Early Immunomodulatory Program Triggered by Protolerogenic Bifidobacterium pseudolongum Drives Cardiac Transplant Outcomes.

BACKGROUND: Despite ongoing improvements to regimens preventing allograft rejection, most cardiac and other organ grafts eventually succumb to chronic vasculopathy, interstitial fibrosis, or endothelial changes, and eventually graft failure. The events leading to chronic rejection are still poorly understood and the gut microbiota is a known driving force in immune dysfunction. We previously showed that gut microbiota dysbiosis profoundly influences the outcome of vascularized cardiac allografts and subsequently identified biomarker species associated with these differential graft outcomes. METHODS: In this study, we further detailed the multifaceted immunomodulatory properties of protolerogenic and proinflammatory bacterial species over time, using our clinically relevant model of allogenic heart transplantation. RESULTS: In addition to tracing longitudinal changes in the recipient gut microbiome over time, we observed that Bifidobacterium pseudolongum induced an early anti-inflammatory phenotype within 7 d, whereas Desulfovibrio desulfuricans resulted in a proinflammatory phenotype, defined by alterations in leukocyte distribution and lymph node (LN) structure. Indeed, in vitro results showed that B pseudolongum and D desulfuricans acted directly on primary innate immune cells. However, by 40 d after treatment, these 2 bacterial strains were associated with mixed effects in their impact on LN architecture and immune cell composition and loss of colonization within gut microbiota, despite protection of allografts from inflammation with B pseudolongum treatment. CONCLUSIONS: These dynamic effects suggest a critical role for early microbiota-triggered immunologic events such as innate immune cell engagement, T-cell differentiation, and LN architectural changes in the subsequent modulation of protolerant versus proinflammatory immune responses in organ transplant recipients.

Rapid intestinal and systemic metabolic reprogramming in an immunosuppressed environment.

Intrinsic metabolism shapes the immune environment associated with immune suppression and tolerance in settings such as organ transplantation and cancer. However, little is known about the metabolic activities in an immunosuppressive environment. In this study, we employed metagenomic, metabolomic, and immunological approaches to profile the early effects of the immunosuppressant drug tacrolimus, antibiotics, or both in gut lumen and circulation using a murine model. Tacrolimus induced rapid and profound alterations in metabolic activities within two days of treatment, prior to alterations in gut microbiota composition and structure. The metabolic profile and gut microbiome after seven days of treatment was distinct from that after two days of treatment, indicating continuous drug effects on both gut microbial ecosystem and host metabolism. The most affected taxonomic groups are Clostriales and Verrucomicrobiae (i.e., Akkermansia muciniphila), and the most affected metabolic pathways included a group of interconnected amino acids, bile acid conjugation, glucose homeostasis, and energy production. Highly correlated metabolic changes were observed between lumen and serum metabolism, supporting their significant interactions. Despite a small sample size, this study explored the largely uncharacterized microbial and metabolic events in an immunosuppressed environment and demonstrated that early changes in metabolic activities can have significant implications that may serve as antecedent biomarkers of immune activation or quiescence. To understand the intricate relationships among gut microbiome, metabolic activities, and immune cells in an immune suppressed environment is a prerequisite for developing strategies to monitor and optimize alloimmune responses that determine transplant outcomes.

Rapid intestinal and systemic metabolic reprogramming in an immunosuppressed environment.

Intrinsic metabolism shapes the immune environment associated with immune suppression and tolerance in settings such as organ transplantation and cancer. However, little is known about the metabolic activities in an immunosuppressive environment. In this study, we employed metagenomic, metabolomic, and immunological approaches to profile the early effects of the immunosuppressant drug tacrolimus, antibiotics, or both in gut lumen and circulation using a murine model. Tacrolimus induced rapid and profound alterations in metabolic activities within two days of treatment, prior to alterations in gut microbiota composition and structure. The metabolic profile and gut microbiome after seven days of treatment was distinct from that after two days of treatment, indicating continuous drug effects on both gut microbial ecosystem and host metabolism. The most affected taxonomic groups are Clostriales and Verrucomicrobiae (i.e., Akkermansia muciniphila), and the most affected metabolic pathways included a group of interconnected amino acids, bile acid conjugation, glucose homeostasis, and energy production. Highly correlated metabolic changes were observed between lumen and serum metabolism, supporting their significant interactions. Despite a small sample size, this study explored the largely uncharacterized microbial and metabolic events in an immunosuppressed environment and demonstrated that early changes in metabolic activities can have significant implications that may serve as antecedent biomarkers of immune activation or quiescence. To understand the intricate relationships among gut microbiome, metabolic activities, and immune cells in an immune suppressed environment is a prerequisite for developing strategies to monitor and optimize alloimmune responses that determine transplant outcomes.

