Maternal immune cell gene expression associates with maternal gut microbiome, milk composition and infant gut microbiome.

BACKGROUND: Pre-pregnancy overweight and obesity promote deleterious health impacts on both mothers during pregnancy and the offspring. Significant changes in the maternal peripheral blood mononuclear cells (PBMCs) gene expression due to obesity are well-known. However, the impact of pre-pregnancy overweight on immune cell gene expression during pregnancy and its association with maternal and infant outcomes is not well explored. METHODS: Blood samples were collected from healthy normal weight (NW, pre-pregnancy BMI 18.5-24.9) or overweight (OW, pre-pregnancy BMI 25-29.9) 2nd parity pregnant women at 12, 24 and 36 weeks of pregnancy. PBMCs were isolated from the blood and subjected to mRNA sequencing. Maternal and infant microbiota were analyzed by 16S rRNA gene sequencing. Integrative multi-omics data analysis was performed to evaluate the association of gene expression with maternal diet, gut microbiota, milk composition, and infant gut microbiota. RESULTS: Gene expression analysis revealed that 453 genes were differentially expressed in the OW women compared to NW women at 12 weeks of pregnancy, out of which 354 were upregulated and 99 were downregulated. Several up-regulated genes in the OW group were enriched in inflammatory, chemokine-mediated signaling and regulation of interleukin-8 production-related pathways. At 36 weeks of pregnancy healthy eating index score was positively associated with several genes that include, DTD1, ELOC, GALNT8, ITGA6-AS1, KRT17P2, NPW, POT1-AS1 and RPL26. In addition, at 36 weeks of pregnancy, genes involved in adipocyte functions, such as NG2 and SMTNL1, were negatively correlated to human milk 2'FL and total fucosylated oligosaccharides content collected at 1 month postnatally. Furthermore, infant Akkermansia was positively associated with maternal PBMC anti-inflammatory genes that include CPS1 and RAB7B, at 12 and 36 weeks of pregnancy. CONCLUSIONS: These findings suggest that prepregnancy overweight impacts the immune cell gene expression profile, particularly at 12 weeks of pregnancy. Furthermore, deciphering the complex association of PBMC's gene expression levels with maternal gut microbiome and milk composition and infant gut microbiome may aid in developing strategies to mitigate obesity-mediated effects.

Deep immune cell phenotyping and induced immune cell responses at admission stratified by BMI in patients hospitalized with COVID-19: An observational multicenter cohort pilot study.

INTRODUCTION: Overweight and obesity are linked to increased hospitalization and mortality in COVID-19 patients. This study aimed to characterize induced immune responses and deep immune cell profiles stratified by BMI in hospitalized COVID-19 patients. METHODS AND RESULTS: This observational multicenter cohort pilot study included 122 adult patients with PCR-confirmed COVID-19 in Denmark, stratified by BMI (normal weight, overweight, obese). Inflammation was assessed using TruCulture® and immune cell profiles by flow cytometry with a customized antibody panel (DuraClone®). Patients with obesity had a more pro-inflammatory phenotype with increased TNF-α, IL-8, IL-17, and IL-10 levels post-T cell stimulation, and altered B cell profiles. Patients with obesity showed higher concentrations of naïve, transitional, and non-isotype switched memory B cells, and plasmablasts compared to normal weight patients and healthy controls. CONCLUSIONS: Obesity in hospitalized COVID-19 patients may correlate with elevated pro-inflammatory cytokines, anti-inflammatory IL-10, and increased B cell subset activation, highlighting the need for further studies.

The effects of nonsoy legumes consumption on serum levels of inflammatory biomarkers and Adiponectin in overweight/obese adults: A systematic review and meta-analysis of randomized controlled trials.

