Urban living in healthy Tanzanians is associated with an inflammatory status driven by dietary and metabolic changes

Sub-Saharan Africa currently experiences an unprecedented wave of urbanization, which has important consequences for health and disease patterns. This study aimed to investigate and integrate the immune and metabolic consequences of rural or urban lifestyles and the role of nutritional changes associated with urban living. In a cohort of 323 healthy Tanzanians, urban as compared to rural living was associated with a pro-inflammatory immune phenotype, both at the transcript and protein levels. We identified different food-derived and endogenous circulating metabolites accounting for these differences. Serum from urban dwellers induced reprogramming of innate immune cells with higher tumor necrosis factor production upon microbial re-stimulation in an in vitro model of trained immunity. These data demonstrate important shifts toward an inflammatory phenotype associated with an urban lifestyle and provide new insights into the underlying dietary and metabolic factors, which may affect disease epidemiology in sub-Sahara African countries. Rapid urbanization can be associated with adverse health implications. de Mast and colleagues compare urban and rural Tanzanian populations using multi-omics and observe that urbanization is associated with an elevated but reversible inflammatory state

Genetic and nongenetic drivers of platelet reactivity in healthy Tanzanian individuals

Background: Platelets play a key role in hemostasis, inflammation, and cardiovascular diseases. Platelet reactivity is highly variable between individuals. The drivers of this variability in populations from Sub-Saharan Africa remain largely unknown. Objectives: We aimed to investigate the nongenetic and genetic determinants of platelet reactivity in healthy adults living in a rapidly urbanizing area in Northern Tanzania. Methods: Platelet activation and reactivity were measured by platelet P-selectin expression and the binding of fibrinogen in unstimulated blood and after ex vivo stimulation with adenosine diphosphate and PAR-1 and PAR-4 ligands. We then analyzed the associations of platelet parameters with host genetic and nongenetic factors, environmental factors, plasma inflammatory markers, and plasma metabolites. Results: Only a few associations were found between platelet reactivity parameters and plasma inflammatory markers and nongenetic host and environmental factors. In contrast, untargeted plasma metabolomics revealed a large number of associations with food-derived metabolites, including phytochemicals that were previously reported to inhibit platelet reactivity. Genome-wide single-nucleotide polymorphism genotyping identified 2 novel single-nucleotide polymorphisms (rs903650 and rs4789332) that were associated with platelet reactivity at the genome-wide level (P &lt; 5 × 10−8) as well as a number of variants in the PAR4 gene (F2RL3) that were associated with PAR4-induced reactivity. Conclusion: Our study uncovered factors that determine variation in platelet reactivity in a population in East Africa that is rapidly transitioning to an urban lifestyle, including the importance of genetic ancestry and the gradual abandoning of the traditional East African diet.</p

Circulating Blood Monocyte Subclasses and Lipid-Laden Adipose Tissue Macrophages in Human Obesity

<div><p>Background</p><p>Visceral adipose tissue foam cells are increased in human obesity, and were implicated in adipose dysfunction and increased cardio-metabolic risk. In the circulation, non-classical monocytes (NCM) are elevated in obesity and associate with atherosclerosis and type 2 diabetes. We hypothesized that circulating NCM correlate and/or are functionally linked to visceral adipose tissue foam cells in obesity, potentially providing an approach to estimate visceral adipose tissue status in the non-surgical obese patient.</p><p>Methods</p><p>We preformed <i>ex-vivo</i> functional studies utilizing sorted monocyte subclasses from healthy donors. Moreover, we assessed circulating blood monocyte subclasses and visceral fat adipose tissue macrophage (ATM) lipid content by flow-cytometry in paired blood and omental-fat samples collected from patients (n = 65) undergoing elective abdominal surgery.</p><p>Results</p><p><i>Ex-vivo</i>, NCM and NCM-derived macrophages exhibited lower lipid accumulation capacity compared to classical or intermediate monocytes/-derived macrophages. Moreover, of the three subclasses, NCM exhibited the lowest migration towards adipose tissue conditioned-media. In a cohort of n = 65, increased %NCM associated with higher BMI (r = 0.250,p<0.05) and ATM lipid content (r = 0.303,p<0.05). Among patients with BMI≥25Kg/m², linear regression models adjusted for age, sex or BMI revealed that NCM independently associate with ATM lipid content, particularly in men.</p><p>Conclusions</p><p>Collectively, although circulating blood NCM are unlikely direct functional precursor cells for adipose tissue foam cells, their increased percentage in the circulation may clinically reflect higher lipid content in visceral ATMs.</p></div

%NCM as a statistical predictor of omental ATM lipids content: Dependent variable ATMs' lipids content

<p>%NCM as a statistical predictor of omental ATM lipids content: Dependent variable ATMs' lipids content</p

Monocyte subclasses association with clinical and adipose tissue parameters.

<p><b>A)</b> Spearman Correlation analysis between clinical parameters and omental adipose tissue parameter and % circulating monocyte subclass (CM-classical monocytes; IM-intermediate monocytes; NCM-non-classical monocytes). <b>B)</b> Distribution of the patients' cohort to %NCM-low and–high according to the median value (13.2%). Omental ATM lipid content was compared between %NCM-low and %NCM-high <b>C)</b> in the whole cohort (n = 32 vs. n = 33, respectively), or separately <b>D)</b> in men (left graph, n = 13 vs. n = 11, respectively) and in women (right graph, n = 19 vs. n = 22, respectively). Adipose tissue chemokine expression was compared between %NCM-low and %NCM-high <b>E)</b> in the whole cohort (n = 11 vs. n = 15, respectively), or separately <b>F)</b> in men (left graph, n = 4 vs. n = 6, respectively) and in women (right graph, n = 7 vs. n = 9, respectively). Statistical comparison was obtained by the Mann-Whitney U test. *p< 0.05, **p<0.01.</p

Non-classical and intermediate monocytes migrate less towards conditioned medium of omental adipose tissue.

<p><b>A)</b> Following isolation of PBMCs from peripheral blood of healthy male donors, monocytes were enriched by CD14+ magnetic separation and stained for CD14 and CD16. 1–1.5*10⁶ cells were placed in the upper part of a migration chamber, placed on top of RPMI media containing 10% FBS or 10% human omental adipose tissue conditioned media (hOAT-CM). After 2.5 hours in 37°C, cells in the lower chamber were collected, counted, and <b>B)</b> analyzed by FACS, and the percentage of migrating cells of each subclass from the original fraction cultured was calculated. Summary of the results obtained from 6 independent donors are shown in <b>C</b>. Statistical comparison was obtained by the Wilcoxon matched pairs non-parametric test, *p<0.05.</p