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Raw Cow's Milk and Its Protective Effect on Allergies and Asthma.
Sozańska, B
Nutrients. 2019;11(2)
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In the last decades, a significant increase in the prevalence of allergic diseases and asthma has been observed. Living on a farm can reduce the risk of allergen sensitisation and allergic diseases in children. Most proposed explanations have been based on variations in the “hygiene hypothesis” and a possible effects on immune balance of a farm environment. Here, the author reviews epidemiological and experimental evidence for the documented protective effects of unpasteurised milk on allergies and asthma. Epidemiological studies from a number of countries show that children who consume raw milk early in life are less likely to develop allergies, independent of other factors. In one study that looked into possible components for this effect found that certain milk proteins (α-lactalbumin, β-lactoglobulin, and bovine serum albumin whey protein) reduced the risk of developing asthma . Total fat and protein content, amount of bacteria in the milk, and lactose levels were not associated with allergies or asthma. Another study found that higher levels of total fat and of omega-3 polyunsaturated fatty acids in raw milk had protective effects. The author discusses differences between raw and treated milk. Homogenisation changes the physical structure of fats and proteins, resulting in casein proteins being more easily adsorbed. The aim of heating milk, either through pasteurisation or UHT sterilisation, is to reduce bacterial numbers and growth, but it also affects heat-sensitive milk components, including whey proteins, immunoglobulins and lactoferrin, which have been shown to modulate the immune system. The author concludes that components of raw milk can influence immune function, and acknowledges the controversy with regards to raw milk carrying a risk of bacterial pathogens and that a proof based on controlled studies in infants is not possible due to ethical reasons.
Abstract
Living on a farm and having contact with rural exposures have been proposed as one of the most promising ways to be protected against allergy and asthma development. There is a significant body of epidemiological evidence that consumption of raw milk in childhood and adulthood in farm but also nonfarm populations can be one of the most effective protective factors. The observation is even more intriguing when considering the fact that milk is one of the most common food allergens in childhood. The exact mechanisms underlying this association are still not well understood, but the role of raw milk ingredients such as proteins, fat and fatty acids, and bacterial components has been recently studied and its influence on the immune function has been documented. In this review, we present the current understanding of the protective effect of raw milk on allergies and asthma.
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Longitudinal Study of the Psoriasis-Associated Skin Microbiome during Therapy with Ustekinumab in a Randomized Phase 3b Clinical Trial.
Loesche, MA, Farahi, K, Capone, K, Fakharzadeh, S, Blauvelt, A, Duffin, KC, DePrimo, SE, Muñoz-Elías, EJ, Brodmerkel, C, Dasgupta, B, et al
The Journal of investigative dermatology. 2018;138(9):1973-1981
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Chronic plaque psoriasis is an immune-mediated disease of the skin and joints. A growing appreciation of the role of the innate immune system in psoriasis pathogenesis stems from the prominent role of inflammatory cytokines and cells associated with innate immunity in the disease and associations observed between psoriasis and genetic variations involved in innate immunity. The aim of this study was to assess changes of the skin microbiome in the setting of a longitudinal phase 3b study of patients receiving up to 2 years of ustekinumab therapy. Results show that prior to treatment, there were minor, body-site specific differences in microbial diversity and composition when comparing lesional with non-lesional skin. Microbial heterogeneity was greater in lesional skin than non-lesional skin. During ustekinumab treatment, the composition of microbiota diverged further between lesional and non-lesional skin across body sites. The divergence observed between lesional and non-lesional skin during ustekinumab treatment varied by body site. Authors conclude that their findings may help inform future study design and it may also have medically relevant implications for diagnostics and therapeutics involving the skin microbiome.