Nonsoy legumes offer many health benefits, including improved arterial function, reduced cholesterol levels, and better management of cardiovascular diseases and type 2 diabetes. This systematic review and meta-analysis aim to clarify the inconclusive findings from randomized controlled trials (RCTs) by comprehensively evaluating the effects of nonsoy legumes consumption on serum levels of inflammatory biomarkers and Adiponectin. The search encompassed databases up to January 2024, including PubMed, EMBASE, MEDLINE, Scopus, Web of Science, and Cochrane CENTRAL to retrieve all RCTs examining the effects of nonsoy legumes on inflammatory biomarkers or Adiponectin. The effect sizes quantified as mean differences (MD) and standard deviations (SD) of outcomes, and an overall effect estimate was derived using a random-effects model. RCTs examining serum levels of C-reactive protein (CRP), Interleukin-6 (IL-6), Tumor Necrosis Factor-alpha (TNF-α), Interleukin-1ß (IL-1ß), and Adiponectin were included in the final meta-analysis. Results revealed that consumption of nonsoy legumes increased Adiponectin serum levels (P=.0017) and reduced IL-1ß serum levels (P<.0001). However, it may not significantly affect CRP (P=.2951), IL-6 (P=.2286), and TNF-α (P=.6661) levels. Subgroup analyses showed that nonsoy legumes consumption significantly decreased TNF-α serum levels in studies involving healthy participants. Additionally, sensitivity analysis using the leave-one-out method suggested a potential significant reduction in serum levels of IL-6. This study indicates that consuming nonsoy legumes can increase levels of Adiponectin and decrease serum levels of IL-1ß in overweight or obese adults.

Free sugar intake is associated with reduced proportion of circulating invariant natural killer T cells among women experiencing overweight and obesity.

Background: Higher prevalence of obesity has been observed among women compared to men, which can be explained partly by the higher consumption of sweets and physical inactivity. Obesity can alter immune cell infiltration, and therefore increase the susceptibility to develop chronic inflammation and metabolic disorders. In this study, we aimed to explore the association between free sugar intake and other unhealthy lifestyle habits in relation to the proportion of circulating iNKT cells among women with healthy weight and women experiencing overweight and obesity. Methods: A cross-sectional study was conducted on 51 Saudi women > 18 years, wherein their daily free sugar intake was assessed using the validated Food Frequency Questionnaire. Data on smoking status, physical activity, and supplement use were also collected. Anthropometric data including height, weight, waist circumference were objectively measured from each participants. The proportion of circulating iNKT cells was determined using flow cytometry. Results: Smoking, physical activity, supplement use, and weight status were not associated with proportion of circulating iNKT cells. Significant association was found between proportion of circulating iNKT cells and total free sugar intake and free sugar intake coming from solid food sources only among women experiencing overweight and obesity (Beta: -0.10: Standard Error: 0.04 [95% Confidence Interval: -0.18 to -0.01], p= 0.034) and (Beta: -0.15: Standard Error: 0.05 [95% Confidence Interval: -0.25 to -0.05], p= 0.005), respectively. Conclusion: Excessive free sugar consumption may alter iNKT cells and consequently increase the risk for chronic inflammation and metabolic disorders.

Calorie restriction-induced leptin reduction and T-lymphocyte activation in blood and adipose tissue in men with overweight and obesity.

BACKGROUND: T-Lymphocyte activation is modulated by the adipokine leptin and serum concentrations of this hormone can be reduced with short-term calorie restriction. The aim of this study was to understand whether leptin per se is important in determining levels of T-lymphocyte activation in humans, by investigating whether the reduction in leptin concentration following calorie restriction is associated with a decrease in T-Lymphocyte activation in blood and adipose tissue. METHODS: Twelve men with overweight and obesity (age 35-55 years, waist circumference 95-115 cm) reduced their calorie intake by 50% for 3 consecutive days. Blood and subcutaneous adipose tissue were obtained for isolation of immune cells and cytokine analysis. CD4+ and CD8 + T-Lymphocytes were identified and characterised according to their expression of activation markers CD25 and CD69 by flow cytometry. RESULTS: Serum leptin was reduced by (mean ± SEM) 31 ± 16% (p < 0.001) following calorie restriction. The percentage of blood CD4 + CD25 + T-lymphocytes and level of CD25 expression on these lymphocytes were significantly reduced by 8 ± 10% (p = 0.016) and 8 ± 4% (p = 0.058), respectively. After calorie restriction, ex vivo leptin secretion from abdominal subcutaneous adipose tissue explants was not changed, and this corresponded with a lack of change in adipose tissue resident T-Lymphocyte activation. CONCLUSIONS: Serum leptin was reduced after calorie restriction and this was temporally associated with a reduction in activation of blood CD4 + CD25 + T-Lymphocytes. In abdominal subcutaneous adipose tissue, however, leptin secretion was unaltered, and there were no observed changes in adipose resident T-Lymphocyte activation.