Strain-specific alterations in gut microbiome and host immune responses elicited by tolerogenic Bifidobacterium pseudolongum.

The beneficial effects attributed to Bifidobacterium are largely attributed to their immunomodulatory capabilities, which are likely to be species- and even strain-specific. However, their strain-specificity in direct and indirect immune modulation remain largely uncharacterized. We have shown that B. pseudolongum UMB-MBP-01, a murine isolate strain, is capable of suppressing inflammation and reducing fibrosis in vivo. To ascertain the mechanism driving this activity and to determine if it is specific to UMB-MBP-01, we compared it to a porcine tropic strain B. pseudolongum ATCC25526 using a combination of cell culture and in vivo experimentation and comparative genomics approaches. Despite many shared features, we demonstrate that these two strains possess distinct genetic repertoires in carbohydrate assimilation, differential activation signatures and cytokine responses signatures in innate immune cells, and differential effects on lymph node morphology with unique local and systemic leukocyte distribution. Importantly, the administration of each B. pseudolongum strain resulted in major divergence in the structure, composition, and function of gut microbiota. This was accompanied by markedly different changes in intestinal transcriptional activities, suggesting strain-specific modulation of the endogenous gut microbiota as a key to immune modulatory host responses. Our study demonstrated a single probiotic strain can influence local, regional, and systemic immunity through both innate and adaptive pathways in a strain-specific manner. It highlights the importance to investigate both the endogenous gut microbiome and the intestinal responses in response to probiotic supplementation, which underpins the mechanisms through which the probiotic strains drive the strain-specific effect to impact health outcomes.

Introspective Meditation before Seeking Pleasurable Activities as a Stress Reduction Tool among College Students: A Multi-Theory Model-Based Pilot Study.

In the realm of behavioral interventions, a combined approach of yoga and a cognitive-behavioral strategy in the form of introspective meditation (manan-dhyana) may offer benefits as a stress management tool. This pilot study focuses on introspective meditation performed before seeking pleasurable activities, which is a self-reflection about whether to pursue a goal that will bring sensory pleasure in life. A non-probability sample of college students was recruited from a mid-sized Southern University of the United States using a 52-items web-based survey built in Qualtrics. Univariate, bivariate, and multivariate statistics were used to analyze data. Of total 65 students, only 21.5% students reported being engaged in the introspective meditation. The sample constituted predominantly females (75.4%), White (64.6%), and undergraduate students (87.7%). The proportions of anxiety, depression, and moderate/high stress were 50.8%, 40.0%, 86.1% respectively. In the hierarchical regression for initiation, the final model explained nearly 21.1% of variance in initiating introspective meditation among participants (n = 51) who had not been practicing it. With each unit increment in subscales of initiation (i.e., changes in physical environment), the conditional mean for initiating introspective meditation behavior increased by 0.373 units. In the hierarchical regression for sustenance, the final model explained nearly 50.5% of variance in sustaining introspective meditation behavior among participants (n = 51) who had not been practicing it. With each unit increment in subscales of sustenance (i.e., emotional transformation), the conditional mean for sustaining introspective meditation behavior increased by 0.330 units. This study can pave a way for designing interventions for college students to promote introspective meditation directed toward seeking pleasurable activities before engaging in them. This has implications for the reduction of stress as well as a preemptive measure for sexual risk-taking, indulgence in maladaptive behaviors such as smoking, vaping, alcohol, and substance use.

PD-L1 signaling selectively regulates T cell lymphatic transendothelial migration.

