Salt-responsive gut commensal modulates TH17 axis and disease.

A Western lifestyle with high salt consumption can lead to hypertension and cardiovascular disease. High salt may additionally drive autoimmunity by inducing T helper 17 (TH17) cells, which can also contribute to hypertension. Induction of TH17 cells depends on gut microbiota; however, the effect of salt on the gut microbiome is unknown. Here we show that high salt intake affects the gut microbiome in mice, particularly by depleting Lactobacillus murinus. Consequently, treatment of mice with L. murinus prevented salt-induced aggravation of actively induced experimental autoimmune encephalomyelitis and salt-sensitive hypertension by modulating TH17 cells. In line with these findings, a moderate high-salt challenge in a pilot study in humans reduced intestinal survival of Lactobacillus spp., increased TH17 cells and increased blood pressure. Our results connect high salt intake to the gut-immune axis and highlight the gut microbiome as a potential therapeutic target to counteract salt-sensitive conditions.

Natural variants of α-gliadin peptides within wheat proteins with reduced toxicity in coeliac disease.

The only generally accepted treatment of coeliac disease (CD) is a lifelong gluten-free diet. Wheat gluten proteins include gliadins, low and high molecular weight glutenins. However, we have found significant structural variations within these protein families among different cultivars. To determine which structural motifs might be less toxic than others, we assessed five variants of α-gliadin immunodominant CD-toxic peptides synthesised as 16mers in CD T cell stimulation assays with gluten-sensitive T cell lines generated from duodenal biopsies from CD-affected individuals. The peptides harboured the overlapping T cell epitopes DQ 2.5-glia-α-2 and naturally occurring variants that differed in certain amino acids (AA). The results revealed that introduction of two selected AA substitutions in α-gliadin peptides reduced immunogenicity. A peptide with three AA substitutions involving two glutamic acids (E) and one glutamine residue (G) revealed the peptide was negative in 5:5 samples. We used CD small-intestinal organ culture to assess CD toxicity that revealed two peptides with selected substitution of both glutamic acid (E) and proline (P) residues abrogated evidence of CD toxicity.

Addictive Potential of Social Media: A Cross Sectional Study in Portugal.

INTRODUCTION: The use of social media is an extremely popular activity, with an average time spent of two and a half hours daily. The number of users continues to rise, with 4.65 billion around the world in 2022, approximately 58.7% of the world population. A rising number of studies show that a minority of these persons will develop a behavioral addiction on social media. The aim of this study was to understand if the use of a specific social media platform predicts increased addictive potential. MATERIAL AND METHODS: A cross-sectional sample of 300 persons (aged 18 years-old or older, 60.33% female), completed an online survey including sociodemographic questions, data regarding the use of social media and the Bergen Social Media Addiction Scale (BSMAS). Linear and logistic regression models were performed to determine the risk for each media platform. RESULTS: Instagram® use was a significant predictor of higher scores on the BSMAS (B 2.51; p < 0.0001; CI 1.33 - 3.69). The use of other platforms including Facebook® (B -0.31), Twitter® (B 1.38) and Pinterest® (B -0.15) was not found to predict a higher risk of social media addiction. CONCLUSION: Instagram® scored a higher grade in BSMAS scale, with statistical significance, which could suggest a higher addictive potential. More research is needed to establish the direction of this relationship, since the cross-sectional study design does not allow inferences about directionality.

Introdução: A utilização de redes sociais é uma atividade bastante popular nos dias de hoje, com um tempo médio de utilização diária de duas horas e meia. O número de utilizadores continua a aumentar, perfazendo 4,65 mil milhões em 2022, aproximadamente 58,7% da população mundial. Um número crescente de estudos mostra que uma minoria destes utilizadores irá desenvolver uma adicção comportamental às redes sociais. O objetivo deste estudo é compreender se o uso de uma plataforma de rede social específica é um preditor de maior potencial adictivo. Material e Métodos: Uma amostra de 300 pessoas (idade igual ou superior a 18 anos, 60,33% sexo feminino), completou um questionário online, com fatores sociodemográficos, dados acerca do uso de redes sociais e a Bergen Social Media Addiction Scale (BSMAS). Foram feitas análises de regressão linear e logística para determinar o potencial de adicção de cada plataforma. Resultados: A utilização do Instagram® foi um preditor significativo para pontuações mais altas na BSMAS (B 2,51; p < 0,0001; CI 1,33 - 3,69). O uso de outras plataformas, incluindo o Facebook® (B -0,31), o Twitter® (B 1,38) e o Pinterest® (B -0,15) não pareceu ser um preditor de maior risco adictivo Conclusão: O Instagram® atingiu uma maior classificação na BSMAS, com significância estatística, o que pode sugerir um maior potencial adictivo. É necessária mais investigação para estabelecer a direção desta relação, visto que o desenho transversal não permite inferências sobre a direccionalidade.