Clinical verification of body mass index and tumor immune response in patients with breast cancer receiving preoperative chemotherapy.

PURPOSE: The body mass index (BMI) is commonly used as a simple indicator of obesity; patients with early-stage breast cancer who are obese (OB) per BMI measurements have been shown to have high postoperative recurrence and low survival rates. On the other hand, it has been shown that lymphocytes present in the vicinity of malignant growths that are involved in the tumors' immune responses influence the efficacy chemotherapy. Therefore, we hypothesized that OB patients with breast cancer have a lower density of tumor-infiltrating lymphocytes (TILs), which may influence the therapeutic effect of preoperative chemotherapy (POC). In this study, we measured pretreatment BMI and TILs in patients with breast cancer who underwent POC, examined the correlations between these two factors, and retrospectively analyzed their therapeutic outcomes and prognoses. METHODS: The participants in this study were 421 patients with breast cancer who underwent surgical treatment after POC between February 2007 and January 2019. The patient's height and weight were measured before POC to calculate the BMI (weight [kg] divided by the square of the height [m2]). According to the World Health Organization categorization, patients who weighed under 18.5 kg/m2 were classified as underweight (UW), those ≥18.5 kg/m2 and > 25 kg/m2 were considered normal weight (NW), those ≥25 kg/m2 and < 30 kg/m2 were overweight (OW), and those ≥30 kg/m2 were OB. The TILs were those lymphocytes that infiltrated the tumor stroma according to the definition of the International TILs Working Group 2014. RESULTS: The median BMI was 21.9 kg/m2 (range, 14.3-38.5 kg/m2); most patients (244; 64.5%) were NW. Among all 378 patients with breast cancer, the TIL density was significantly lower in OB than in NW and OW patients (vs. NW: p = 0.001; vs. OW: p = 0.003). Furthermore, when examining patients with each breast cancer type individually, the OS of those with TNBC who had low BMIs was significantly poorer than that of their high-BMI counterparts (log rank p = 0.031). CONCLUSIONS: Our data did not support the hypothesis that obesity affects the tumor immune microenvironment; however, we showed that being UW does affect the tumor immune microenvironment.

Metabolic disease and adverse events from immune checkpoint inhibitors.

OBJECTIVE: Obese and overweight body mass index (BMI) categories have been associated with increased immune-related adverse events (irAEs) in patients with cancer receiving immune checkpoint inhibitors (ICIs); however, the impact of being overweight in conjunction with related metabolic syndrome-associated factors on irAEs have not been investigated. We aimed to evaluate the impact of overweight and obese BMI according to metabolic disease burden on the development of irAEs. DESIGN AND METHODS: We conducted a retrospective observational study of patients receiving ICIs at a cancer center. Our main study outcome was development of ≥grade 2 (moderate) irAEs. Our main predictor was weight/metabolic disease risk category: (1) normal weight (BMI 18.5-24.9 kg/m2)/low metabolic risk (<2 metabolic diseases [diabetes, dyslipidemia, hypertension]), (2) normal weight/high metabolic risk (≥2 metabolic diseases), (3) overweight (BMI ≥25 kg/m2)/low metabolic risk, and (4) overweight/high metabolic risk. RESULTS: Of 411 patients in our cohort, 374 were eligible for analysis. Overall, 111 (30%) patients developed ≥grade 2 irAEs. In Cox analysis, overweight/low metabolic risk was significantly associated with ≥grade 2 irAEs (hazard ratio [HR]: 2.0, 95% confidence interval [95% CI]: 1.2-3.4) when compared to normal weight/low metabolic risk, while overweight/high metabolic risk (HR: 1.3, 95% CI: 0.7-2.2) and normal weight/high metabolic risk (HR: 1.5, 95% CI: 0.7-3.0) were not. CONCLUSIONS: Overweight patients with fewer metabolic comorbidities were at increased risk for irAEs. This study provides an important insight that BMI should be evaluated in the context of associated metabolic comorbidities in assessing risk of irAE development and ICI immune response.

