Inborn errors of immunity and related microbiome.

Inborn errors of immunity (IEI) are characterized by diverse clinical manifestations that are dominated by atypical, recurrent, chronic, or severe infectious or non-infectious features, including autoimmunity, lymphoproliferative disease, granulomas, and/or malignancy, which contribute substantially to morbidity and mortality. Some data suggest a correlation between clinical manifestations of IEI and altered gut microbiota. Many IEI display microbial dysbiosis resulting from the proliferation of pro-inflammatory bacteria or a decrease in anti-inflammatory bacteria with variations in the composition and function of numerous microbiota. Dysbiosis is considered more established, mainly within common variable immunodeficiency, selective immunoglobulin A deficiency, severe combined immunodeficiency diseases, Wiskott-Aldrich syndrome, Hyper-IgE syndrome, autoimmune polyendocrinopathy-candidiasis-ectodermal-dystrophy (APECED), immune dysregulation, polyendocrinopathy, enteropathy X-linked (IPEX) syndrome, IL-10 receptor deficiency, chronic granulomatous disease, and Kostmann disease. For certain IEIs, the specific predominance of gastrointestinal, respiratory, and cutaneous involvement, which is frequently associated with dysbiosis, justifies the interest for microbiome identification. With the better understanding of the relationship between gut microbiota, host immunity, and infectious diseases, the integration of microbiota modulation as a therapeutic approach or a preventive measure of infection becomes increasingly relevant. Thus, a promising strategy is to develop optimized prebiotics, probiotics, postbiotics, and fecal microbial transplantation to rebalance the intestinal microbiota and thereby attenuate the disease activity of many IEIs.

Immune-microbe interactions early in life: A determinant of health and disease long term.

Research on newborn immunity has revealed the importance of cell ontogeny, feto-maternal tolerance, and the transfer of maternal antibodies. Less is known about postnatal adaptation to environmental exposures. The microbiome and its importance for health have been extensively studied, but it remains unclear how mutually beneficial relationships between commensal microbes and human cells first arise and are maintained throughout life. Such immune-microbe mutualism, and perturbations thereof, is most likely a root cause of increasing incidences of immune-mediated disorders such as allergies and autoimmunity across many industrialized nations during the past century. In this Review, I discuss our current understanding of immune development and propose that mismatches among ancestral, early-life, and adult environments can explain perturbations to immune-microbe interactions, immune dysregulation, and increased risks of immune-mediated diseases.

The Synergistic Effects of Polysaccharides and Ginsenosides From American Ginseng (Panax quinquefolius L.) Ameliorating Cyclophosphamide-Induced Intestinal Immune Disorders and Gut Barrier Dysfunctions Based on Microbiome-Metabolomics Analysis.

Cyclophosphamide (CTX), used in cancer chemotherapy, a high dose of which would cause immunosuppressive effect and intestinal mucosa damage. American ginseng (Panax quinquefolius L.) has a long history of functional food use for immunological disorder, colitis, cancer, and so on. This study aimed to illustrate the underlying mechanism of American ginseng's immunomodulatory effect in CTX-induced mice. In this study, all groups of American ginseng (American ginseng polysaccharide [AGP], American ginseng ginsenoside [AGG], co-treated with American ginseng polysaccharide and ginsenoside [AGP_AGG]) have relieve the immune disorder by reversing the lymphocyte subsets ratio in spleen and peripheral blood, as well as stimulating CD4+T cells and IgA-secreting cells in small intestine. These three treatment groups, especially AGP_AGG co-treated group recovered the intestine morphology that up-regulated villus height (VH)/crypt depth (CD) ratio, areas of mucins expression, quantity of goblet cells, and expression of tight junction proteins (ZO-1, occludin). Importantly, the microbiome-metabolomics analysis was applied in this study to illustrate the possible immuno-modulating mechanism. The synergistic effect of polysaccharides and ginsenosides (AGP_AGG group) restored the gut microbiota composition and increased various beneficial mucosa-associated bacterial taxa Clostridiales, Bifidobacterium, and Lachnospiraceae, while decreased harmful bacteria Escherichia-Shigella and Peptococcaceae. Also, AGP_AGG group altered various fecal metabolites such as uric acid, xanthurenic acid, acylcarnitine, 9,10-DHOME, 13-HDoHE, LysoPE15:0, LysoPC 16:0, LysoPI 18:0, and so on, that associated with immunometabolism or protective effect of gut barrier. These results suggest AG, particularly co-treated of polysaccharide and ginsenoside may be used as immunostimulants targeting microbiome-metabolomics axis to prevent CTX-induced side effects in cancer patients.

The microbiome and rodent models of immune mediated diseases.

