The upcoming exploration missions will imply a much longer duration than any of the missions flown so far. In these missions, physiological adaptation to the new environment leads to changes in different body systems, such as the cardiovascular and musculoskeletal systems, metabolic and neurobehavioral health and immune function. To keep space travelers healthy on their trip to Moon, Mars and beyond and their return to Earth, a variety of countermeasures need to be provided to maintain body functionality. From research on the International Space Station (ISS) we know today, that for instance prescribing an adequate training regime for each individual with the devices available in the respective spacecraft is still a challenge. Nutrient supply is not yet optimal and must be optimized in exploration missions. Food intake is intrinsically linked to changes in the gut microbiome composition. Most of the microbes that inhabit our body supply ecosystem benefit to the host-microbe system, including production of important resources, bioconversion of nutrients, and protection against pathogenic microbes. The gut microbiome has also the ability to signal the host, regulating the processes of energy storage and appetite perception, and influencing immune and neurobehavioral function. The composition and functionality of the microbiome most likely changes during spaceflight. Supporting a healthy microbiome by respective measures in space travelers might maintain their health during the mission but also support rehabilitation when being back on Earth. In this review we are summarizing the changes in the gut microbiome observed in spaceflight and analog models, focusing particularly on the effects on metabolism, the musculoskeletal and immune systems and neurobehavioral disorders. Since space travelers are healthy volunteers, we focus on the potential of countermeasures based on pre- and probiotics supplements.

Disruption in cholesterol metabolism, particularly hypercholesterolemia, is a significant cause of atherosclerotic cardiovascular disease. Large interindividual variations in plasma cholesterol levels are traditionally related to genetic factors, and the remaining portion of their variance is accredited to environmental factors. In recent years, the essential role played by intestinal microbiota in human health and diseases has emerged. The gut microbiota is currently viewed as a fundamental regulator of host metabolism and of innate and adaptive immunity. Its bacterial composition but also the synthesis of multiple molecules resulting from bacterial metabolism vary according to diet, antibiotics, drugs used, and exposure to pollutants and infectious agents. Microbiota modifications induced by recent changes in the human environment thus seem to be a major factor in the current epidemic of metabolic/inflammatory diseases (diabetes mellitus, liver diseases, inflammatory bowel disease, obesity, and dyslipidemia). Epidemiological and preclinical studies report associations between bacterial communities and cholesterolemia. However, such an association remains poorly investigated and characterized. The objectives of this review are to present the current knowledge on and potential mechanisms underlying the host-microbiota dialogue for a better understanding of the contribution of microbial communities to the regulation of cholesterol homeostasis.

The mechanisms governing adipose tissue macrophage (ATM) metabolic adaptation during diet-induced obesity (DIO) are poorly understood. In obese adipose tissue, ATMs are exposed to lipid fluxes, which can influence the activation of specific inflammatory and metabolic programs and contribute to the development of obesity-associated insulin resistance and other metabolic disorders. In the present study, we demonstrate that the membrane ATP-binding cassette g1 (Abcg1) transporter controls the ATM functional response to fatty acids (FAs) carried by triglyceride-rich lipoproteins, which are abundant in high-energy diets. Mice genetically lacking Abcg1 in the myeloid lineage presented an ameliorated inflammatory status in adipose tissue and reduced insulin resistance. Abcg1-deficient ATMs exhibited a less inflammatory phenotype accompanied by a low bioenergetic profile and modified FA metabolism. A closer look at the ATM lipidome revealed a shift in the handling of FA pools, including a redirection of saturated FAs from membrane phospholipids to lipid droplets, leading to a reduction in membrane rigidity and neutralization of proinflammatory FAs. ATMs from human individuals with obesity presented the same reciprocal relationship between ABCG1 expression and this inflammatory and metabolic status. Abolition of this protective, anti-inflammatory phenotype in Abcg1-deficient ATMs was achieved through restoration of lipoprotein lipase (Lpl) activity, thus delineating the importance of the Abcg1/Lpl axis in controlling ATM metabolic inflammation. Overall, our study identifies the rewiring of FA pools by Abcg1 as a major pathway orchestrating ATM plasticity and insulin resistance in DIO.