Metabolic surgery improves the unbalanced proportion of peripheral blood myeloid dendritic cells and T lymphocytes in obese patients.

BACKGROUND: Obesity is associated with impaired immune function and chronic low-grade inflammation. Metabolic surgery is one of the most effective therapies for treating obesity and related metabolic disorders. We aimed to explore the pathophysiological roles of peripheral dendritic cells (DCs) and T lymphocytes in metabolic surgery. METHOD: In this observational cohort study, a total of 106 individuals, including obese participants with or without T2DM, overweight subjects and normal controls, were recruited. All obese participants underwent laparoscopic sleeve gastrectomy surgery and returned for the evaluation of the clinical indicators after surgery. We evaluated the frequencies of circulating DCs subsets (myeloid (mDCs) and plasmacytoid (pDCs)), the pro-inflammatory (Th1 and Th17) and anti-inflammatory (Th2 and Treg) T cell subsets by flow cytometry. RESULTS: Compared with normal controls, the frequencies of mDCs, Th1 and Th17 cells increased, while Treg and Th2 cells decreased in the obese participants. The frequency of mDCs and Th1 cells consistently declined after surgery compared with baseline in the obese patients and were restored to the levels observed in the normal controls after surgery. Moreover, the frequency of Treg cells was increased at 6 months after surgery in the obese patients with T2DM, and Th17 cells declined at 6 months after surgery in the severely obese patients without T2DM. CONCLUSION: This study indicates that metabolic surgery can effectively improve imbalanced immune cells in peripheral blood and restore the proportion of immune cells to a normal range during a 12-month follow-up.

An Oily Fish Diet Improves Subclinical Inflammation in People at High Cardiovascular Risk: A Randomized Controlled Study.

Interest has arisen on the anti-inflammatory action of dietary components, including long-chain n-3 fatty acids (LCn3) and polyphenols (PP). The aim of this study was to evaluate the effects of diets rich in PP and oily fish (high-LCn3 diets) on markers of subclinical inflammation and growth factors in people at high cardiometabolic risk. Individuals with high waist circumference and one more component of metabolic syndrome were randomized to one of the following isoenergetic diets: low LCn3&PP, high LCn3, high PP, high LCn3&PP. Before and after 8 weeks, fasting and postprandial plasma concentrations of hs-CRP and fasting serum concentrations of IL-1, IL-4, IL-6, IL-10, IL-17, INF-, TNF-, FGF, VEGF, PDGF-, G-CSF, and GM-CSF were determined. An oily fish diet reduced fasting plasma hs-CRP (1.28 ± 12.0, -12.5 ± 6.9, 22.5 ± 33.6, -12.2 ± 11.9; 8-week percent change, Mean ± SEM; low LCn3&PP, high LCn3, high PP, high LCn3&PP group, respectively), postprandial 6h-AUC hs-CRP (4.6 ± 16.3, -18.2 ± 7.2, 26.9 ± 35.1, -11.5 ± 11.8, 8-week percent change) and fasting IL-6 (20.8 ± 18.7, -2.44 ± 12.4, 28.1 ± 17.4, -9.6 ± 10.2), IL-17 (2.40 ± 4.9, -13.3 ± 4.9, 3.8 ± 4.43, -11.5 ± 4.7), and VEGF (-5.7 ± 5.8, -5.6 ± 7.5, 3.5 ± 5.8, -11.1 ± 5.5) (8-week percent change; p < 0.05 for LCn3 effect for all; no significant effect for PP; 2-factor ANOVA). An oily fish diet improved subclinical inflammation, while no significant effect was observed for dietary polyphenols.

Serum IL-35 is decreased in overweight patients with rheumatoid arthritis: its correlation with Th1/Th2/Th17-related cytokines.