Abstract
Plaque psoriasis, a chronic inflammatory disease primarily affecting the skin, is thought to have a multifactorial etiology, including innate immune system dysregulation, environmental triggers, and genetic susceptibility. We sought to further understand the role of skin microbiota in psoriasis pathogenesis, as well as their response to therapy. We systematically analyzed dynamic microbiota colonizing psoriasis lesions and adjacent nonlesional skin in 114 patients prior to and during ustekinumab treatment in a phase 3b clinical trial. By sequencing the bacterial 16S ribosomal RNA gene from skin swab samples obtained at six anatomical sites, we identified minor, site-specific differences in microbial diversity and composition between pretreatment lesional and nonlesional skin. During therapy, microbial communities within lesional and nonlesional skin diverged, and body-site dispersion increased, reflecting microbial skin site-specificity. Microbiota demonstrated greater pretreatment heterogeneity in psoriatic lesions than in nonlesional skin, and variance increased as treatment progressed. Microbiota colonizing recurrent lesions did not overlap with pretreatment lesional microbiota, suggesting colonization patterns varied between initial and recurrent psoriatic lesions. While plaque psoriasis does not appear to be associated with specific microbes and/or microbial diversity, this large dataset provides insight into microbial variation associated with (i) disease in different body locations, (ii) initial versus recurrent lesions, and (iii) anti-IL12/23 therapy.
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Gut microbiota varies by opioid use, circulating leptin and oxytocin in African American men with diabetes and high burden of chronic disease.
Barengolts, E, Green, SJ, Eisenberg, Y, Akbar, A, Reddivari, B, Layden, BT, Dugas, L, Chlipala, G
PloS one. 2018;13(3):e0194171
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Obesity and type 2 diabetes (T2D) can lead to alterations of the composition of the gut microbiota. The gut microbiota, in turn, has been suggested to play a role in the development of psychological conditions, such as anxiety, depression and drug addiction. This cross-sectional study included 99 mostly overweight/obese African American men, with or without T2D, and with or without opioid addiction and other psychiatric disorders. The aim of the study was to determine, whether the gut microbiota composition was linked to T2D and the use of opioids in these patients. Furthermore, the researchers looked at the associations between leptin and oxytocin levels in the blood and the gut microbiota, and whether these hormone biomarkers could be indicative of obesity and psychosocial behaviour, such as opioid addiction. The authors found that some bacterial species in the gut were affected by T2D, diabetes medication and opioid use in the studied subjects. A relationship was also observed between leptin and oxytocin levels and the abundance of certain bacteria in the gut in subjects without T2D. The authors conclude that targeting the gut microbiota could be used for the management of T2D and associated psychiatric disorders. However, more studies are needed to provide further understanding of the connections between the gut microbiota and the brain.
Abstract
OBJECTIVE The gut microbiota is known to be related to type 2 diabetes (T2D), psychiatric conditions, and opioid use. In this study, we tested the hypothesis that variability in gut microbiota in T2D is associated with psycho-metabolic health. METHODS A cross-sectional study was conducted among African American men (AAM) (n = 99) that were outpatients at a Chicago VA Medical Center. The main outcome measures included fecal microbiota ecology (by 16S rRNA gene sequencing), psychiatric disorders including opioid use, and circulating leptin and oxytocin as representative hormone biomarkers for obesity and psychological pro-social behavior. RESULTS The study subjects had prevalent overweight/obesity (78%), T2D (50%) and co-morbid psychiatric (65%) and opioid use (45%) disorders. In the analysis of microbiota, the data showed interactions of opioids, T2D and metformin with Bifidobacterium and Prevotella genera. The differential analysis of Bifidobacterium stratified by opioids, T2D and metformin, showed significant interactions among these factors indicating that the effect of one factor was changed by the other (FDR-adjusted p [q] < 0.01). In addition, the pair-wise comparison showed that participants with T2D not taking metformin had a significant 6.74 log2 fold increase in Bifidobacterium in opioid users as compared to non-users (q = 2.2 x 10-8). Since metformin was not included in this pair-wise comparison, the significant 'q' suggested association of opioid use with Bifidobacterium abundance. The differences in Bifidobacterium abundance could possibly be explained by opioids acting as organic cation transporter 1 (OCT1) inhibitors. Analysis stratified by lower and higher leptin and oxytocin (divided by the 50th percentile) in the subgroup without T2D showed lower Dialister in High-Leptin vs. Low-Leptin (p = 0.03). Contrary, the opposite was shown for oxytocin, higher Dialister in High-Oxytocin vs. Low-Oxytocin (p = 0.04). CONCLUSIONS The study demonstrated for the first time that Bifidobacterium and Prevotella abundance was affected by interactions of T2D, metformin and opioid use. Also, in subjects without T2D Dialister abundance varied according to circulating leptin and oxytocin.
