Tag: Cytokine

Mediterranean and vegetarian diets boost heart health by improving novel CVD markers

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In a recent study published in the journal Nutrition & Metabolism, researchers evaluated the impact of the lacto-ovo vegetarian diet (VD) and Mediterranean diet (MD) on apolipoprotein levels and cardiovascular disease (CVD) risk factors among low-moderate-risk individuals.

CVD is the leading cause of global mortality, necessitating the development of novel biomarkers for prevention, early diagnosis, and treatment. Apoproteins, which regulate lipoprotein metabolism, are considered a risk marker for CVD. The European Society of Cardiology (ESC) recommends ApoB as a CVD risk marker. ApoA-I, mainly found in high-density lipoprotein (HDL) lipids, play protective roles in reverse cholesterol transport. However, data on diet’s influence on apolipoproteins is limited.

Study: Effects of a dietary intervention with lacto-ovo-vegetarian and Mediterranean diets on apolipoproteins and inflammatory cytokines: results from the CARDIVEG study. Image Credit: Brian A Jackson / Shutterstock

About the study

In the present study, researchers assessed the influences of MD and VD diets on circulating apolipoproteins and their association with cardiovascular disease risk estimators, such as inflammatory cytokine levels and lipid profiles.

The study included 52 participants (39 women; mean age of 49 years) in the Cardiovascular Prevention with Vegetarian (CARDIVEG) diet randomized, crossover clinical trial. All individuals were at low-moderate CVD risk (<5.0% at ten years, using the ESC guidelines) and selected from the Clinical Nutrition Department of Careggi Hospital, Italy.

Eligibility individuals were overweight or obese with body mass index (BMI) ≥25 kg/m2 and ≥1.0 cardiovascular disease risk factors: low-density lipoprotein (LDL) beyond 115 mg dL^-1; triglyceride levels above 150 mg dL^-1; total cholesterol above 190 g/dL; and fasting blood glucose ranging from 110 to 125.0 mg dL^-1. The researchers excluded individuals with unstable medical conditions, medication prescriptions, expecting or breastfeeding women, and those who consumed poultry, fish, meat, or meat products or participated in weight loss programs in the previous six months.

The participants followed the MD (27 individuals) and VD (25 individuals) diets for three months. Both diets comprised 50% to 55% carbohydrates, 15% to 20% proteins, and 25% to 30% total fats (≤7.0% of saturated fat, less than 300 milligrams of cholesterol). The team provided the participants with one-week menu plans, different recipes, and precise data on foods to consume and avoid.

The primary outcomes were changes in body weight, fat mass, and BMI, and the secondary outcomes included changes in circulating CVD risk markers and apolipoprotein levels. The team obtained medical history, demographics, comorbidities, risk factors, lifestyle, and dietary data at study initiation. They collected blood samples with body composition and BMI data before and after the interventions.

The team used the Medi-Lite and National Health and Nutrition Examination Survey (NHANES) questionnaires to assess adherence to MD and VD diets, respectively. They conducted a primary analysis using general linear modeling, evaluating differences in apolipoprotein levels by sex, age, and CVD risk factors. They used linear regressions to examine the association between these changes and lipid profiles, inflammatory profiles, and dietary components.

Results

MD and VD improved lipid profiles and anthropometric variables, reducing total energy, fats, and cholesterol and increasing total carbohydrates. VD lowered protein and increased dietary fiber, while MD decreased body weight, fat mass, and BMI. VD also reduces fat-free body mass. VD reduced LDL by 5.0%, while MD reduced serum triglycerides by 9.0%. Both diets lowered inflammatory parameters, with MD significantly decreasing interleukin-10 by 37% and interleukin-17 by 49%.

Both diets reduced inflammatory parameters, with significantly higher (24%) ApoC-I levels after VD. Both diets increased ApoA-I (2.7% by VD and 6.1% by MD), ApoC-I (24% by VD and 11% by MD), and ApoD (6.5% by VD and 6.2% by MD) levels. However, ApoB/ApoA-I ratios reduced by 1.9% and 7.4% after VD and MD, respectively. Conversely, the team observed opposite trends for ApoB (+0.7% by VD and −1.6% by MD), ApoC-III (−5.6% by VD and +1.8% by MD), and ApoE (+14% by VD and −1.6% by MD).

The team found negative correlations between apolipoprotein C-III and carbohydrates after MD and between ApoD levels and saturated fats after VD. In contrast, they found positive correlations between HDL and ApoD after VD and between serum triglycerides, ApoCI, and ApoD after MD. IL-17 positively correlated with ApoB and ApoC-III after VD. However, they found significant negative correlations between ApoC-III and carbohydrate percentage after MD and between ApoD and saturated fat percentage after VD. Serum triglycerides showed positive correlations with ApoC-I and ApoD levels after MD.