BACKGROUND: Obesity is correlated with worse drug responses and high disease activity in patients with rheumatoid arthritis (RA). Interleukin (IL)-35 is a novel anti-inflammatory cytokine that mainly produced by regulatory T (Treg). This study was performed to analyze whether IL-35 was correlated with obesity in RA and investigate the correlation between other Th1/Th2/Th17-related cytokines and obesity in RA. RESULTS: The serum IL-35 level was analyzed in RA (n = 81) and healthy donors (n = 53) by ELISA assay, and was compared between three groups (body mass index (BMI) < 18.5,≥18.5 to 25, > 25). Serum cytokines including IL-2, IL-4, IL-10, IL-17, INF-γ, TNF-α levels were measured using Flowcytometry assay. Clinical information was extracted from medical records. Serum IL-35 level in overweight patients were significantly decreased than those in lean patients. Furthermore, Th1/Th2/Th17-related cytokines from overweight patients with RA showed the characteristic immunological features. Serum IL-6, IL-17 and TNF-α levels were positively correlated with BMI. However, serum IL-2, IL-4, IL-10 and IFN-γ concentrations were not correlated with BMI. CONCLUSIONS: Quantitative changes in serum IL-35 level were characteristic in overweight patients with RA. These findings indicate that IL-35 plays an important role in the development of RA and may prove to be a potential biomarker of active RA.

Reduced concentrations of the B cell cytokine interleukin 38 are associated with cardiovascular disease risk in overweight subjects.

The IL-1 family member IL-38 (IL1F10) suppresses inflammatory and autoimmune conditions. Here, we report that plasma concentrations of IL-38 in 288 healthy Europeans correlate positively with circulating memory B cells and plasmablasts. IL-38 correlated negatively with age (p = 0.02) and was stable in 48 subjects for 1 year. In comparison with primary keratinocytes, IL1F10 expression in CD19+ B cells from PBMC was lower, whereas cell-associated IL-38 expression was comparable. In vitro, IL-38 is released from CD19+ B cells after stimulation with rituximab. Intravenous LPS in humans failed to induce circulating IL-38, compared to 100-fold induction of IL-6 and IL-1 receptor antagonist. In a cohort of 296 subjects with body mass index > 27 at high risk for cardiovascular disease, IL-38 plasma concentrations were significantly lower than in healthy subjects (p < 0.0001), and lowest in those with metabolic syndrome (p < 0.05). IL-38 also correlated inversely with high sensitivity C-reactive protein (p < 0.01), IL-6, IL-1Ra, and leptin (p < 0.05). We conclude that a relative deficiency of the B cell product IL-38 is associated with increased systemic inflammation in aging, cardiovascular and metabolic disease, and is consistent with IL-38 as an anti-inflammatory cytokine.

Changes in Dietary Inflammatory Index Patterns with Weight Loss in Women: A Randomized Controlled Trial.

Dietary composition can influence systemic inflammation; higher levels of circulating inflammatory biomarkers are associated with increased risk of breast and other cancers. A total of 438 overweight/obese, healthy, postmenopausal women were randomized to a caloric-restriction diet (goal: 10% weight-loss), aerobic-exercise (225 min/week moderate-to-vigorous activity), combined diet+exercise, or control. Dietary inflammatory index (DII) and energy-adjusted (E-DII) scores were derived from food frequency questionnaires (FFQ) and could be calculated for 365 participants with complete FFQs at baseline and 12 months. Changes from baseline to 12 months in E-DII scores in the intervention arms versus controls were analyzed using generalized estimating equations, adjusted for confounders. We examined associations between changes in previously measured biomarkers and E-DII at 12 months. Participants randomized to diet and diet+exercise arms had greater reductions in E-DII (-104.4% and -84.4%), versus controls (-34.8%, both P < 0.001). Weight change had a more marked effect than E-DII change on biomarkers at 12-months; associations between E-DII and biomarker changes were reduced after adjustment by weight change. Changes in E-DII at 12 months, adjusted for weight change, were negatively associated with changes in ghrelin [r = -0.19; P = 0.05 (diet), r = -0.29; P = 0.02 (diet+exercise)], and positively with VEGF [r = 0.22; P = 0.03 (diet+exercise)], and red blood cell counts [r = 0.30; P = 0.004 (exercise)]. C-reactive protein (CRP) and IL6 levels were not associated with E-DII changes at 12 months. In conclusion, a behavior change of low-calorie, low-fat diet significantly reduces dietary inflammatory potential, modulating biomarkers that are associated with tumorigenesis, such as VEGF, but not CRP or IL6. PREVENTION RELEVANCE: Diets high in saturated fats and low in fruit and vegetable intake are associated with increased inflammation, which increases cancer risk. This study showed that changes in diet quality had effects on factors associated with cancer; however, the majority of beneficial effects were associated with weight loss rather than diet quality.