Mice reconstituted with a human immune system and bearing human tumors represent a promising model for developing novel cancer immunotherapies. Here, we used mass cytometry and multi-parametric flow cytometry to characterize human leukocytes infiltrating a human breast cancer tumor model in immunocompromised NOD.SCID.γc-null mice reconstituted with a human immune system and compared it to samples of breast cancer patients. We observed highly activated human CD4⁺ and CD8⁺ T cells in the tumor, as well as minor subsets of innate immune cells in both settings. We also report that ICOS⁺ CD4⁺ regulatory T cells (Treg) were enriched in the tumor relative to the periphery in humanized mice and patients, providing a target to affect Treg and tumor growth. Indeed, administration of a neutralizing mAb to human ICOS reduced Treg proportions and numbers and improved CD4 + T cell proliferation in humanized mice. Moreover, a combination of the anti-ICOS mAb with cyclophosphamide reduced tumor growth, and that was associated with an improved CD8 to Treg ratio. Depletion of human CD8⁺ T cells or of murine myeloid cells marginally affected the effect of the combination therapy. Altogether, our results indicate that a combination of anti-ICOS mAb and chemotherapy controls tumor growth in humanized mice, opening new perspectives for the treatment of breast cancer. One sentence summary: Targeting ICOS in combination with chemotherapy is a promising strategy to improve tumor immunity in humans.

Bile acids (BAs) regulate dietary lipid hydrolysis and absorption in the proximal intestine. Several studies have highlighted a determinant role of circulating levels and/or metabolism of BAs in the pathogenesis of major cardiometabolic diseases. Whether changes in BA profiles are causative or are consequence of these diseases remains to be determined. Healthy male volunteers (n = 71) underwent a postprandial exploration following consumption of a hypercaloric high fat typical Western meal providing 1200 kcal. We investigated variations of circulating levels of 28 BA species, together with BA synthesis marker 7α-hydroxy-4-cholesten-3-one (C4) over an approximately diurnal 12 h period. Analysis of BA variations during the postprandial time course revealed two major phenotypes with opposite fluctuations, i.e., circulating levels of each individual species of unconjugated BAs were reduced after meal consumption whereas those of tauro- and glyco-conjugated BAs were increased. By an unbiased classification strategy based on absolute postprandial changes in BA species levels, we classified subjects into three distinct clusters; the two extreme clusters being characterized by the smallest absolute changes in either unconjugated-BAs or conjugated-BAs. Finally, we demonstrated that our clustering based on postprandial changes in BA profiles was associated with specific clinical and biochemical features, including postprandial triglyceride levels, BMI or waist circumference. Altogether, our study reveals that postprandial profiles/patterns of BAs in response to a hypercaloric high fat challenge is associated with healthy or unhealthy metabolic phenotypes that may help in the early identification of subjects at risk of developing metabolic disorders.

BACKGROUND: Previous clinical studies have indicated reduced circulating mucosal-associated invariant T (MAIT) cells in individuals with coronary artery disease. However, the precise role and underlying mechanisms of MAIT cells in this context remain unclear. Immune homeostasis plays a pivotal role in the development of atherosclerosis. This study explores the impact of MAIT cells on atherosclerosis. METHODS: Vα19 ^+/− Ldlr ^−/− mice, characterized by a high MAIT cell frequency, and MAIT cell deficient MR1 ^−/− (major histocompatibility complex-related molecule 1) Ldlr ^−/− mice and their respective controls were used. Starting at 6 weeks of age, mice were subjected to a 1% cholesterol diet for 16 weeks. Additionally, the study analyzed circulating MAIT cell frequency and cholesterol levels in 68 patients with hypercholesterolemia. RESULTS: In Vα19 ^+/− Ldlr ^−/− mice, increased MAIT cells demonstrated a protective effect against atherosclerosis by reducing VLDL-C (very-low-density lipoprotein cholesterol) levels through heightened cholesterol excretion. This effect was accompanied by elevated jejunal ABCB1a, ABCG5, and ABCG8 expression, mediated by augmented levels of Liver X receptor transcription and activation, likely through intestinal IL-22 (interleukin-22) signaling. Conversely, cholesterol reduction mediated by intestinal cholesterol excretion was blocked by inhibition of MAIT cells. Moreover, MAIT cell-deficient MR1 ^−/− Ldlr ^−/− mice exhibited elevated total cholesterol levels and increased atherosclerotic lesions. In patients with hypercholesterolemia, circulating MAIT cell frequency displayed negative correlations with VLDL-C levels and positive correlations with HDL-C (high-density lipoprotein cholesterol) levels. CONCLUSIONS: Our findings demonstrate a new mechanism for plasma VLDL-C clearance by MAIT cell-mediated cholesterol excretion. The results provide further evidence that immunity is involved in cholesterol homeostasis. Targeting intestinal immunity to regulate cholesterol homeostasis holds promise as a new cholesterol-lowering modality to prevent atherosclerotic cardiovascular disease.