HDL changes positively correlated with ApoD levels after VD. Linear regressions confirmed the results, adjusted for potential confounders such as weight change and the treatment order. The subgroup analyses showed that both diets positively influenced circulating apolipoproteins, especially in women aged ≥50 years with less than three cardiovascular disease risk factors.

The study findings showed that VD and MD improve cardiovascular disease risk in low-moderate CVD-risk individuals by regulating lipid and inflammatory profiles. MD more positively affects apolipoprotein levels, especially in women, individuals aged >50 years, and those with one or two CVD risk factors. The study also found differences in associations between apolipoprotein levels and specific nutrients, with an unexpected inverse association between carbohydrate intake and ApoC-III after MD.

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February 14, 2024
Pregnant women show significant immune system changes linked to gut microbiome

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In a recent study published in Clinical Microbiology, a group of researchers investigated how gut microbiota and metabolite changes relate to immune function during pregnancy by comparing the gut microbiota, fecal and plasma metabolites, and cytokines in pregnant and non-pregnant women.

Study: Multi-omics analysis reveals the associations between altered gut microbiota, metabolites, and cytokines during pregnancy. Image Credit: Ground Picture/Shutterstock.com

Background

Pregnancy induces significant changes in hormonal levels, body structure, and immune function, essential for fetal development.

Initially, the maternal immune system is pro-inflammatory, becoming anti-inflammatory, then shifting back to pro-inflammatory to initiate labor.

The role of the gut microbiome in immune regulation during pregnancy is increasingly recognized, with studies showing its influence on pregnancy outcomes and conditions like preeclampsia through changes in the microbial composition and interactions with immune cells.

However, the detailed mechanisms remain unclear. Metabolites, rather than direct microbial interactions, predominantly mediate the relationship between the microbiome and the immune system, highlighting areas for further research to understand pregnancy-related immune adjustments and develop new therapeutic strategies.

About the study

In the study conducted at the First Affiliated Hospital of Jinan University between February 2019 and August 2020, 30 pregnant and 15 non-pregnant women were recruited to explore the interactions between gut microbiota, metabolites, and immune function.

Eligible pregnant participants were between 18 and 34 years old, had naturally conceived singleton pregnancies, and had pre-pregnancy body mass index (BMI) of 18.5 to 21.9 kg/m², excluding those with pregnancy complications or immune disorders.

The control group consisted of healthy females matching the pregnant group in age and BMI, with neither group using probiotics or antibiotics in the six months before the study.

Fecal and blood samples were collected from pregnant women in the late third trimester and non-pregnant women on the 14th day of their menstrual cycle.

Fecal samples were obtained using sterile techniques and stored at -80°C, while blood samples were processed to separate the serum for storage under the same conditions.

The study employed 16S ribosomal ribonucleic acid (rRNA) gene sequencing to analyze the gut microbiota, with deoxyribonucleic acid (DNA) extracted and sequenced to identify microbial species.

A combination of random forest analysis and Weighted Gene Co-expression Network Analysis (WGCNA) was used to differentiate microbial profiles between groups.

Untargeted liquid chromatography-tandem mass spectrometry (LC-MS/MS) metabolomics analyzed the fecal and plasma samples to identify metabolic changes, employing quality control measures to ensure data reliability.

The metabolomic data were processed and analyzed to determine significant differences and map them to biological pathways using the Kyoto Encyclopedia of Genes and Genomes (KEGG) database.

Plasma cytokines were measured using a multiplex bead assay to assess immune function differences between the groups.

Finally, using statistical and visualization tools, multi-omics analysis integrated the data from microbial, metabolomic, and cytokine analyses to explore potential correlations and mediation effects.

Study results

The study found no significant differences between average age or pre-pregnancy BMI between the two groups. Immune profiling revealed that pregnant participants had lower levels of pro-inflammatory cytokines and higher levels of certain anti-inflammatory cytokines than the controls, indicating a shift towards immunosuppression during pregnancy.

The study also investigated gut microbiota, finding distinct microbial compositions between pregnant and non-pregnant women.

Pregnant women had a higher diversity of operational taxonomic units (OTUs) and differences in the abundance of specific bacterial phyla.

Using random forest models and WGCNA methods, the researchers identified microbial modules that correlated negatively with pro-inflammatory cytokines, suggesting that certain gut bacteria groups have a consistent impact on reducing inflammation during pregnancy.

Notably, bacteria like Bifidobacterium and Ruminococcus, known for their anti-inflammatory properties, were more abundant in pregnant women and were negatively correlated with pro-inflammatory cytokines.

Metabolomic analysis of fecal and plasma samples using untargeted LC-MS revealed significant metabolic alterations during pregnancy. Differential metabolites, particularly lipids and bile acids, were identified, with many showing downregulation in pregnant women.