Effects of Daily Raspberry Consumption on Immune-Metabolic Health in Subjects at Risk of Metabolic Syndrome: A Randomized Controlled Trial.

Consumption of red raspberries has been reported to exert acute beneficial effects on postprandial glycemia, insulinemia, triglyceridemia, and cytokine levels in metabolically disturbed subjects. In a two-arm parallel-group, randomized, controlled trial, 59 subjects with overweight or abdominal obesity and with slight hyperinsulinemia or hypertriglyceridemia were randomized to consume 280 g/day of frozen raspberries or to maintain their usual diet for 8 weeks. Primary analyses measured metabolic differences between the groups. Secondary analyses performed with omics tools in the intervention group assessed blood gene expression and plasma metabolomic changes following the raspberry supplementation. The intervention did not significantly affect plasma insulin, glucose, inflammatory marker concentrations, nor blood pressure. Following the supplementation, 43 genes were differentially expressed, and several functional pathways were enriched, a major portion of which were involved in the regulation of cytotoxicity, immune cell trafficking, protein signal transduction, and interleukin production. In addition, 10 serum metabolites were found significantly altered, among which ß-alanine, trimethylamine N-oxide, and bioactive lipids. Although the supplementation had no meaningful metabolic effects, these results highlight the impact of a diet rich in raspberry on the immune function and phospholipid metabolism, thus providing novel insights into potential immune-metabolic pathways influenced by regular raspberry consumption.

NLRP3 Inflammasome Activation in Hemodialysis and Hypertensive Patients with Intact Kidney Function.

Hypertension is not only an integrative characteristic of hemodialysis (HD) patients but is also very common in the general population. There is evidence that the inflammatory cytokine IL-ß, regulated by the NLRP3 inflammasome via caspase-1, contributes to the hypertensive setting. Therefore, we investigated in an observational pilot study whether IL-1ß secretion and inflammatory cell death (pyroptosis) are different in HD and hypertensive patients with intact kidney function. Twenty HD patients were age-, gender-, and diabetes-mellitus-matched to patients with hypertension and intact kidney function. Caspase-1 activity and pyroptosis rates were measured by flow cytometry. IL-1ß was determined by qPCR and the ELISA technique. The inflammatory status (CRP) did not differ between both groups; however, the body mass index, a classical cardiovascular risk factor, was significantly elevated in blood pressure (BP) patients. BP patients had a higher frequency of caspase-1-positive monocytes compared to HD (p < 0.001). IL1-ß protein secretion was significantly enhanced in BP, but ex vivo stimulation of blood cells resulted in higher pyroptosis rates in HD compared to BP patients (p < 0.01). Therefore, HD and BP patients differ in the extent of the NLRP3 inflammasome activation. The consequences of overweight, present in BP patients, may contribute to the significantly higher inflammasomal induction level. Whether low pyroptotic rates are equivalent to a dysfunctional immune response or a high pyroptotic output corresponds to over-activation remains to be clarified.

Poor Oral Hygiene and High Levels of Inflammatory Cytokines in Saliva Predict the Risk of Overweight and Obesity.

The study aimed to determine if oral hygiene influences not only oral health but also potentially metabolic disorders such as overweight or obesity. Participants were 94 patients: 40 with increased body mass and 54 with normal body mass. The methods included dental examination, a questionnaire concerning hygienic habits and an assessment of selected salivary inflammatory markers. The new parameter named "cleaning index" (describing the interaction between average time of tooth brushing in minutes and its frequency per day) significantly correlated with Body Mass Index (RSpearman = 0.300). The multivariate regression model incorporating cleaning index, approximal plaque index, receptor 1 for tumor necrosis factor-alpha (TNFα-R1) and interleukin-15 (IL-15) had a high power to predict overweight or obesity (AUC = 0.894). Patients with poor oral hygiene (approximal plaque index >40%) were more than eight times more likely to suffer from obesity than patients with good oral hygiene. Cleaning index higher than 4 decreased the odds by about 85%. Oral hygiene habits, adjusted by salivary concentrations of selected inflammatory markers may allow predicting effectively overweight or obesity risk. Early proper dental prophylaxis and treatment could lead to the better prevention of metabolic disorders.