Programmed death-1 (PD-1) and its ligand PD-L1 are checkpoint molecules which regulate immune responses. Little is known about their functions in T cell migration and there are contradictory data about their roles in regulatory T cell (Treg) function. Here we show activated Tregs and CD4 effector T cells (Teffs) use PD-1/PD-L1 and CD80/PD-L1, respectively, to regulate transendothelial migration across lymphatic endothelial cells (LECs). Antibody blockade of Treg PD-1, Teff CD80 (the alternative ligand for PD-L1), or LEC PD-L1 impairs Treg or Teff migration in vitro and in vivo. PD-1/PD-L1 signals through PI3K/Akt and ERK to regulate zipper junctional VE-cadherin, and through NFκB-p65 to up-regulate VCAM-1 expression on LECs. CD80/PD-L1 signaling up-regulates VCAM-1 through ERK and NFκB-p65. PD-1 and CD80 blockade reduces tumor egress of PD-1high fragile Tregs and Teffs into draining lymph nodes, respectively, and promotes tumor regression. These data provide roles for PD-L1 in cell migration and immune regulation.

Treg tissue stability depends on lymphotoxin beta-receptor- and adenosine-receptor-driven lymphatic endothelial cell responses.

Regulatory T cell (Treg) lymphatic migration is required for resolving inflammation and prolonging allograft survival. Focusing on Treg interactions with lymphatic endothelial cells (LECs), we dissect mechanisms and functional consequences of Treg transendothelial migration (TEM). Using three genetic mouse models of pancreatic islet transplantation, we show that Treg lymphotoxin (LT) αß and LEC LTß receptor (LTßR) signaling are required for efficient Treg migration and suppressive function to prolong allograft survival. Inhibition of LT signaling increases Treg conversion to Foxp3loCD25lo exTregs. In a transwell-based model of TEM across polarized LECs, non-migrated Tregs become exTregs. Such conversion is regulated by LTßR nuclear factor κB (NF-κB) signaling in LECs, which increases interleukin-6 (IL-6) production and drives exTreg conversion. Migrating Tregs are ectonucleotidase CD39hi and resist exTreg conversion in an adenosine-receptor-2A-dependent fashion. Human Tregs migrating across human LECs behave similarly. These molecular interactions can be targeted for therapeutic manipulation of immunity and suppression.

Can the Multi-Theory Model (MTM) of Health Behavior Change Explain the Intent for People to Practice Meditation?

Meditation is gaining popularity as adjuvant therapy for many chronic ailments, mental well-being, and spiritual growth. Behavioral theories have been underutilized in understanding meditation behavior. This study aimed to test if a fourth-generation multi-theory model (MTM) could explain the intent for starting and maintaining meditation behavior in a sample of US adults. A face and content valid 48-item instrument based on MTM was administered in a cross-sectional design through an online survey (n = 330). Internal consistency (Cronbach's alpha > 0.70) and construct validation using structural equation modeling of the subscales were all acceptable. Hierarchical multiple regression revealed that, after controlling for demographic covariates, the MTM constructs of participatory dialogue (ß = 0.153; P = .002) and behavioral confidence (ß = 0.479; P < .001) were statistically significant in predicting intent for starting meditation behavior and accounted for 32.9% of the variance. Furthermore, after controlling for demographic covariates, the MTM constructs of emotional transformation (ß = 0.390; P < .001) and changes in the social environment (ß = 0.395; P < .001) were statistically significant and accounted for 52.9% of the variance in the intent for maintaining meditation behavior. Based on this study, it can be concluded that MTM offers a pragmatic framework to design, implement, and evaluate evidence-based (theory-based) meditation behavior change interventions.

The Role of Vitamin E in Slowing Down Mild Cognitive Impairment: A Narrative Review.

With the aging population, dementia emerges as a public health concern. In 2012, the Health and Retirement Study found that 8.8% of adults over 65 years suffered from dementia. The etiopathogenesis and treatment of dementia are not well understood. Antioxidant properties of Vitamin E and its major elements tocopherols and tocotrienols have been reported to be effective in slowing down the progression of dementia from its initial stage of Mild cognitive impairment (MCI). Therefore, the current review aims to explore the role of vitamin E on MCI. A literature search using the key words "Vitamin E, tocopherols, tocotrienols, and mild cognitive impairment" was conducted in MEDLINE (PubMed), CINAHL, and Google Scholar. The inclusion criteria were: (1) articles published in the past ten years; (2) published in English language; (3) published in peer-reviewed journals; and (4) descriptive and epidemiological or evaluation studies. Articles published prior to 2010, focused on other forms of dementia than MCI, grey literature and non-peer-reviewed articles were excluded. A total of 22 studies were included in the narrative synthesis. The results were equivocal. Eleven studies showed some level of the neuroprotective effect of Vitamin E, tocopherols and tocotrienols on the progression of MCI. The mixed results of this review suggest further exploration of the possible protective effects of Vitamin E on the development of dementia. Future studies can be conducted to decipher antioxidant properties of vitamin E and its association with slowing down the cognitive decline.