These included arachidonic acid and various bile acids, known to be associated with inflammation. The analysis highlighted the significant role of bile acid metabolism during pregnancy.

Correlation studies between metabolites and cytokines indicated that certain metabolites enriched in pregnant women were negatively correlated with pro-inflammatory cytokines, suggesting their involvement in modulating immune responses.

The study further explored the associations between gut microbiota, metabolites, and cytokines, finding that metabolites might mediate the relationship between microbiota and the immune system.

Directional mediation analysis identified specific linkages among microbes, metabolites, and cytokines, suggesting that certain gut microbes could influence cytokine levels by modulating metabolite concentrations.

For example, Ruminococcus callidus and other bacteria could decrease pro-inflammatory cytokines by affecting specific metabolites like deoxycholic acid and arachidonic acid levels.

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February 12, 2024
CRISPR-Cas9 gene-editing tool repairs defective T cells to treat rare hereditary disease

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Some hereditary genetic defects cause an exaggerated immune response that can be fatal. Using the CRISPR-Cas9 gene-editing tool, such defects can be corrected, thus normalizing the immune response, as researchers led by Klaus Rajewsky from the Max Delbrück Center now report in “Science Immunology.”

Familial hemophagocytic lymphohistiocytosis (FHL) is a rare disease of the immune system that usually occurs in infants and young children under the age of 18 months. The condition is severe and has a high mortality rate. It is caused by various gene mutations that prevent cytotoxic T cells from functioning normally. These are a group of immune cells that kill virus-infected cells or otherwise altered cells. If a child with FHL contracts a virus – such as the Epstein-Barr virus (EBV), but also other viruses – the cytotoxic T cells cannot eliminate the infected cells. Instead, the immune response gets out of control. This leads to a cytokine storm and an excessive inflammatory reaction that affects the entire organism.

“Doctors treat FHL with a combination of chemotherapy, immunosuppression and bone marrow transplantation, but many children still die of the disease,” says Professor Klaus Rajewsky, who heads the Immune Regulation and Cancer Lab at the Max Delbrück Center. He and his team have therefore developed a new therapeutic strategy. Using the CRISPR-Cas9 gene-editing tool, the researchers succeeded in repairing defective T cells from mice and from two critically ill infants. The repaired cytotoxic T cells then functioned normally, with the mice recovering from hemophagocytic lymphohistiocytosis. Rajewsky and his team have now published their findings in the journal “Science Immunology.”

Gene repair strategy works in mice

The starting point for the study were mice in which the team could mimic EBV infections. In these animals, the researchers altered a gene called perforin so that its function was completely lost or severely compromised – a common genetic defect in patients with FHL. When they then elicited a condition resembling an EBV infection, the affected B cells multiplied uncontrollably because the defective cytotoxic T cells were unable to eliminate them. As a result, the immune response went into overdrive and the mice developed hemophagocytic lymphohistiocytosis.

The team next collected T memory stem cells – that is, long-lived T cells from which active cytotoxic T cells can mature – from the blood of the mice. The researchers used the CRISPR-Cas9 gene-editing tool to repair the defective perforin gene in the memory T cells and then injected the corrected cells back into the mice. The immune response in the animals quieted down and their symptoms disappeared.

How long protection lasts is uncertain

The first author of the paper, Dr Xun Li, used blood samples from two sick infants to test whether the strategy also works in humans. One had a defective perforin gene, the other a different defective gene.

Our gene repair technique is more precise than previous methods, and the T cells are virtually unchanged after undergoing gene editing. It was also fascinating to see how effectively the memory T cells could be multiplied and repaired from even a small amount of blood.”

Dr Xun Li, First Author

Cell culture experiments showed that the infants’ repaired T memory cells were capable of a normal cytotoxic T cell response.

This means the therapeutic mechanism works in principle. But before patients can benefit from this discovery, the team needs to first resolve open questions and test the treatment concept in clinical trials. “It is still uncertain how long the protective effect lasts,” says Dr Christine Kocks, a scientist in Rajewsky’s team. “Since the T memory stem cells remain in the body for a long time, we hope the therapy provides long-term or even permanent protection. It is also conceivable that patients could be treated with their repaired T cells over and over again.”

The procedure is minimally invasive since only a small amount of blood is needed, and the mice did not require any preparatory treatment – unlike, for example, with a bone marrow transplant. “We very much hope that our mechanism of action is a breakthrough in treating FHL,” says Rajewsky, “either to gain more time for a successful bone marrow transplant or even as a treatment itself.”

Source:

Max Delbrück Center for Molecular Medicine in the Helmholtz Association

Journal reference:

Li, X., et al. (2024) Precise CRISPR-Cas9 gene repair in autologous memory T cells to treat familial hemophagocytic lymphohistiocytosis. Science Immunology. doi.org/10.1126/sciimmunol.adi0042.

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February 3, 2024