Over the last six decades production of laboratory rodents have been refined with the aim of eliminating all pathogens, which could influence research results. This has, however, also created rodents with little diversity in their microbiota. Until 10 years ago the impact of the microbiota on the outcome of rodent studies was ignored, but today it is clear that the phenotype of rodent models differs essentially in relation to the environment of origin, i.e. different breeders or different rooms. In this review, we outline the mechanisms behind gut bacterial impact on rodent models of immune mediated diseases, and how differences in environment of origin leads to phenotypic model differences within research areas such as infectious diseases and vaccine development, the metabolic syndrome, gut immunity and inflammation, autoimmunity and allergy. Finally, we sum up some tools to handle this impact to increase reproducibility and translatability of rodent models.

The Impact of Migration on the Gut Metagenome of South Asian Canadians.

South Asian (SA) Canadian immigrants have a higher risk of developing certain immune-mediated inflammatory diseases compared to non-migrant SAs. We sought to investigate the effect of migration on the gut metagenome and to identify microbiological associations between migration and conditions that may influence the development of immune-mediated inflammatory diseases. Metagenomic analysis of 58 first-generation (GEN1) SA immigrants and 38 unrelated Canadian born children-of-immigrants (GEN2) determined that the time lived in Canada was associated with continued changes in gut microbial communities. Migration of GEN1 to Canada early in life results in a gut community with similarities to GEN2 SA Canadians and non-SA North Americans. Conversely, GEN1 immigrants who arrived recently to Canada exhibited pronounced differences from GEN2, while displaying microbial similarities to a non-migrating SA cohort. Multivariate analysis identified that community composition was primarily influenced by high abundance taxa. Prevotella copri dominated in GEN1 and non-migrant SAs. Clostridia and functionally related Bacteroidia spp. replaced P. copri dominance over generations in Canada. Mutually exclusive Dialister species occurred at differing relative abundances over time and generations in Canada. This shift in species composition is accompanied by a change in genes associated with carbohydrate utilization and short-chain fatty acid production. Total energy derived from carbohydrates compared to protein consumption was significantly higher for GEN1 recent immigrants, which may influence the functional requirements of the gut community. This study demonstrates the associations between migration and the gut microbiome, which may be further associated with the altered risk of immune-mediated inflammatory diseases observed for SA Canadians.

Limosilactobacillus reuteri and Lacticaseibacillus rhamnosus GG differentially affect gut microbes and metabolites in mice with Treg deficiency.

Treg deficiency causes a lethal, CD4+ T cell-driven autoimmune disease called IPEX syndrome (immunodysregulation, polyendocrinopathy, and enteropathy, with X-linked inheritance) in humans and in the scurfy (SF) mouse, a mouse model of the disease. Feeding Limosilactobacillus reuteri DSM 17938 (LR 17938, LR) to SF mice reprograms the gut microbiota, reduces disease progression, and prolongs lifespan. However, the efficacy and mechanism of LR, compared with other probiotics, in producing these effects is unknown. We compared LR with Lacticaseibacillus rhamnosus GG (LGG), an extensively investigated probiotic. LR was more effective than LGG in prolonging survival. Both probiotics restored the fecal microbial alpha diversity, but they produced distinct fecal bacterial clusters and differentially modulated microbial relative abundance (RA). LR increased the RA of phylum_Firmicutes, genus_Oscillospira whereas LR reduced phylum_Bacteroidetes, genus_Bacteroides and genus_Parabacteroides, reversing changes attributed to the SF phenotype. LGG primarily reduced the RA of genus_Bacteroides. Both LR and LGG reduced the potentially pathogenic taxon class_γ-proteobacteria. Plasma metabolomics revealed substantial differences among 696 metabolites. We observed similar changes of many clusters of metabolites in SF mice associated with treatment with either LR or LGG. However, a unique effect of LR was to increase the abundance of plasma adenosine metabolites such as inosine, which we previously showed had immune modulatory effects. In conclusion: 1) different probiotics produce distinct signatures in the fecal microbial community in mice with Treg deficiency; and 2) when comparing different probiotics, there are strain-specific microbial products with different anti-inflammatory properties, reinforcing the concept that "one size does not fit all" in the treatment of autoimmune disease.NEW & NOTEWORTHY In the treatment of Treg-deficiency-induced autoimmunity, Limosilactobacillus reuteri DSM 17938 (LR) showed greater efficacy than Lacticaseibacillus rhamnosus GG (LGG). The study demonstrated that two different probiotics produce distinct signatures in the fecal microbial community in mice with Treg deficiency, but with many similarities in global plasma metabolites in general. However, there are strain-specific microbial products with different anti-inflammatory properties, reinforcing the concept that "one size does not fit all" in the treatment of autoimmune disease.

Rebalancing the Oral Microbiota as an Efficient Tool in Endocrine, Metabolic and Immune Disorders.