Chronic rejection as a persisting phantom menace in organ transplantation: a new hope in the microbiota?

PURPOSE OF REVIEW: The microbiota plays an important role in health and disease. During organ transplantation, perturbations in microbiota influence transplant outcome. We review recent advances in characterizing microbiota and studies on regulation of intestinal epithelial barrier function and mucosal and systemic immunity by microbiota and their metabolites. We discuss implications of these interactions on transplant outcomes. RECENT FINDINGS: Metagenomic approaches have helped the research community identify beneficial and harmful organisms. Microbiota regulates intestinal epithelial functions. Signals released by epithelial cells or microbiota trigger pro-inflammatory or anti-inflammatory effects on innate and adaptive immune cells, influencing the structure and function of the immune system. Assessment and manipulation of microbiota can be used for biomarkers for diagnosis, prognosis, and therapy. SUMMARY: The bidirectional dialogue between the microbiota and immune system is a major influence on immunity. It can be targeted for biomarkers or therapy. Recent studies highlight a close association of transplant outcomes with microbiota, suggesting exciting potential avenues for management of host physiology and organ transplantation.

Testing Multi-Theory Model (MTM) in Explaining Sunscreen Use among Florida Residents: An Integrative Approach for Sun Protection.

Florida residents have the second highest incidence of skin cancer in the nation. Sunscreen usage was found to be the one of the most effective integrative health approaches for reducing risk of skin cancer. Given the limited information on the likelihood of adopting and continuing sunscreen usage behavior, this cross-sectional study aimed to examine the correlates of initiating and sustaining sunscreen usage behavior among Florida dwellers, using the fourth-generation, multi-theory model (MTM) of behavior change. A web-based survey containing 51 questions was emailed to Florida residents aged 18 years or above, who were randomly selected from the state voter file. Psychometric validity of the survey instrument was established using structural equation modeling, and Cronbach's alpha values were calculated for assessing the internal consistency. An independent-samples-t-test and hierarchical multiple regression tests were used to analyze the data. The results indicated that participants who engaged in sunscreen usage behavior, participatory dialogue (ß = 0.062, p < 0.05), behavioral confidence (ß = 0.636, p < 0.001), and changes in the physical environment (ß = 0.210, p < 0.001) were statistically significant and accounted for 73.6% of the variance in initiating sunscreen usage behavior. In addition, the constructs of emotional transformation (ß = 0.486, p < 0.001) and practice for change (ß = 0.211, p < 0.001), as well as changes in the social environment (ß = 0.148, p < 0.001) were significant predictors of maintaining sunscreen usage behavior and contributed to 59% of variance in sustenance. These findings offer a valuable insight regarding the applicability of MTM models to guiding public health interventions promoting sunscreen usage and preventing UV radiation risk and related skin cancer.

Quality of Life after Surviving a Spinal Cord Injury: An Observational Study in South India.

BACKGROUND: Spinal cord injury (SCI) and its negative impact on the quality of life (QOL) is a significant public health concern in India. People with SCI suffer from serious health, economic, and social consequences in their lives. Often, care for SCI survivors is left to their immediate family members in India. Appropriate planning is needed for prevention, rehabilitation, health, and psychological care for SCI in the country. PURPOSE: This study assessed the overall QOL of SCI survivors and their satisfaction levels with specific domains and their importance of QOL. MATERIALS AND METHODS: In this observational study, two instruments, Farrens and Power for QOL and Barthel Index for functional abilities, were administered to a convenience sample of participants drawn from Narayana Medical College, Nellore, in South India. RESULTS: Statistically, SCI survivors were found moderately and very satisfied with their QOL. Their perception about importance of health, functioning, social, and economic subscale also did not differ statistically.