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Disruption of the Gut Ecosystem by Antibiotics.
Yoon, MY, Yoon, SS
Yonsei medical journal. 2018;59(1):4-12
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The gut microbiome is a complex ecosystem of different micro-organisms, such as bacteria, viruses and fungi, living in the human intestines. It’s involved in numerous functions, such as extracting energy and nutrition from food, protecting against disease-causing microorganisms, and supporting the immune system of the host, and therefore affecting human health and disease. This paper is a review of studies on the effects of antibiotics on the gut microbiota. It outlines how different types of antibiotics can alter the intestinal environment and the composition of the microbes, resulting in various physiological changes that can trigger disease. Relevant mechanisms, such as inflammatory response and the use of intestinal nutrients by infectious bacteria are discussed. Finally, it discusses faecal microbiota transplantation (FMT) and probiotics as treatment approaches, aimed at restoring a disturbed intestinal environment.
Abstract
The intestinal microbiota is a complex ecosystem consisting of various microorganisms that expands human genetic repertoire and therefore affects human health and disease. The metabolic processes and signal transduction pathways of the host and intestinal microorganisms are intimately linked, and abnormal progression of each process leads to changes in the intestinal environment. Alterations in microbial communities lead to changes in functional structures based on the metabolites produced in the gut, and these environmental changes result in various bacterial infections and chronic enteric inflammatory diseases. Here, we illustrate how antibiotics are associated with an increased risk of antibiotic-associated diseases by driving intestinal environment changes that favor the proliferation and virulence of pathogens. Understanding the pathogenesis caused by antibiotics would be a crucial key to the treatment of antibiotic-associated diseases by mitigating changes in the intestinal environment and restoring it to its original state.
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Crosstalk between the microbiome and epigenome: messages from bugs.
Qin, Y, Wade, PA
Journal of biochemistry. 2018;163(2):105-112
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Trillions of microbes live symbiotically in and on an individual human being, most of them inside the digestive tract and communally known as the gut microbiome. The gut microbiome plays a vital role in the individual host’s health, not only by helping digest food and harvest energy, but also by regulating immune development and influencing gene expression. Diet and factors, such as infections and the use of antibiotics, can alter the balance of the microbiome and lead to various outcomes. This paper reviewed the current understanding of the ways in which the gut microbiome is capable of altering the host’s gene expression through microbial signals, including metabolites, bile acids, inflammation and altered composition. The studies highlighted in the paper show that gut microbes communicate both with local cells in the intestines and with more distant organs, such as the liver and the cardiovascular system. Through this communication, they can regulate the expression of immune cells, cancer cells, enzymes and inflammation-related molecules. The authors concluded that these interactions, or the crosstalk between the microbes and the host, demonstrate a crucial role of the gut microbiome in the host’s response to environmental signals. However, many of the mechanisms are still unclear, so further studies are needed to explain specific microbe-derived signals, affecting host gene expression, and to deepen our understanding of how lifestyle, health status and environmental exposures, such as antibiotics, regulate the microbiome and its influence.
Abstract
Mammals exist in a complicated symbiotic relationship with their gut microbiome, which is postulated to have broad impacts on host health and disease. As omics-based technologies have matured, the potential mechanisms by which the microbiome affects host physiology are being addressed. The gut microbiome, which provides environmental cues, can modify host cell responses to stimuli through alterations in the host epigenome and, ultimately, gene expression. Increasing evidence highlights microbial generation of bioactive compounds that impact the transcriptional machinery in host cells. Here, we review current understanding of the crosstalk between gut microbiota and the host epigenome, including DNA methylation, histone modification and non-coding RNAs. These studies are providing insights into how the host responds to microbial signalling and are predicted to provide information for the application of precision medicine.
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Prenatal and postnatal antibiotic exposure influences the gut microbiota of preterm infants in neonatal intensive care units.
