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Background: Nasopharyngeal Bordetella pertussis (BP) colonization is common, with about 5% of individuals having PCR evidence of subclinical BP infection on nasal swab, even in countries with high vaccination rates. BP secretes pertussis toxin (PTx). PTx is an adjuvant commonly used to induce autoimmunity in multiple animal models of human disease. Colocalization of PTx and myelin from myelinated nerves in the nasopharynx may lead to host sensitization to myelin with subsequent autoimmune pathology., Methods: C57BL/6J female adult mice were given varied doses and schedules of intranasal PTx, MOG 35-55 antigen, or controls to test whether intranasal administration of PTx and myelin oligodendrocyte peptide (MOG 35-55 ) could induce experimental autoimmune encephalomyelitis (EAE) in mice. While we observed systemic cell-mediated immunity against MOG 35-55 , we did not observe EAE. Unexpectedly, many mice developed alopecia. We systematically investigated this finding., Results: Patchy alopecia developed in 36.4% of mice with the optimized protocol. Pathology consistent with alopecia areata was confirmed histologically by documenting concomitant reduced anagen phase and increased telogen phase hair follicles (HFs) in biopsies from patches of hair loss in mice with alopecia. We also found reduced CD200 staining and increased CD3 + T cells surrounding the HFs of mice with alopecia compared to the mice without alopecia, indicating HF Immune Privilege (HFIP) collapse. Systemic immune responses were also found, with increased proportions of activated T cells and B cells, as well as MHCII + dendritic cells in peripheral blood and/or splenocytes. Finally, in mice initially exposed to intranasal MOG 35-55 and PTx in combination, but not to either agent alone, splenocytes were shown to proliferate after in vitro stimulation by MOG 35-55. Consistent with prior investigations, PTx exhibited a dose-response effect on immune cell induction and phenotype, with the lowest PTx dose failing to induce autoimmunity, the highest PTx dose suppressing autoimmunity, and intermediate doses optimizing autoimmunity., Conclusions: We propose that this is the first report of an autoimmune disease in an animal model triggered by colocalization of intranasal PTx and autoantigen. This model parallels a natural exposure and potential intranasal sensitization-to-pathology paradigm and supports the plausibility that nasopharyngeal subclinical BP colonization is a cause of alopecia areata., Competing Interests: KR and SG are employed by ILiAD Biotechnologies LLC, which is developing a vaccine for the prevention of Bordetella pertussis infection. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Author YL declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision. The authors declare that this study received funding from ILiAD Biotechnologies LLC (P00427002 to JR). The funder had the following involvement in the study: the study design and the writing of this article (review and edit)., (Copyright © 2024 Liu, Freeborn, Okeugo, Armbrister, Saleh, Fadhel Alvarez, Hoang, Park, Lindsey, Rapini, Glazer, Rubin and Rhoads.)

Objective: To investigate the relationship between social isolation and substance abuse among adult hospitalizations to better target prevention and intervention., Methods: The 2018 National Inpatient Sample dataset was used to identify adult hospitalizations with social isolation and substance abuse in the United States, omitting long-term and rehabilitation facilities. The study analyzed sociodemographic features and health care resource utilization, with primary end points focusing on the prevalence of substance use disorder (SUD) with social isolation and sex/race-based disparities and secondary end points including mental health and costs. Comparisons were analyzed using SPSS Statistics with weighted data and complex survey modules., Results: The study included 2,050 patients (median age: 48 years, male: 55.6%) with an International Classification of Diseases, Tenth Revision, Clinical Modification social isolation diagnostic code, of which 16.6% had SUD, with higher prevalence in those of younger age, male sex, and black race. Smoking (49.3% vs 36.1%), alcohol disorder (14.4% vs 4.9%), cannabis disorder (14.6% vs 1.4%), stimulant-related disorder (16.3% vs 2.6%), and opioid-related disorder (16.6% vs 3.1%) were the most prevalent SUDs among socially isolated patients. The length of stay was similar among socially isolated patients by substance use; however, hospitalization cost was higher ($6,144 vs $4,745) among patients with SUD., Conclusion: The link between social isolation and substance use highlights the significance of addressing social isolation as a public health issue. Interventions to nurture social ties and reduce social isolation may have significant potential in preventing and managing SUDs., Prim Care Companion CNS Disord 2024;26(5):23m03679 ., Author affiliations are listed at the end of this article., (© Copyright 2024 Physicians Postgraduate Press, Inc.)