Mechanisms of exTreg induction.

CD4+ CD25+ Foxp3+ Tregs play an important role in the maintenance of the immune system by regulating immune responses and resolving inflammation. Tregs exert their function by suppressing other immune cells and mediating peripheral self-tolerance. Under homeostatic conditions, Tregs are stable T-cell populations. However, under inflammatory environments, Tregs are converted to CD4+ CD25low Foxp3low cells. These cells are termed "exTreg" or "exFoxp3" cells. The molecular mechanism of Treg transition to exTregs remains incompletely understood. Uncertainties might be explained by a lack of consensus of biological markers to define Treg subsets in general and exTregs in particular. In this review, we summarize known markers of Tregs and factors responsible for exTreg generation including cytokines, signaling pathways, transcription factors, and epigenetic mechanisms. We also identify studies demonstrating the presence of exTregs in various diseases and sources of exTregs. Understanding the biology of Treg transition to exTregs will help in designing Treg-based therapeutic approaches.

LTßR Signaling Controls Lymphatic Migration of Immune Cells.

The pleiotropic functions of lymphotoxin (LT)ß receptor (LTßR) signaling are linked to the control of secondary lymphoid organ development and structural maintenance, inflammatory or autoimmune disorders, and carcinogenesis. Recently, LTßR signaling in endothelial cells has been revealed to regulate immune cell migration. Signaling through LTßR is comprised of both the canonical and non-canonical-nuclear factor κB (NF-κB) pathways, which induce chemokines, cytokines, and cell adhesion molecules. Here, we focus on the novel functions of LTßR signaling in lymphatic endothelial cells for migration of regulatory T cells (Tregs), and specific targeting of LTßR signaling for potential therapeutics in transplantation and cancer patient survival.

Correlates of COVID-19 Pandemic on Anxiety among Adults in Appalachia, USA.

BACKGROUND: Anxiety problems have increased in the COVID-19 pandemic worldwide. However, very little is known about the anxiety rates in the new normal phase of the disease when adults have been assumed to be adjusted. The study aimed to find out the difference in anxiety in a convenience sample of Appalachian adults during the new normal phase of the COVID-19 pandemic, examine its association with sociodemographic factors, and compare it with the anxiety levels before the pandemic as recalled by the participants. STUDY DESIGN: A cross-sectional study. METHODS: The Generalized Anxiety Disorder-7 scale was used in the present study. The Chi-square test was used to examine the difference between the severity of anxiety before and during the new normal phase of the COVID-19 pandemic in terms of sociodemographic and behavioral correlates. Pearson correlation was used to see the strength of the association between anxiety and age. RESULTS: Although the anxiety rate was stabilized by the time people approached the new normal phase of the COVID-19 pandemic, its severity increased significantly among those with preexisting anxiety (P=0.001). Anxiety was found highly associated with female and minority gender, student status, lower education and income level, marital status, cohabitation with parents, and cigarette consumption (P=0.001). A slight inverse association was observed between age and anxiety before and during the new normal phase of the COVID-19 pandemic (P=0.001). CONCLUSION: The young and females seem to be suffering from a higher burden of anxiety. Research is suggested to identify ways to develop social support-based community programs to address this issue.

Prevalence of Depression, Anxiety, and Stress during COVID-19 Pandemic.

The coronavirus disease 2019 (COVID-19) crisis has greatly affected human lives across the world. Uncertainty and quarantine have been affecting people's mental health. Estimations of mental health problems are needed immediately for the better planning and management of these concerns at a global level. A rapid scoping review was conducted to get the estimation of mental health problems in the COVID-19 pandemic during the first 7 months. Peer-reviewed, data-based journal articles published in the English language were searched in the PubMed, Medline, and Google Scholar electronic databases from December 2019 to June 2020. Papers that met the inclusion criteria were analyzed and discussed in this review. A total of 16 studies were included. Eleven studies were from China, two from India, and one from Spain, Italy, and Iran. Prevalence of all forms of depression was 20%, anxiety 35%, and stress 53% in the combined study population of 113,285 individuals. The prevalence rate of all forms of depression, anxiety, stress, sleep problems, and psychological distress in general population was found to be higher during COVID-19 pandemic.