The current treatment and prevention procedures of oral disorders follow a very targeted approach considering mouth and its structures as a system that is completely independent, than the rest of the body. The main therapeutic approach is to keep the levels of oral bacteria and hygiene in an acceptable range compatible with oral-mouth health, completely separated from systemic microbial homeostasis (eubiosis vs dysbiosis). This can negatively impact the diagnosis of a more complex systemic disease and its progression. Dysbiosis occurs as a consequence of imbalance in oral and gut microbiota which leads to cardiovascular diseases, diabetes mellitus, rheumatoid arthritis, and Alzheimer's disease, as reported in current literature. Likewise, there is a need to highlight and develop a novel philosophical approach in the treatments for oral diseases that will necessarily involve nonconventional approaches.

Refocusing Human Microbiota Research in Infectious and Immune-mediated Diseases: Advancing to the Next Stage.

Changes in the microbiota are associated with disease susceptibility, immune system development, and responses to treatment. Refocusing research to elucidate the causal links between the human microbiota and infectious and immune-mediated diseases will be critical to harnessing its power to prevent, diagnose, and treat such diseases.

Lactobacillus rhamnosus 2016SWU.05.0601 regulates immune balance in ovalbumin-sensitized mice by modulating expression of the immune-related transcription factors and gut microbiota.

BACKGROUND: Probiotics regulate host immune balance, which may reduce immune-related diseases. The effects and mechanisms of Lactobacillus rhamnosus 2016SWU.05.0601 (Lr-0601) on the immune response in ovalbumin (OVA)-sensitized mice were explored. RESULTS: Lr-0601 reduced serum immunoglobulin (Ig)E and OVA-IgE and attenuated the alteration in lung pathology in OVA-sensitized mice. Lr-0601 blocked OVA-induced up-regulation in serum T helper (Th) 2 and Th17 cytokines but increased the serum levels of Th1 and regulatory T (Treg) cytokines in OVA-sensitized mice. OVA also markedly reduced the protein levels of spleen T-box transcription factor and forkhead/winged helix transcription factor p3, leading to the reduced mRNA expression of interferon-γ and interleukin (IL)-10. By contrast, OVA markedly increased the protein expression of spleen GATA-binding protein 3 and retinoid-related orphan receptor γt, as well as the mRNA expression of spleen IL-4 and IL-17. These changes induced by OVA were reversed by Lr-0601. Moreover, Lr-0601 helped alleviate OVA-induced intestinal microbiota dysbiosis. A correlation was found between specific genera and immune-associated cytokines. CONCLUSION: The combined results indicate that Lr-0601 modulated the balance of Th1/Th2 and Treg/Th17 in OVA-sensitized mice, which was associated with the regulation of immune-related transcription factors and gut microbiota. Lr-0601 can potentially be used as a probiotic for preventing immune-related diseases. © 2020 Society of Chemical Industry.

Gut Microbiota and Immune Responses.

The gut microbiota consists of a dynamic multispecies community living within a particular niche in a mutual synergy with the host organism. Recent findings have revealed roles for the gut microbiota in the modulation of host immunity and the development and progression of immune-mediated diseases. Besides, growing evidence supports the concept that some metabolites mainly originated from gut microbiota are linked to the immune regulation implicated in systemic inflammatory and autoimmune disorders. In this chapter, we describe the recent advances in our understanding of how host-microbiota interactions shape the immune system, how they affect the pathogenesis of immune-associated diseases and the impact of these mechanisms in the efficacy of disease therapy.

Antibiotic-modulated microbiome suppresses lethal inflammation and prolongs lifespan in Treg-deficient mice.

BACKGROUND: Regulatory T cell (Treg) deficiency leads to IPEX syndrome, a lethal autoimmune disease, in Human and mice. Dysbiosis of the gut microbiota in Treg-deficient scurfy (SF) mice has been described, but to date, the role of the gut microbiota remains to be determined. RESULTS: To examine how antibiotic-modified microbiota can inhibit Treg deficiency-induced lethal inflammation in SF mice, Treg-deficient SF mice were treated with three different antibiotics. Different antibiotics resulted in distinct microbiota and metabolome changes and led to varied efficacy in prolonging lifespan and reducing inflammation in the liver and lung. Moreover, antibiotics altered plasma levels of several cytokines, especially IL-6. By analyzing gut microbiota and metabolome, we determined the microbial and metabolomic signatures which were associated with the antibiotics. Remarkably, antibiotic treatments restored the levels of several primary and secondary bile acids, which significantly reduced IL-6 expression in RAW macrophages in vitro. IL-6 blockade prolonged lifespan and inhibited inflammation in the liver and lung. By using IL-6 knockout mice, we further identified that IL-6 deletion provided a significant portion of the protection against inflammation induced by Treg dysfunction. CONCLUSION: Our results show that three antibiotics differentially prolong survival and inhibit lethal inflammation in association with a microbiota-IL-6 axis. This pathway presents a potential avenue for treating Treg deficiency-mediated autoimmune disorders.