Triggers for acute mood episodes in bipolar disorder: A systematic review.

OBJECTIVES: To identify triggers of acute mood episodes in bipolar disorder (BD). METHODS: We performed a systematic review in the following databases: Pubmed, Embase, and PsycInfo following the preferred reporting items for systematic reviews and meta-analysis guidelines. The systematic search encompassed all relevant studies published until May 23rd, 2022. RESULTS: A total of 108 studies (case reports/case series, interventional, prospective and retrospective studies) were included in the systematic review. While several decompensation triggers were identified, pharmacotherapy was the one with the largest body of evidence, particularly the use of antidepressants as triggers of manic/hypomanic episodes. Other identified triggers for mania were brain stimulation, energy drinks, acetyl-l-carnitine, St. John's wort, seasonal changes, hormonal changes and viral infections. There is a relative paucity of evidence concerning triggers for depressive relapses in BD, with possible triggers including fasting, decreased sleep and stressful life events. CONCLUSIONS: This is the first systematic review about triggers/precipitants of relapse in BD. Despite the importance of identification and management of potential triggers for BD decompensation, there is a lack of large observational studies addressing this topic, with most of the included studies being case reports/case series. Notwithstanding these limitations, antidepressant use is the trigger with the strongest evidence for manic relapse. More studies are needed to identify and manage triggers for relapse in BD.

Atypical antipsychotic-induced mania: A systematic review and meta-analysis.

BACKGROUND: The possibility of atypical antipsychotics (AA) to induce manic symptoms has been raised by several articles. The objective of this study was to describe whether exposure to AA may induce mania in mood disorders. METHODS: We performed a systematic review following the preferred reporting items for systematic reviews and meta-analysis guidelines. The systematic search encompassed all relevant studies published until April 4th, 2022. A meta-analysis testing whether treatment emergent mania (TEM) is more frequent with the use of AA compared with placebo was performed. RESULTS: A total of 52 studies were included in the systematic review. We found 24 case reports or case series describing 40 manic/hypomanic episodes allegedly induced by AA. Twenty-one placebo-controlled trials were included in a meta-analysis including 4823 individuals treated with AA and 3252 individuals receiving placebo. Our meta-analysis showed that the use of AA protects against the development of TEM (OR: 0.68 [95 % CI: 0.52-0.89], p = 0.005). LIMITATIONS: AA-induced mania/hypomania was not the primary outcome in any of the observational or interventional studies. TEM was not homogeneously defined across studies. In most case reports it was not possible to establish causality between the use of AA and the development of manic symptoms. CONCLUSIONS: TEM is more frequent with placebo than with AA, which suggests that AA exposure does not represent a relevant risk for TEM. Mania/hypomania induced by an AA seems to be rare events, since anecdotal evidence from case reports and case series were not observed in observational prospective and interventional studies.

Fatty acid desaturation by stearoyl-CoA desaturase-1 controls regulatory T cell differentiation and autoimmunity.

The imbalance between pathogenic and protective T cell subsets is a cardinal feature of autoimmune disorders such as multiple sclerosis (MS). Emerging evidence indicates that endogenous and dietary-induced changes in fatty acid metabolism have a major impact on both T cell fate and autoimmunity. To date, however, the molecular mechanisms that underlie the impact of fatty acid metabolism on T cell physiology and autoimmunity remain poorly understood. Here, we report that stearoyl-CoA desaturase-1 (SCD1), an enzyme essential for the desaturation of fatty acids and highly regulated by dietary factors, acts as an endogenous brake on regulatory T-cell (Treg) differentiation and augments autoimmunity in an animal model of MS in a T cell-dependent manner. Guided by RNA sequencing and lipidomics analysis, we found that the absence of Scd1 in T cells promotes the hydrolysis of triglycerides and phosphatidylcholine through adipose triglyceride lipase (ATGL). ATGL-dependent release of docosahexaenoic acid enhanced Treg differentiation by activating the nuclear receptor peroxisome proliferator-activated receptor gamma. Our findings identify fatty acid desaturation by SCD1 as an essential determinant of Treg differentiation and autoimmunity, with potentially broad implications for the development of novel therapeutic strategies and dietary interventions for autoimmune disorders such as MS.

Sodium perturbs mitochondrial respiration and induces dysfunctional Tregs.