Zou, ZH, Liu, D, Li, HD, Zhu, DP, He, Y, Hou, T, Yu, JL
Annals of clinical microbiology and antimicrobials. 2018;17(1):9
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Disturbances in gut bacteria could have long-term effects on a baby’s health. The development of healthy gut bacteria is influenced by factors such as the surrounding environment, gestational age, delivery mode, feeding method and exposure to antibiotics. The aim of this study was to investigate the effects of antibiotic exposure on the development of gut bacteria in premature babies. This study was carried out in a hospital in China. 28 premature babies who had been admitted to the neonatal intensive care unit were included in the study. Stool samples were collected when the babies were 7 and 14 days old. The researchers found that the characteristics of the gut bacteria in babies exposed to antibiotics was different to those who were not. The numbers of beneficial Bifidobacterium were significantly lower in those babies who had received antibiotics compared to those who had not. Exposure to antibiotics for more than 7 days led to increases in the presence of some strains of drug-resistant bacteria. The authors concluded that antibiotic exposure may affect the composition of early gut bacteria in premature babies which could potentially increase the risk of contracting harmful infections.
Abstract
BACKGROUND To explore the influences of prenatal antibiotic exposure, the intensity of prenatal and postnatal antibiotic exposure on gut microbiota of preterm infants and whether gut microbiota and drug resistant strains in the neonatal intensive care unit (NICU) over a defined period are related. METHODS Among 28 preterm infants, there were two groups, the PAT (prenatal antibiotic therapy) group (12 cases), and the PAF (prenatal antibiotic free) group (12 cases). Fecal samples from both groups were collected on days 7 and 14. According to the time of prenatal and postnatal antibiotic exposure, cases were divided into two groups, H (high) group (11 cases) and L (low) group (11 cases), and fecal samples on day 14 were collected. Genomic DNA was extracted from the fecal samples and was subjected to high throughput 16S rRNA amplicon sequencing. Bioinformatics methods were used to analyze the sequencing results. RESULTS Prenatal and postnatal antibiotic exposure exercised influence on the early establishment of intestinal microflora of preterm infants. Bacteroidetes decreased significantly in the PAT group (p < 0.05). The number of Bifidobacterium significantly decreased in the PAT group and H group (p < 0.05). The early gut microbiota of preterm infants with prenatal and postnatal antibiotic exposure was similar to resistant bacteria in NICU during the same period. CONCLUSION Prenatal and postnatal antibiotic exposure may affect the composition of early gut microbiota in preterm infants. Antibiotic-resistant bacteria in NICU may play a role in reshaping the early gut microbiota of preterm infants with prenatal and postnatal antibiotic exposure.
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Human Gut Microbiota and Gastrointestinal Cancer.
Meng, C, Bai, C, Brown, TD, Hood, LE, Tian, Q
Genomics, proteomics & bioinformatics. 2018;16(1):33-49
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In this article the authors review research on the influence of the human gut microbiota on the development and progression of gastrointestinal cancers, and go into significant detail about the molecular mechanisms involved. Helicobacter pylori is a known risk factor for gastric cancer (GC) but other dysbiotic changes in the gut microbiota are also observed in GC. On the other hand, H. pylori is associated with a decreased risk for oesophageal cancer (OC). An increase in gram-negative bacteria is associated with OC, whilst gram-positive bacteria are dominant in a healthy oesophagus. Dietary factors are associated with the risk for colorectal cancer (CRC) and may be due to their effect on the bacterial composition of the bowel. The authors explore possible mechanisms for these links. Although the liver is considered sterile, carcinogenesis can be influenced by the gut microbiota through pathogens and bacterial metabolites which can disturb metabolic pathways and immune responses in the liver. In pancreatic cancer (PC), the gut microbiota may influence carcinogenesis by promoting inflammation. In addition to various lifestyle factors, H. pylori is a risk factor for PC. The authors also review the use of prebiotics, probiotics, synbiotics (a combination of pre- and pro-biotics) and Traditional Chinese Medicine as an adjunct to conventional cancer treatment to reduce side effects, as well as their potential preventive mechanisms.