The Human Breast Milk Metabolome in Overweight and Obese Mothers.

Pre-pregnancy body mass index (BMI) is a major relevance factor, since maternal overweight and obesity can impair the pregnancy outcome and represent risk factors for several neonatal, childhood, and adult conditions, including excessive weight gain, cardiovascular disease, diabetes mellitus, and even behavioral disorders. Currently, breast milk (BM) composition in such category of mothers was not completely defined. In this field, metabolomics represents the ideal technology, able to detect the whole profile of low molecular weight molecules in BM. Limited information is available on human BM metabolites differences in overweight or obese compared to lean mothers. Analyzing all the metabolomics studies published on Medline in English language, this review evaluated the effects that 8 specific types of metabolites found altered by maternal overweight and obesity (nucleotide derivatives, 5-methylthioadenosine, sugar-alcohols, acylcarnitine and amino acids, polyamines, mono-and oligosaccharides, lipids) can exert on the risk of offspring obesity development and other potentially associated health outcomes and complications. However, metabolites variations in samples collected from overweight and obese mothers and the potentially correlated effects highlighted below still need further investigations and should be confirmed in future metabolomics studies on larger samples. Finally, the positive or negative influence of maternal overweight and obesity on the offspring, potentially exerted by breastfeeding, should be analyzed in close correlation with maternal age, genetic and environmental factors, including diet, and taking into account the interactions occurring between BM metabolites and lactobiome. The evaluation of all the factors affecting BM metabolites in overweight and obese mothers can lead to the comprehensive description of such biofluid and the related effects on breastfed subjects, potentially highlighting personalized needs of BM supplementation or short- and long-term prevention strategies to optimize offspring health.

A carbohydrate-active enzyme (CAZy) profile links successful metabolic specialization of Prevotella to its abundance in gut microbiota.

Gut microbiota participates in diverse metabolic and homeostatic functions related to health and well-being. Its composition varies between individuals, and depends on factors related to host and microbial communities, which need to adapt to utilize various nutrients present in gut environment. We profiled fecal microbiota in 63 healthy adult individuals using metaproteomics, and focused on microbial CAZy (carbohydrate-active) enzymes involved in glycan foraging. We identified two distinct CAZy profiles, one with many Bacteroides-derived CAZy in more than one-third of subjects (n = 25), and it associated with high abundance of Bacteroides in most subjects. In a smaller subset of donors (n = 8) with dietary parameters similar to others, microbiota showed intense expression of Prevotella-derived CAZy including exo-beta-(1,4)-xylanase, xylan-1,4-beta-xylosidase, alpha-L-arabinofuranosidase and several other CAZy belonging to glycosyl hydrolase families involved in digestion of complex plant-derived polysaccharides. This associated invariably with high abundance of Prevotella in gut microbiota, while in subjects with lower abundance of Prevotella, microbiota showed no Prevotella-derived CAZy. Identification of Bacteroides- and Prevotella-derived CAZy in microbiota proteome and their association with differences in microbiota composition are in evidence of individual variation in metabolic specialization of gut microbes affecting their colonizing competence.

Microbiota Composition of Breast Milk from Women of Different Ethnicity from the Manawatu-Wanganui Region of New Zealand.