FOXP3+ regulatory T cells (Tregs) are central for peripheral tolerance, and their deregulation is associated with autoimmunity. Dysfunctional autoimmune Tregs display pro-inflammatory features and altered mitochondrial metabolism, but contributing factors remain elusive. High salt (HS) has been identified to alter immune function and to promote autoimmunity. By investigating longitudinal transcriptional changes of human Tregs, we identified that HS induces metabolic reprogramming, recapitulating features of autoimmune Tregs. Mechanistically, extracellular HS raises intracellular Na+, perturbing mitochondrial respiration by interfering with the electron transport chain (ETC). Metabolic disturbance by a temporary HS encounter or complex III blockade rapidly induces a pro-inflammatory signature and FOXP3 downregulation, leading to long-term dysfunction in vitro and in vivo. The HS-induced effect could be reversed by inhibition of mitochondrial Na+/Ca2+ exchanger (NCLX). Our results indicate that salt could contribute to metabolic reprogramming and that short-term HS encounter perturb metabolic fitness and long-term function of human Tregs with important implications for autoimmunity.

Long Time, No Sleep: Sleep in Older Adults During the COVID-19 Pandemic.

Objective: The coronavirus disease 2019 (COVID-19) pandemic has had a major impact globally. While sleep problems have increased during the pandemic, their impact on specific populations is less well known. The objective of this study was to measure the impact of the COVID-19 pandemic on sleep and how it correlates with the feeling of isolation in individuals aged ≥ 50 years.Methods: A cross-sectional study was conducted using data from the Survey of Health, Aging, and Retirement conducted between June and August 2020. A multivariate logistic regression model was performed to analyze the outcome "more or less trouble sleeping since the outbreak" and its main predictors.Results: The mean ± SD age of the participants was 71 ± 9 years. Since the outbreak, 29% reported a deterioration of their quality of sleep. Being male and older were found to be significant predictors of more sleep complaints (OR = 1.13; P = .004; CI, 1.04-1.23 and OR = 1.02; P = .000; CI, 1.02-1.03, respectively). Moreover, those who claimed that they often felt alone or more loneliness since the beginning of the outbreak also had more trouble sleeping (OR = 1.21; P = .002; CI, 1.07-1.37 and OR = 4.06; P = .000; CI, 2.75-5.99, respectively).Conclusions: Male sex, older age, and loneliness are associated with more sleeping difficulties since the beginning of the COVID-19 pandemic. These findings can aid health authorities to address sleep issues in this vulnerable population more directly.

High-Salt Diet Induces Depletion of Lactic Acid-Producing Bacteria in Murine Gut.

Dietary habits are amongst the main factors that influence the gut microbiome. Accumulating evidence points to the impact of a high-salt diet (HSD) on the composition and function of the intestinal microbiota, immune system and disease. In the present study, we thus investigated the effects of different NaCl content in the food (0.03%/sodium deficient, 0.5%/control, 4% and 10% NaCl) on the gut microbiome composition in mice. The bacterial composition was profiled using the 16S ribosomal RNA (rRNA) gene amplicon sequencing. Our results revealed that HSD led to distinct gut microbiome compositions compared to sodium-deficient or control diets. We also observed significant reduction in relative abundances of bacteria associated with immuno-competent short-chain fatty acid (SCFA) production (Bifidobacterium, Faecalibaculum, Blautia and Lactobacillus) in HSD-fed mice along with significant enrichment of Clostridia, Alistipes and Akkermansia depending on the sodium content in food. Furthermore, the predictive functional profiling of microbial communities indicated that the gut microbiota found in each category presents differences in metabolic pathways related to carbohydrate, lipid and amino acid metabolism. The presented data show that HSD cause disturbances in the ecological balance of the gastrointestinal microflora primarily through depletion of lactic acid-producing bacteria in a dose-dependent manner. These findings may have important implications for salt-sensitive inflammatory diseases.

Dissecting the role of CSF2RB expression in human regulatory T cells.