Primary immunodeficiency diseases (PIDs) caused by a single-gene defect generally are referred to as monogenic autoimmune disorders. For example, mutations in the transcription factor autoimmune regulator (AIRE) result in a condition called autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy; while mutations in forkhead box P3 lead to regulatory T cell (Treg)-deficiency-induced multiorgan inflammation, which in humans is called "immune dysregulation, polyendocrinopathy, enteropathy with X-linked inheritance" (or IPEX syndrome). Previous studies concluded that monogenic diseases are insensitive to commensal microbial regulation because they develop even in germ-free (GF) animals, a conclusion that has limited the number of studies determining the role of microbiota in monogenic PIDs. However, emerging evidence shows that although the onset of the disease is independent of the microbiota, several monogenic PIDs vary in severity in association with the microbiome. In this review, we focus on monogenic PIDs associated with Treg deficiency/dysfunction, summarizing the gut microbial dysbiosis that has been shown to be linked to these diseases. From limited studies, we have gleaned several mechanistic insights that may prove to be of therapeutic importance in the early stages of life. IMPACT: This review paper serves to refute the concept that monogenic PIDs are not linked to the microbiome. The onset of monogenic PIDs is independent of microbiota; single-gene mutations such as AIRE or Foxp3 that affect central or peripheral immune tolerance produce monogenic diseases even in a GF environment. However, the severity and outcome of PIDs are markedly impacted by the microbial composition. We suggest that future research for these conditions may focus on targeting the microbiome., (© 2021. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Background: Probiotic Lactobacillus reuteri DSM 17938 (LR 17938) is beneficial to infants with colic. To understand its mechanism of action, we assessed ultrasonic vocalizations (USV) and brain pain/stress genes in newborn mice exposed to maternal separation stress., Methods: Pups were exposed to unpredictable maternal separation (MSU or SEP) or MSU combined with unpredictable maternal stress (MSU + MSUS or S + S), from postnatal days 5 to 14. USV calls and pain/stress/neuroinflammation-related genes in the brain were analyzed., Results: We defined 10 different neonatal call patterns, none of which increased after MSU. Stress reduced overall USV calls. Orally feeding LR 17938 also did not change USV calls after MSU. However, LR 17938 markedly increased vocalizations in mice allowed to stay with their dams. Even though LR 17938 did not change MSU-related calls, LR 17938 modulated brain genes related to stress and pain. Up-regulated genes following LR 17938 treatment were opioid peptides, kappa-opioid receptor 1 genes, and CD200, important in anti-inflammatory signaling. LR 17938 down-regulated CCR2 transcripts, a chemokine receptor, in the stressed neonatal brain., Conclusions: USV calls in newborn mice are interpreted as "physiological calls" instead of "cries." Feeding LR 17938 after MSU did not change USV calls but modulated cerebral genes favoring pain and stress reduction and anti-inflammatory signaling., Impact: We defined mouse ultrasonic vocalization (USV) call patterns in this study, which will be important in guiding future studies in other mouse strains. Newborn mice with maternal separation stress have reduced USVs, compared to newborn mice without stress, indicating USV calls may represent "physiological calling" instead of "crying." Oral feeding of probiotic Lactobacillus reuteri DSM 17938 raised the number of calls when newborn mice continued to suckle on their dams, but not when mice were under stress. The probiotic bacteria had a dampening effect on monocyte activation and on epinephrine and glutamate-related stress gene expression in the mouse brain., (© 2021. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

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.