Abstract
Human gut microbiota play an essential role in both healthy and diseased states of humans. In the past decade, the interactions between microorganisms and tumors have attracted much attention in the efforts to understand various features of the complex microbial communities, as well as the possible mechanisms through which the microbiota are involved in cancer prevention, carcinogenesis, and anti-cancer therapy. A large number of studies have indicated that microbial dysbiosis contributes to cancer susceptibility via multiple pathways. Further studies have suggested that the microbiota and their associated metabolites are not only closely related to carcinogenesis by inducing inflammation and immune dysregulation, which lead to genetic instability, but also interfere with the pharmacodynamics of anticancer agents. In this article, we mainly reviewed the influence of gut microbiota on cancers in the gastrointestinal (GI) tract (including esophageal, gastric, colorectal, liver, and pancreatic cancers) and the regulation of microbiota by diet, prebiotics, probiotics, synbiotics, antibiotics, or the Traditional Chinese Medicine. We also proposed some new strategies in the prevention and treatment of GI cancers that could be explored in the future. We hope that this review could provide a comprehensive overview of the studies on the interactions between the gut microbiota and GI cancers, which are likely to yield translational opportunities to reduce cancer morbidity and mortality by improving prevention, diagnosis, and treatment.
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Association between duration of intravenous antibiotic administration and early-life microbiota development in late-preterm infants.
Zwittink, RD, Renes, IB, van Lingen, RA, van Zoeren-Grobben, D, Konstanti, P, Norbruis, OF, Martin, R, Groot Jebbink, LJM, Knol, J, Belzer, C
European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology. 2018;37(3):475-483
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Premature newborn babies are commonly given antibiotics in hospital to prevent or treat infections such as sepsis. This study, carried out in the Netherlands, looked at the effect of intravenous antibiotics on the development of the gut bacteria in premature babies. Stool samples were taken from 15 premature babies who had been exposed to either no antibiotic treatment, or short (less than 3 days) or long (at least 5 days) treatment with the commonly prescribed antibiotics amoxicillin or ceftazidime. At 3 weeks old, babies who had been treated with both short and long courses of antibiotics had significantly lower abundance of the beneficial bacteria Bifidobacterium than those who had received no antibiotics. In babies who received antibiotic treatment lasting 5 days or more, Bifidobacterium levels didn’t recover until they were 6 weeks old. Antibiotics were effective against Enterobacteriaceae, but allowed Enterococcus to thrive and remain dominant for up to two weeks after antibiotic treatment was stopped. The authors concluded that intravenous antibiotics during the first week of a baby’s life greatly affects the gut bacteria. However, short courses of antibiotics allow for a quicker recovery compared to longer courses. Disturbances in the development of gut bacteria caused by antibiotic treatment could influence the development of infants' immune and digestive systems.
Abstract
Antibiotic treatment is common practice in the neonatal ward for the prevention and treatment of sepsis, which is one of the leading causes of mortality and morbidity in preterm infants. Although the effect of antibiotic treatment on microbiota development is well recognised, little attention has been paid to treatment duration. We studied the effect of short and long intravenous antibiotic administration on intestinal microbiota development in preterm infants. Faecal samples from 15 preterm infants (35 ± 1 weeks gestation and 2871 ± 260 g birth weight) exposed to no, short (≤ 3 days) or long (≥ 5 days) treatment with amoxicillin/ceftazidime were collected during the first six postnatal weeks. Microbiota composition was determined through 16S rRNA gene sequencing and by quantitative polymerase chain reaction (qPCR). Short and long antibiotic treat ment significantly lowered the abundance of Bifidobacterium right after treatment (p = 0.027) till postnatal week three (p = 0.028). Long treatment caused Bifidobacterium abundance to remain decreased till postnatal week six (p = 0.009). Antibiotic treatment was effective against members of the Enterobacteriaceae family, but allowed Enterococcus to thrive and remain dominant for up to two weeks after antibiotic treatment discontinuation. Community richness and diversity were not affected by antibiotic treatment, but were positively associated with postnatal age (p < 0.023) and with abundance of Bifidobacterium (p = 0.003). Intravenous antibiotic administration during the first postnatal week greatly affects the infant's gastrointestinal microbiota. However, quick antibiotic treatment cessation allows for its recovery. Disturbances in microbiota development caused by short and, more extensively, by long antibiotic treatment could affect healthy development of the infant via interference with maturation of the immune system and gastrointestinal tract.