Colony stimulating factor 2 receptor subunit beta (CSF2RB; CD131) is the common subunit of the type I cytokine receptors for granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-3 and IL-5. Interestingly, FOXP3+ regulatory T cells (Tregs), which play a pivotal role in prevention of autoimmunity have been demonstrated to highly overexpress CSF2RB and genome-wide association studies (GWAS) identified CSF2RB as being linked to autoimmune diseases like multiple sclerosis (MS). However, the exact biological role of CD131 in human Tregs has not been defined yet. Here we investigated CD131 importance on Treg phenotype and function in a broad range of in vitro studies. Although we could not recognize a specific function of CSF2RB; CD131 in human Tregs, our data show that CD131 expression is vastly restricted to Tregs even under stimulatory conditions, indicating that CD131 could aid as a potential marker to identify Treg subpopulations from pools of activated CD4+ T cells. Importantly, our analysis further demonstrate the overexpression of CSF2RB in Tregs of patients with autoimmune diseases like MS and systemic lupus erythematosus (SLE) in comparison to healthy controls, thereby indicating that CSF2RB expression in Tregs could serve as a potential novel biomarker for disease.

[The Impact of COVID-19 in Older People in Portugal: Results from the Survey of Health, Ageing and Retirement (SHARE)]. / O Impacto da COVID-19 na População Idosa em Portugal: Resultados do Survey of Health, Ageing and Retirement (SHARE).

INTRODUCTION: In March 2020, the World Health Organization declared COVID-19 as a pandemic, and Portugal reported its initial cases. In this study, we aimed to determine the impact of COVID-19 on Portuguese individuals aged over 60 years old. MATERIAL AND METHODS: We performed a cross-sectional study using data from the Survey of Health, Ageing and Retirement in Europe (SHARE 8: COVID-19 Survey). We selected a sample of 1080 noninstitutional Portuguese individuals aged ≥ 60 years. RESULTS: The study sample consisted of 605 (56%) women and 475 (44%) men, with a mean age of 70 ± 9.1 years. In total, 80% of the participants experienced higher levels of anxiety, 73% felt more depressed and 30% experienced additional sleep problems comparedto the period before the pandemic. Interestingly, there were no statistically significant differences between the sexes or the two selected age groups (60 - 74 and over 75 years old) regarding the incidence of these changes. Only 23%, of those that were interviewed maintained their walking routines. In addition, only 8% of the participants continued visiting family members as frequently as before. While 8% of the participants were refused some form of medical treatment, 56% claimed that they experienced healthcare delays. However,only 15% of the participants reported that their health status worsened during the pandemic. DISCUSSION: The pandemic has had a significant impact on Portuguese individuals aged ≥ 60 years; which is in agreement with the findings of previous international studies. It changed the participants' routines and increased their anxiety and depression levels. Despite the deterioration of healthcare services, most participants did not experience worsening of their health status. CONCLUSION: In conclusion, a COVID-19 pandemic had a significant impact on the elderly population, particularly regarding their mental health.

Introdução: Em março de 2020, a COVID-19 foi declarada pandemia pela Organização Mundial da Saúde e Portugal registou os seus primeiros casos. Este estudo visou determinar o impacto da COVID-19 na população portuguesa maior de 60 anos. Material e Métodos: Trata-se de um estudo observacional transversal que analisa várias variáveis de saúde, comportamentais, sociais e económicas. Utilizaram-se dados do projecto Survey of Health, Ageing and Retirement (SHARE 8: COVID-19 Survey), seleccionando uma amostra de 1080 portugueses não institucionalizados e maiores de 60 anos. Resultados: A amostra englobou 605 mulheres (56%) e 475 homens (44%), com idade média de 70 ± 9,1 anos. No total, 80% dos participantes notou aumento da ansiedade, 73% sentiu-se mais deprimido e 30% considerou que o seu sono piorou em relação ao período anterior à pandemia. Não houve diferenças estatisticamente significativas entre os sexos ou as duas faixas etárias analisadas (60 - 74 e ≥ 75 anos) quanto à incidência destas alterações. No respeitante a saídas de casa, apenas 23% dos entrevistados manteve os hábitos de passeio e 8% manteve as visitas a familiares no seu padrão habitual. Relativamente ao acesso a cuidados médicos, a 8% foi negado algum tratamento e 56% queixou-se do adiamento dos cuidados. Apenas 13% referiu um agravamento do seu estado de saúde durante a pandemia. Discussão: Este trabalho mostra que esta pandemia impactou a população portuguesa com mais de 60 anos, o que está em linha com o reportado noutros estudos internacionais. Os hábitos alteraram-se, e a ansiedade e depressão aumentaram. Apesar da deterioração dos cuidados de saúde, a maioria dos participantes não notou agravamento do seu estado de saúde. Conclusão: Em conclusão, a pandemia por COVID-19 teve um impacto significativo na população idosa particularmente no que concerne à sua saúde mental.

Fast and Efficient Genome Editing of Human FOXP3+ Regulatory T Cells.

