypertensive medication after an HDP initiated use within 3 months of delivery (severe preeclampsia, 86.6% [95% CI, 84.6%-89.4%]; preeclampsia, 75.3% [95% CI, 73.8%-76.2%]; and gestational hypertension, 75.1% [95% CI, 72.9%-77.1%]). However, 13.4% (95% CI, 11.9%-14.1%) of women with severe preeclampsia, 24.7.% (95% CI, 24.0%-26.0%) of women with preeclampsia, 24.9% (95% CI, 22.5%-27.5%) of women with gestational hypertension, and 76.7% (95% CI, 76.3%-77.1%) of those without an HDP first filled a prescription for antihypertensive medication more than 3 months after delivery. Women with gestational hypertension had the highest rate of initiating medication after more than 1 year post partum, with 11.6% (95% CI, 10.0%-13.2%) starting treatment after this period. Among women who filled a prescription in the first 3 months post partum, up to 55.9% (95% CI, 46.2%-66.1%) required further prescriptions more than 3 months post partum, depending on HDP status and antenatal medication use. CONCLUSIONS AND RELEVANCE: In this cohort study of postpartum women, the incidence of initiation of postnatal antihypertensive medication use varied by HDP status, HDP severity, and antenatal antihypertensive medication use. Up to 24.9% of women initiated antihypertensive medication use more than 3 months after an HDP, with up to 11.6% initiating treatment after 1 year. Routine postpartum blood pressure monitoring might prevent diagnostic delays in initiation of antihypertensive medication use and improve cardiovascular disease prevention among women

The potential for immunoglobulins and host defense peptides (HDPs) to reduce the use of antibiotics in animal production

Abstract Innate defense mechanisms are aimed at quickly containing and removing infectious microorganisms and involve local stromal and immune cell activation, neutrophil recruitment and activation and the induction of host defense peptides (defensins and cathelicidins), acute phase proteins and complement activation. As an alternative to antibiotics, innate immune mechanisms are highly relevant as they offer rapid general ways to, at least partially, protect against infections and enable the build-up of a sufficient adaptive immune response. This review describes two classes of promising alternatives to antibiotics based on components of the innate host defense. First we describe immunoglobulins applied to mimic the way in which they work in the newborn as locally acting broadly active defense molecules enforcing innate immunity barriers. Secondly, the potential of host defense peptides with different modes of action, used directly, induced in situ or used as vaccine adjuvants is described

Boganmeldelser

Book review

Third-Trimester Cardiovascular Function and Risk of Hypertensive Disorders of Pregnancy

Background: Whether cardiovascular dysfunction is associated with preeclampsia in women without fetal growth restriction (FGR) is unclear. Our objective was to investigate associations between third‐trimester cardiac output (CO) and systemic vascular resistance and risk of hypertensive disorders of pregnancy in women with and without FGR. Methods and Results: A case–cohort study in 906 pregnant women in Denmark with repeated third‐trimester cardiac function assessments was performed using the Ultrasound Cardiac Output Monitor 1A. Using Cox regression, we compared rates of hypertensive disorders of pregnancy in women with low, normal, and high CO and normal and high systemic vascular resistance, by FGR status and gestational age, and evaluated associations between a third‐trimester drop in CO or increase in systemic vascular resistance and preeclampsia risk in women without FGR. The analysis included 249 women with preeclampsia (42 with FGR) and 119 women with gestational hypertension. Low CO was strongly associated with preeclampsia at 75th percentile and preeclampsia in women without FGR (odds ratio, 1.91 [95% CI, 0.84–4.36]). High systemic vascular resistance was strongly associated with increased rates of all forms of hypertensive disorders of pregnancy. Conclusions: Low CO is associated with preeclampsia risk in women with and without FGR, particularly before 37 weeks. Repeated measurements of third‐trimester cardiovascular function might identify women without FGR for monitoring for preeclampsia, but this result needs to be confirmed in other studies.publishedVersio

L-Cell Differentiation Is Induced by Bile Acids Through GPBAR1 and Paracrine GLP-1 and Serotonin Signaling.

Glucagon-like peptide 1 (GLP-1) mimetics are effective drugs for treatment of type 2 diabetes, and there is consequently extensive interest in increasing endogenous GLP-1 secretion and L-cell abundance. Here we identify G-protein-coupled bile acid receptor 1 (GPBAR1) as a selective regulator of intestinal L-cell differentiation. Lithocholic acid and the synthetic GPBAR1 agonist, L3740, selectively increased L-cell density in mouse and human intestinal organoids and elevated GLP-1 secretory capacity. L3740 induced expression of Gcg and transcription factors Ngn3 and NeuroD1 L3740 also increased the L-cell number and GLP-1 levels and improved glucose tolerance in vivo. Further mechanistic examination revealed that the effect of L3740 on L cells required intact GLP-1 receptor and serotonin 5-hydroxytryptamine receptor 4 (5-HT4) signaling. Importantly, serotonin signaling through 5-HT4 mimicked the effects of L3740, acting downstream of GLP-1. Thus, GPBAR1 agonists and other powerful GLP-1 secretagogues facilitate L-cell differentiation through a paracrine GLP-1-dependent and serotonin-mediated mechanism.Wellcome Trust (106262/Z/14/Z, 106263/Z/14/Z) UK Medical Research Council (MRC_MC_UU_12012/