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The microbiome and autoimmunity: a paradigm from the gut-liver axis.
Li, B, Selmi, C, Tang, R, Gershwin, ME, Ma, X
Cellular & molecular immunology. 2018;15(6):595-609
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The incidence of autoimmune and inflammatory diseases has been increasing worldwide. Changes in environmental factors, such as modern lifestyle, diet, antibiotics and hygiene are thought to play a critical role in the development of various autoimmune diseases. It is the mucosal microbial flora that is shaped by our environment and communicates with the innate and adaptive immune systems, and when disrupted, can lead to the loss of immune tolerance and dysregulated immune cells. This review paper provides an overview of the interactions between the intestinal microbiome and the immune system. It explains how these interactions affect host autoimmunity locally and systemically and sheds light on the molecular mechanisms, utilised by microbes that may contribute to systemic autoimmunity in genetically susceptible individuals. The links between the gut microbiome and various autoimmune diseases, such as rheumatoid arthritis, type 1 diabetes and multiple sclerosis, as well as the gut-liver axis, involving intestinal microbiome and autoimmune liver diseases, are discussed in more detail.
Abstract
Microbial cells significantly outnumber human cells in the body, and the microbial flora at mucosal sites are shaped by environmental factors and, less intuitively, act on host immune responses, as demonstrated by experimental data in germ-free and gnotobiotic studies. Our understanding of this link stems from the established connection between infectious bacteria and immune tolerance breakdown, as observed in rheumatic fever triggered by Streptococci via molecular mimicry, epitope spread and bystander effects. The availability of high-throughput techniques has significantly advanced our capacity to sequence the microbiome and demonstrated variable degrees of dysbiosis in numerous autoimmune diseases, including rheumatoid arthritis, type 1 diabetes, multiple sclerosis and autoimmune liver disease. It remains unknown whether the observed differences are related to the disease pathogenesis or follow the therapeutic and inflammatory changes and are thus mere epiphenomena. In fact, there are only limited data on the molecular mechanisms linking the microbiota to autoimmunity, and microbial therapeutics is being investigated to prevent or halt autoimmune diseases. As a putative mechanism, it is of particular interest that the apoptosis of intestinal epithelial cells in response to microbial stimuli enables the presentation of self-antigens, giving rise to the differentiation of autoreactive Th17 cells and other T helper cells. This comprehensive review will illustrate the data demonstrating the crosstalk between intestinal microbiome and host innate and adaptive immunity, with an emphasis on how dysbiosis may influence systemic autoimmunity. In particular, a gut-liver axis involving the intestinal microbiome and hepatic autoimmunity is elucidated as a paradigm, considering its anatomic and physiological connections.
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Reversing the immune ageing clock: lifestyle modifications and pharmacological interventions.
Duggal, NA
Biogerontology. 2018;19(6):481-496
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Advancing age is accompanied by a compromised ability of older adults to combat bacterial and viral infections, increased risk of autoimmunity, poor vaccination responses and the re-emergence of latent infections. This review discusses current understanding of immunesenescence [the gradual deterioration of our immune system as we get older] and also focuses on lifestyle interventions and therapeutic strategies that have been shown to restore immune functioning in aged individuals. Findings show that: - changes in nutrition and lifestyle can be an effective approach towards improving immune outcome in older adults but may be hard to achieve at a population level. - improving immune responses, such as the developments of vaccines, may be used as an early biomarker for anti-ageing effects. Authors conclude that immunomodulation represents a promising therapeutic approach to improve the health of older adults.
Abstract
It is widely accepted that ageing is accompanied by remodelling of the immune system, including reduced numbers of naïve T cells, increased senescent or exhausted T cells, compromise to monocyte, neutrophil and natural killer cell function and an increase in systemic inflammation. In combination these changes result in increased risk of infection, reduced immune memory, reduced immune tolerance and immune surveillance, with significant impacts upon health in old age. More recently it has become clear that the rate of decline in the immune system is malleable and can be influenced by environmental factors such as physical activity as well as pharmacological interventions. This review discusses briefly our current understanding of immunesenescence and then focuses on lifestyle interventions and therapeutic strategies that have been shown to restore immune functioning in aged individuals.