FOXP3+ regulatory T cells (Tregs) are central for maintaining peripheral tolerance and immune homeostasis. Because of their immunosuppressive characteristics, Tregs are a potential therapeutic target in various diseases such as autoimmunity, transplantation and infectious diseases like COVID-19. Numerous studies are currently exploring the potential of adoptive Treg therapy in different disease settings and novel genome editing techniques like CRISPR/Cas will likely widen possibilities to strengthen its efficacy. However, robust and expeditious protocols for genome editing of human Tregs are limited. Here, we describe a rapid and effective protocol for reaching high genome editing efficiencies in human Tregs without compromising cell integrity, suitable for potential therapeutic applications. By deletion of IL2RA encoding for IL-2 receptor α-chain (CD25) in Tregs, we demonstrated the applicability of the method for downstream functional assays and highlighted the importance for CD25 for in vitro suppressive function of human Tregs. Moreover, deletion of IL6RA (CD126) in human Tregs elicits cytokine unresponsiveness and thus may prevent IL-6-mediated instability of Tregs, making it an attractive target to potentially boost functionality in settings of adoptive Treg therapies to contain overreaching inflammation or autoimmunity. Thus, our rapid and efficient protocol for genome editing in human Tregs may advance possibilities for Treg-based cellular therapies.

The Impact of Dietary Components on Regulatory T Cells and Disease.

The rise in the prevalence of autoimmune diseases in developed societies has been associated with a change in lifestyle patterns. Among other factors, increased consumption of certain dietary components, such as table salt and fatty acids and excessive caloric intake has been associated with defective immunological tolerance. Dietary nutrients have shown to modulate the immune response by a direct effect on the function of immune cells or, indirectly, by acting on the microbiome of the gastrointestinal tract. FOXP3+ regulatory T cells (Tregs) suppress immune responses and are critical for maintaining peripheral tolerance and immune homeostasis, modulating chronic tissue inflammation and autoimmune disease. It is now well-recognized that Tregs show certain degree of plasticity and can gain effector functions to adapt their regulatory function to different physiological situations during an immune response. However, plasticity of Tregs might also result in conversion into effector T cells that may contribute to autoimmune pathogenesis. Yet, which environmental cues regulate Treg plasticity and function is currently poorly understood, but it is of significant importance for therapeutic purposes. Here we review the current understanding on the effect of certain dietary nutrients that characterize Western diets in Treg metabolism, stability, and function. Moreover, we will discuss the role of Tregs linking diet and autoimmunity and the potential of dietary-based interventions to modulate Treg function in disease.

High Salt Inhibits Tumor Growth by Enhancing Anti-tumor Immunity.

Excess salt intake could affect the immune system by shifting the immune cell balance toward a pro-inflammatory state. Since this shift of the immune balance is thought to be beneficial in anti-cancer immunity, we tested the impact of high salt diets on tumor growth in mice. Here we show that high salt significantly inhibited tumor growth in two independent murine tumor transplantation models. Although high salt fed tumor-bearing mice showed alterations in T cell populations, the effect seemed to be largely independent of adaptive immune cells. In contrast, depletion of myeloid-derived suppressor cells (MDSCs) significantly reverted the inhibitory effect on tumor growth. In line with this, high salt conditions almost completely blocked murine MDSC function in vitro. Importantly, similar effects were observed in human MDSCs isolated from cancer patients. Thus, high salt conditions seem to inhibit tumor growth by enabling more pronounced anti-tumor immunity through the functional modulation of MDSCs. Our findings might have critical relevance for cancer immunotherapy.

Immunometabolic Regulation of Interleukin-17-Producing T Helper Cells: Uncoupling New Targets for Autoimmunity.

Interleukin-17-producing T helper (Th17) cells are critical for the host defense of bacterial and fungal pathogens and also play a major role in driving pathogenic autoimmune responses. Recent studies have indicated that the generation of Th17 cells from naïve CD4+ T cells is coupled with massive cellular metabolic adaptations, necessary to cope with different energy and metabolite requirements associated with switching from a resting to proliferative state. Furthermore, Th17 cells have to secure these metabolic adaptations when facing nutrient-limiting environments, such as at the sites of inflammation. Accumulating data indicates that this metabolic reprogramming is significantly linked to the differentiation of T helper cells and, particularly, that the metabolic changes of Th17 cells and anti-inflammatory Forkhead box P3+ regulatory T cells are tightly and reciprocally regulated. Thus, a better understanding of these processes could offer potential new targets for therapeutic interventions for autoimmune diseases. In this mini-review, we will highlight some of the recent advances and discoveries in the field, with a particular focus on metabolic demands of Th17 cells and their implications for autoimmunity.