The intestinal microbiota influences the development and function of the mucosal immune system. However, the exact mechanisms by which commensal microbes modulate immunity is not clear. We previously demonstrated that commensal Bacteroides ovatus ATCC 8384 reduces mucosal inflammation. Herein, we aimed to identify immunomodulatory pathways employed by B. ovatus. In germ-free mice, mono-association with B. ovatus shifted the CD11b + /CD11c + and CD103 + /CD11c + dendritic cell populations. Because indole compounds are known to modulate dendritic cells, B. ovatus cell-free supernatant was screened for tryptophan metabolites by liquid chromatography-tandem mass spectrometry and larger quantities of indole-3-acetic acid were detected. Analysis of cecal and fecal samples from germ-free and B. ovatus mono-associated mice confirmed that B. ovatus could elevate indole-3-acetic acid concentrations in vivo. Indole metabolites have previously been shown to stimulate immune cells to secrete the reparative cytokine IL-22. Addition of B. ovatus cell-free supernatant to immature bone marrow-derived dendritic cells stimulated IL-22 secretion. The ability of IL-22 to drive repair in the intestinal epithelium was confirmed using a physiologically relevant human intestinal enteroid model. Finally, B. ovatus shifted the immune cell populations in trinitrobenzene sulfonic acid-treated mice and up-regulated colonic IL-22 expression, effects that correlated with decreased inflammation. Our data suggest that B. ovatus-produced indole-3-acetic acid promotes IL-22 production by immune cells, yielding beneficial effects on colitis., (Copyright © 2021 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Recent advances in systems biology have shifted vaccine development from a largely trial-and-error approach to an approach that promote rational design through the search for immune signatures and predictive correlates of protection. These advances will doubtlessly accelerate the development of a vaccine for schistosomiasis, a neglected tropical disease that currently affects over 250 million people. For over 15 years and with contributions of over 120 people, we have endeavored to test and optimize Sm-p80-based vaccines in the non-human primate model of schistosomiasis. Using RNA-sequencing on eight different Sm-p80-based vaccine strategies, we sought to elucidate immune signatures correlated with experimental protective efficacy. Furthermore, we aimed to explore the role of antibodies through in vivo passive transfer of IgG obtained from immunized baboons and in vitro killing of schistosomula using Sm-p80-specific antibodies. We report that passive transfer of IgG from Sm-p80-immunized baboons led to significant worm burden reduction, egg reduction in liver, and reduced egg hatching percentages from tissues in mice compared to controls. In addition, we observed that sera from Sm-p80-immunized baboons were able to kill a significant percent of schistosomula and that this effect was complement-dependent. While we did not find a universal signature of immunity, the large datasets generated by this study will serve as a substantial resource for further efforts to develop vaccine or therapeutics for schistosomiasis., (Copyright © 2020 Zhang, Le, Ahmad, Molehin, Siddiqui, Torben, Karmakar, Rojo, Sennoune, Lazarus, Khatoon, Freeborn, Sudduth, Rezk, Carey, Wolf, Papin, Damian, Gray, Marks, Carter and Siddiqui.)

Early administration of Lactobacillus reuteri DSM 17938 (LR) prevents necrotizing enterocolitis and inhibits regulatory T-cell (Treg)-deficiency-associated autoimmunity in mice. In humans, LR reduces crying time in breastfed infants with colic, modifies severity in infants with acute diarrheal illnesses, and improves pain in children with functional bowel disorders. In healthy breastfed newborns with evolving microbial colonization, it is unclear if early administration of LR can modulate gut microbiota and their metabolites in such a way as to promote homeostasis. We gavaged LR (10 7 colony-forming units/day, daily) to C57BL/6J mice at age of day 8 for 2 wk. Both male and female mice were investigated in these experiments. We found that feeding LR did not affect clinical phenotype or inflammatory biomarkers in plasma and stool, but LR increased the proportion of Foxp3 + regulatory T cells (Tregs) in the intestine. LR also increased bacterial diversity and the relative abundance of p_Firmicutes, f_Lachnospiraceae , f_Ruminococcaceae , and genera Clostridium and Candidatus arthromitus , while decreasing the relative abundance of p_Bacteriodetes, f_Bacteroidaceae , f_Verrucomicrobiaceae , and genera Bacteroides , Ruminococcus, Akkermansia , and Sutterella . Finally, LR exerted a major impact on the plasma metabolome, upregulating amino acid metabolites formed via the urea, tricarboxylic acid, and methionine cycles and increasing tryptophan metabolism. In conclusion, early oral administration of LR to healthy breastfed mice led to microbial and metabolic changes which could be beneficial to general health. NEW & NOTEWORTHY Oral administration of Lactobacillus reuteri DSM 17938 (LR) to healthy breastfed mice promotes intestinal immune tolerance and is linked to proliferation of beneficial gut microbiota. LR upregulates plasma metabolites that are involved in the urea cycle, the TCA cycle, methionine methylation, and the polyamine pathway. Herein, we show that LR given to newborn mice specifically increases levels of tryptophan metabolites and the purine nucleoside adenosine that are known to enhance tolerance to inflammatory stimuli.

The gut microbiome plays an important role in immune function and has been implicated in multiple sclerosis (MS). However, how and if the modulation of microbiota can prevent or treat MS remain largely unknown. In this study, we showed that probiotic Lactobacillus reuteri DSM 17938 ( L. reuteri ) ameliorated the development of murine experimental autoimmune encephalomyelitis (EAE), a widely used animal model of MS, a model which is primarily mediated by T H 17 and T H 1 cells. We discovered that L. reuteri treatment reduced T H 1/T H 17 cells and their associated cytokines IFN-γ/IL-17 in EAE mice. We also showed that the loss of diversity of gut microbiota induced by EAE was largely restored by L. reuteri treatment. Taxonomy-based analysis of gut microbiota showed that three "beneficial" genera Bifidobacterium, Prevotella , and Lactobacillus were negatively correlated with EAE clinical severity, whereas the genera Anaeroplasma, Rikenellaceae , and Clostridium were positively correlated with disease severity. Notably, L. reuteri treatment coordinately altered the relative abundance of these EAE-associated taxa. In conclusion, probiotic L. reuteri changed gut microbiota to modulate immune responses in EAE, making it a novel candidate in future studies to modify the severity of MS.