Microbiota, immunity and immunologically-mediated diseases.

Each individual is colonized by broad spectrum of microbes. Recent surge of interest in microbiota across all fields of medicine was motivated by an increasing body of knowledge on how commensals influence human health. This is most notable in the gut, where most microbes reside, but microbes colonizing other niches, such as oral cavity or skin, may influence health as well. Microbiota fundamentally influences the immune system development and its perturbation, i.e. dysbiosis, is associated with many inflammatory, autoimmune and neoplastic diseases. Microbiota forms a symbiotic relationship with the host - maintaining balanced and efficient immune response and protects from colonization by pathogens. Modern medicine may benefit greatly by adopting these ideas for therapeutic or prophylactic purposes. These may include manipulation with microbiota by diet, changes in lifestyle or directly by probiotics or fecal microbiota transfer.

Risk of tuberculosis in patients with immune-mediated diseases on biological therapies: a population-based study in a tuberculosis endemic region.

OBJECTIVE: Real-world epidemiological data on the risk of tuberculosis (TB) in patients with immune-mediated diseases treated with biologics are scarce in TB endemic areas. We investigated the incidence of TB in a population-based setting and stratified the risk of TB among different biological therapies. METHODS: We collected medical data from a territory-wide computerized database in Hong Kong. We reported the incidence of TB in patients treated with various classes of biologics, and calculated standardized incidence ratio by comparing with the general population. Subgroup analyses were performed based on disease subtypes and biological drugs. RESULTS: Among 2485 subjects with immune-mediated diseases (82.5% rheumatology diseases; 10.6% IBD; 6.9% dermatology diseases), 54 subjects developed active TB during 6921 person-years of follow-up. The mean age (±s.d.) was 43 (14) years, and the median follow-up duration was 24.9 months (interquartile range 4.9-45.0). The overall standardized incidence ratio of TB was 10.91 (95% CI 8.00-13.82), and patients treated with infliximab had a nearly 26 times increased risk of TB compared with the general population (standardized incidence ratio 25.95; 95% CI 17.23-34.67). The risk of TB with TNF inhibitor was higher than with a non-TNF biologic (hazard ratio 4.34; 95% CI 1.31-14.39), while the risk of infliximab was higher than etanercept and adalimumab (hazard ratio: 4.10 and 2.08, respectively). CONCLUSION: The risk of TB is much higher in patients with immune-mediated diseases on biological therapy compared with the general population, and infliximab is associated with the highest risk of TB among the biologics analysed.

Microbiome and disease in the upper airway.

PURPOSE OF REVIEW: Microbiome refers to the genetic potential of resident microorganisms that inhabit a given niche. The exact role of the microbiome and its relation to chronic disease processes remains largely unknown, although various associations have been observed. We reviewed current literature investigating the microbiome of the upper airway by subsite (nasal cavity, sinus cavities, nasopharynx, and larynx) and its relation to chronic inflammatory disease processes. RECENT FINDINGS: The disruption of indigenous microbiota at a specific subsite may lead to pathogen overgrowth and increased susceptibility to infection. This has previously been demonstrated in the gastrointestinal tract and lower airways. The role of the microbiome and its relation to pathogenesis of disease in the upper airway, however, is less clearly understood. The present review discusses the recent studies that appear to link dysbiosis to upper airway chronic inflammatory diseases. SUMMARY: Despite mounting research, the role of microbiota in the upper airway remains poorly understood. Based on review of the current literature comparing healthy versus diseased patients with site-specific inflammatory conditions, a complex consortium of microbial communities inhabits the upper airway. Fluctuations in the baseline microbiome may contribute to disease pathogenesis, and improved understanding of the dynamics between shifting microbiota may be critical to guiding future medical therapy.

Causal effects of the microbiota on immune-mediated diseases.

The mammalian immune system has evolved in the presence of a complex community of indigenous microorganisms that constitutively colonize all barrier surfaces. This intimate relationship has resulted in the development of a vast array of reciprocal interactions between the microbiota and the host immune system, particularly in the intestine, where the density and diversity of indigenous microbes are greatest. Alterations in the gut microbiota have been correlated with almost every known immunological disease, but in most cases, it remains unclear whether these changes are a cause or effect of the disease or merely a reflection of epidemiological differences between groups. Here, we review recent efforts to demonstrate a causal role for the microbiota in health and disease, outline experimental advances that have made these studies possible, and highlight how changes in microbial composition may influence immune system function.