ALCYDON SPACE

Studies have shown that microgravity could affect the functions of the digestive system, such as the gastric mucosal barrier, the intestinal bacterial microenvironment, the secretion of digestive juices and digestive hormones, and the absorption and processing of nutrients.  The mechanism of microgravity affects the digestive system is complex, but it could lead us to solve the problems that arise in the digestive system under microgravity conditions. 

Hepatocytes

The liver is a sensitive organ during space flight. Hepatocytes comprise approximately 80% of the liver volume, and a commonly used hepatocyte model is CCL-13 cells, which function similarly to normal hepatocytes. Hepatocyte proliferation can be inhibited by upregulating miR-223 abnormally in simulated microgravity. Down-regulation of cell cycle proteins A1 and A2, cell cycle protein D1, and cell cycle protein-dependent kinase 6 (Cdk6)), as well as attenuation of α-microtubulin 3 and β-actin in the SMG milieu inhibited liver Chang cell proliferation. Elevated miR-223 leads to impaired hepatocyte proliferation at least in part by targeting CDK2 and CUL1. In addition, decreased levels of CDK2 and CUL1 were associated with upregulation of p27 in vivo and in vitro, which may also contribute to impaired hepatocyte proliferation. KCs are hepatic resident macrophages located in the hepatic sinusoids with self-renewal capacity independent of hematopoietic stem cells. KCs phagocytose microbiota, antigens, and endotoxins to maintain hepatic homeostasis. Microgravity can affect the expression of LMO2 and EZH2, which reduces the transcription of Racgap1, Ccna2, Nek2, Aurka, Plk1, Haus4, Cdc20, and Bub1b, and thus reduces the proliferation of KCs. The SMG created by the rotating cell culture system promotes primary human hepatocyte aggregation and the formation of liver tissue-like structures. Under SMG conditions, the human hepatocyte cell line (HepG2) showed decreased transcription of CYP3A4 markers, increased amino acid consumption, and increased release of ketoacids and formate. The liver is highly perfused with blood and contains large amounts of CYP450, a superfamily of heme-containing enzymes responsible for the metabolism of most endogenous compounds and xenobiotics, including drugs, pesticides, and pollutants101. In addition, SM promotes drug metabolism by significantly upregulating the expression of CYP450 isoforms.

Stellate cells

Hepatic stellate cells (HSC) are connective tissue cells within the hepatic lobules that are involved in homeostasis, repair, and regeneration of the hepatic extracellular matrix (ECM), fibrosis, and regulation of retinol metabolism, storage, and release. After liver injury, HSC are transformed into myofibroblast-like cells, which are the main source of type I collagen in fibrotic livers. SMG affected mitochondrial function by upregulating reactive oxygen species, activating upstream regulators such as Smad3, NFkB, and FN, and inhibiting cell permeability inhibitors such as Ly294002 and U0126 to inhibit HSC cell proliferation.

Material metabolism

Several studies have shown that spaceflight significantly affects hepatic glycogen, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) in humans and rats, suggesting that microgravity can lead to liver dysfunction. Ferremodulin, a 25 amino acid peptide hormone secreted by the liver, plays a major role in iron metabolism and inhibits iron export by degrading iron export proteins. In addition, iron-modulin decreases iron absorption by duodenal enterocytes. As a result, iron-modulin leads to decreased iron utilization in the blood and increased iron storage in cells that express iron transport proteins (i.e., macrophages and enterocytes). In microgravity, astronauts and bedridden patients have higher serum ferritin levels, indicating increased iron stores and decreased iron utilization. Excess iron in tissues impairs bone and muscle metabolism, disrupts immune function, and increases susceptibility to radiation damage. Conversely, a reduction in circulating iron may promote anemia, referred to as “spaceflight anemia” during space missions. Iron-modulin is mainly activated through activation of the bone morphogenetic protein/SMAD (BMP/SMAD) signaling pathway, inflammation activation of the interleukin 6/Janus kinase 2/signal transducer and activator of transcription 3 (IL-6/JAK2/STAT3) signaling pathway, and the ERK1/2 signaling pathway to increase synthesis in the liver to further alter iron distribution. These data suggest that early microgravity induces a systemic pro-inflammatory state and promotes ferredoxin synthesis.

Prolonged simulated weightlessness induces alterations in hepatic gluconeogenesis, and alterations in glucose metabolism are associated with an increase in glycolysis, a decrease in fat oxidation, and an accumulation of triglycerides and glycogen. Morphologic changes such as hepatocyte degeneration (chronic hepatitis), swelling of the endoplasmic reticulum, and loss of membrane integrity were observed under transmission electron microscopy. Increased expression of the stress sensor heat shock protein 70 in the liver after 6 hours in microgravity. However, reduced production of heat shock protein 90 and the cell cycle and apoptosis regulator p53 in the liver was found in rats flown for 9 days on the Spacelab Life Sciences 1 mission. High levels of the proinflammatory cytokine tumor necrosis factor-α (TNFα) were recorded in the livers of mice unloaded from the hind limbs. Similarly, tail suspension for 4 weeks in endotoxin-sensitive mice increased plasma TNFα levels, whereas endotoxin-resistant mice or rats did not. This was accompanied by high endotoxin levels in the hepatic portal vein, histopathologic liver injury associated with inflammation, and hepatic expression of acute-phase protein-binding bead protein, serum amyloid A, and lipopolysaccharide-binding protein.

After spaceflight, astronauts have decreased glucose tolerance, elevated plasma glucose levels, and relatively low plasma insulin levels, all of which are exacerbated with longer flight duration. Microgravity reduces the decreased activity of hepatic enzymes involved in glycogenolysis, leading to elevated glucose levels and changes in hepatic insulin receptors. The livers of mice were examined after space flight by proteomic analysis. Levels of proteins associated with amino acid metabolism were significantly elevated after acclimatization, which may indicate an increased rate of gluconeogenesis. Unlike actual spaceflight, 10 days of simulated weightlessness in rats using suspension straps decreased hepatic glycogen levels and increased the activity of glucose-6-phosphatase, the enzyme that catalyzes gluconeogenesis. Blood glucose and hepatic glycogen were decreased after 2 months of tail suspension in rats. Plasma glucose levels were associated with increased hepatic glycogen storage glycolysis, decreased fat oxidation, and accumulation of triglycerides and glycogen. Altered carbohydrate, lipid, and exogenous metabolism in rat liver flown on Cosmos 1887. Elevated hepatic glycogen was also observed in rats flown on Spacelab 3, with a slight increase in glycogen content and a significant decrease in glycogen phosphorylase activity observed after other missions. Higher plasma cholesterol and HMG-CoA reductase activity may indicate slower removal of lipoprotein cholesterol from the circulation in these animals. In contrast, serum cholesterol decreased during both the Apollo and Skylab missions. There are some inconsistent results in the effects of simulated microgravity on the metabolism of hepatic glycogen. Additional studies are required.