Human breastmilk components, the microbiota and immune modulatory proteins have vital roles in infant gut and immune development. In a population of breastfeeding women (n = 78) of different ethnicities (Asian, Maori and Pacific Island, New Zealand European) and their infants living in the Manawatu-Wanganui region of New Zealand, we examined the microbiota and immune modulatory proteins in the breast milk, and the fecal microbiota of mothers and infants. Breast milk and fecal samples were collected over a one-week period during the six to eight weeks postpartum. Breast milk microbiota differed between the ethnic groups. However, these differences had no influence on the infant's gut microbiota composition. Based on the body mass index (BMI) classifications, the mother's breast milk and fecal microbiota compositions were similar between normal, overweight and obese individuals, and their infant's fecal microbiota composition also did not differ. The relative abundance of bacteria belonging to the Bacteroidetes phylum was higher in feces of infants born through vaginal delivery. However, the bacterial abundance of this phylum in the mother's breast milk or feces was similar between women who delivered vaginally or by cesarean section. Several immune modulatory proteins including cytokines, growth factors, and immunoglobulin differed between the BMI and ethnicity groups. Transforming growth factor beta 1 and 2 (TGFß1, TGFß2) were present in higher concentrations in the milk from overweight mothers compared to those of normal weight. The TGFß1 and soluble cluster of differentiation 14 (sCD14) concentrations were significantly higher in the breast milk from Maori and Pacific Island women compared with women from Asian and NZ European ethnicities. This study explores the relationship between ethnicity, body mass index, mode of baby delivery and the microbiota of infants and their mothers and their potential impact on infant health.

Effect of excess weight and immune-related adverse events on the efficacy of cancer immunotherapy with anti-PD-1 antibodies.

Immunotherapy is an effective treatment in advanced cancer, although predictors of response are limited. We studied whether excess weight influences the efficacy outcomes of immunotherapy. We have also evaluated the combined prognostic effect of excess weight and immune-related adverse events (irAEs). Efficacy of anti-PD-1 treatment was evaluated with both objective radiological response (ORR) rate and progression-free survival (PFS), and toxicity with irAEs. We studied the association between excess weight and ORR, PFS or irAEs. 132 patients diagnosed with advanced cancer were included. Median body mass index (BMI) was 24.9 kg/m2. 64 patients had normal weight (BMI<25 kg/m2), and 64 patients had excess weight (BMI≥25 kg/m2). Four patients had underweight and were excluded from further analysis. ORR was achieved in 50 patients (38.0%), median PFS was 6 months. 44 patients developed irAEs (33.3%). ORR was higher in excess weight patients than in patients with normal weight (51.6% vs 25.0%; OR 3.45, p = .0009). PFS was improved in patients with excess weight (7.25 months vs 4 months, HR 1.72, p = .01). The incidence of IrAEs was not different in patients with excess weight (54.5% vs 43.2%, p = .21). When high BMI and irAEs were combined, we observed a marked prognostic trend in ORR rate (87.5% vs 6.2%; OR 161.0, p < .00001), and in PFS (14 months vs 3 months; HR 5.89, p < .0001). Excess weight patients with advanced cancer that receive single-agent anti-PD-1 antibody therapy exhibit a significantly improved clinical outcome compared with normal BMI patients. This association was especially marked when BMI and irAEs were considered combined.

Acute Effects of the Consumption of Passiflora setacea Juice on Metabolic Risk Factors and Gene Expression Profile in Humans.

BACKGROUND: Passiflora setacea (PS) is a passionfruit variety of the Brazilian savannah and is a rich source of plant food bioactives with potential anti-inflammatory activity. This study aimed to investigate the effect of an acute intake of PS juice upon inflammation, metabolic parameters, and gene expression on circulating immune cells in humans. METHODS: Overweight male volunteers (n = 12) were enrolled in two double-blind placebo-controlled studies. Blood samples were collected from fasting volunteers 3 h after the consumption of 250 mL of PS juice or placebo (PB). Metabolic parameters (insulin, glucose, total cholesterol, high-density lipoprotein (LDL), high-density lipoprotein (HDL), and total triglycerides) and circulating cytokines were evaluated (study 1). Peripheral blood mononuclear cell (PBMC) from the same subjects were isolated and RNA was extracted for transcriptomic analyses using microarrays (study 2). RESULTS: Insulin and homeostatic model assessment for insulin resistance (HOMA-IR) levels decreased statistically after the PS juice intake, whereas HDL level increased significantly. Interleukin (IL)-17A level increased after placebo consumption, whereas its level remained unchanged after PS juice consumption. Nutrigenomic analyses revealed 1327 differentially expressed genes after PS consumption, with modulated genes involved in processes such as inflammation, cell adhesion, or cytokine-cytokine receptor. CONCLUSION: Taken together, these clinical results support the hypothesis that PS consumption may help the prevention of cardiometabolic diseases.