Background and Objective: Breast milk has many growth-promoting and immune-active components, including transforming growth factor-β, lactoferrin, lysozyme, immunoglobulin A, and prebiotics such as the human milk oligosaccharides. Treatment with Lactobacillus reuteri DSM 17938 (LR), a probiotic with immunomodulatory functions, significantly increases regulatory T cells (Tregs) in the intestinal mucosa of newborn suckling rats. In humans, treatment with LR of infants with colic reduces crying optimally if the infants are breast-fed. Therefore, we examined the effects of human breast milk (HBM) on LR-associated immune modulation., Methods: Newborn rats were divided into 8 feeding groups, including dam-fed ± LR (10 6 CFU/kg bw/day, daily), formula-fed ± LR, formula with 20% (v/v) HBM-fed ± LR, and HBM-fed ± LR. Pups were fed by gavage from d1 to d3 of age. Subsequently, we measured intestinal immune cell profiles, including Tregs and tolerogenic dendritic cells (tDCs) by flow cytometry. We also measured inflammatory cytokine and chemokine levels of interleukin (IL)-1β and cytokine-induced neutrophil chemoattratant (CINC)-1 in intestinal tissue lysates by ELISA., Results and Conclusion: (1) Formula feeding increased intestinal CD3+ T cells, CD4+ helper T (TH) cells and CD11c+ DCs, pro-inflammatory effects which were reversed by HBM. (2) When comparing HBM-fed with formula-fed newborns, HBM supplementation produced a lower percentage of CD4+ TH cells and a higher percentage of CD8+ (cytotoxic) T cells, while reducing protein levels of IL-1β and CINC-1 in the intestine. (3) Probiotic LR feeding maximally stimulated the percentage of intestinal Tregs and tDCs when the pups were fed HBM. In conclusion, HBM reduced formula-induced intestinal gut immune activation, and the addition of LR further promoted immune tolerance.

Sm-p80-based vaccine efficacy for Schistosoma mansoni was evaluated in a baboon model of infection and disease. The study was designed to replicate a human vaccine implementation scenario for endemic regions in which vaccine would be administered following drug treatment of infected individuals. In our study, the Sm-p80-based vaccine reduced principal pathology producing hepatic egg burdens by 38.0% and egg load in small and large intestines by 72.2% and 49.4%, respectively, in baboons. Notably, hatching rates of eggs recovered from liver and small and large intestine of vaccinated animals were significantly reduced, by 60.4%, 48.6%, and 82.3%, respectively. Observed reduction in egg maturation/hatching rates was supported by immunofluorescence and confocal microscopy showing unique differences in Sm-p80 expression in worms of both sexes and matured eggs. Vaccinated baboons had a 64.5% reduction in urine schistosome circulating anodic antigen, a parameter that reflects worm numbers/health status in infected hosts. Preliminary analyses of RNA sequencing revealed unique genes and canonical pathways associated with establishment of chronic disease, praziquantel-mediated parasite killing, and Sm-p80-mediated protection in vaccinated baboons. Overall, our study demonstrated efficacy of the Sm-p80 vaccine and provides insight into some of the epistatic interactions associated with protection., (© 2018 New York Academy of Sciences.)

Schistosomiasis is of public health importance to an estimated one billion people in 79 countries. A vaccine is urgently needed. Here, we report the results of four independent, double-blind studies of an Sm-p80-based vaccine in baboons. The vaccine exhibited potent prophylactic efficacy against transmission of Schistosoma mansoni infection and was associated with significantly less egg-induced pathology, compared with unvaccinated control animals. Specifically, the vaccine resulted in a 93.45% reduction of pathology-producing female worms and significantly resolved the major clinical manifestations of hepatic/intestinal schistosomiasis by reducing the tissue egg-load by 89.95%. A 35-fold decrease in fecal egg excretion in vaccinated animals, combined with an 81.51% reduction in hatching of eggs into the snail-infective stage (miracidia), demonstrates the parasite transmission-blocking potential of the vaccine. Substantially higher Sm-p80 expression in female worms and Sm-p80-specific antibodies in vaccinated baboons appear to play an important role in vaccine-mediated protection. Preliminary analyses of RNA sequencing revealed distinct molecular signatures of vaccine-induced effects in baboon immune effector cells. This study provides comprehensive evidence for the effectiveness of an Sm-p80-based vaccine for schistosomiasis., (© 2018 New York Academy of Sciences.)