Source: Medical Reference News

Diabetes mellitus (DM) is a chronic metabolic disease characterized by high blood sugar and has two most common forms, type 1 diabetes (T1DM) and Type 2 diabetes (T2DM). T2DM accounts for about 90% of all diabetes cases and is caused by insulin resistance and impaired insulin secretion. Unlike T1DM, the symptoms of T2DM are often more subtle at onset, and it is difficult to diagnose the disease at its initial onset. In recent years, the prevalence of T2DM has increased sharply in all countries in the world. It is reported that the overall prevalence of type 2 diabetes in China from 2015 to 2019 has reached 14.92%, while the figure was only 1.29% in 1980 to 1984. At present, the main treatment measures for T2DM include hypoglycemic drugs, oral insulin sensitizer, diet therapy and exercise therapy. Some emerging therapeutic methods, such as mesenchymal stem cell (MSCs) therapy, intestinal flora transplantation (FMT), etc., have been gradually developed and achieved good therapeutic effects in clinical practice.

一、MSCs therapy improves the clinical efficacy of T2DM

stem cells (SC) can be divided into totipotent stem cells, pluripotent stem cells, and monopotent stem cells. MSCs are derived from mesoderm and have multidirectional differentiation potential, which has been the focus of clinical application in recent years. When allogeneic or even allogeneic MSCs are injected into the host, they can have multiple beneficial effects on the host under induced conditions such as cytokines, multidimensional differentiation signals, extracellular matrix components and contact between allogeneic or allogeneic cells in the microenvironment.

In recent years, many international researchers and biotechnology companies have focused on developing MSCs products and exploring their clinical application value. A single-arm clinical study on the efficacy and safety of human umbilical cord mesenchymal stem cells (hUC-MSC) in the treatment of type 2 diabetes has been reported from Peking University Shenzhen Hospital. We enrolled 16 patients with T2DM who received hUC-MSC intravenous infusion of 1×106 cells /kg per week for 3 weeks. The results showed that during the entire intervention period, the fasting blood glucose level and glycosylated hemoglobin (HbA1c) level of patients were significantly reduced, and the function of pancreatic islet beta cells was significantly improved. All patients reduced or even stopped hypoglycemic drugs, and no serious adverse events occurred during the study.

In terms of diabetes complications, South Korean biotech company Anterogen has developed a product containing adipose-derived mesenchymal stem cells (ADSC), Allo-ASC-DFU, to treat diabetic foot ulcers. The Phase II clinical trial of the new drug has been completed (NCT02619877) and the results are published in the Journal Diabetes. Allo-ASC-DFU or hydrogel complex were applied weekly to the wounds of enrolled patients. All patients were followed up for 12 weeks and Wagner scores were performed. At week 12, 82% of patients in the treatment group had completely closed their wounds, compared with 53% of patients in the control group, and the median time to complete closure between the two groups was 28.5 and 63.0 days, respectively, a difference of more than double. These findings confirm that MSCs are safe and effective in treating diabetic foot ulcers. In general, MSCs are currently considered to be effective and safe in the treatment of T2DM and its complications.

二、Intestinal flora transplantation (FMT) alleviates the clinical symptoms of T2DM

There are 100 to 1,500 types of bacteria in the human gastrointestinal tract, and the total number of bacteria is close to 100 trillion. These bacteria are called intestinal flora. Human health is closely related to the structure of the intestinal flora, which interacts with the human body to promote the absorption of various nutrients, while secreting a large number of metabolites and regulating various physiological activities of the human body. In the process of long-term development and evolution of individual intestinal flora, individuals dynamically adjust different flora and environment through adaptation and natural selection, so that individual intestinal flora is always in a state of dynamic balance, forming an interdependent and mutually restrictive system.

FMT is a treatment method to regulate the imbalance of intestinal flora. By transplanting the intestinal flora of healthy people into the intestinal tract of patients, patients can regain healthy and stable intestinal flora, so as to achieve the treatment of intestinal and extraterrital diseases. Over the past 10 years, FMT has been successfully used to treat a variety of human diseases, such as inflammatory bowel disease, obesity, metabolic syndrome, and functional gastrointestinal disorders. FMT is also an effective treatment for recurrent Clostridium difficile infection (rCDI). In 2022, the US FDA approved Rebyota, a new active biotherapeutic drug based on intestinal flora, for the clinical treatment of rCDI patients, and although Rebyota is not completely consistent with FMT, it still provides a reference precedent for the clinical application of FMT.

Previous studies have shown that FMT has a good effect on improving the clinical symptoms of patients with metabolic syndrome. In a double-blind randomized trial published in 2021, patients with metabolic syndrome were divided into FMT+ high-fermentation (HF), FMT+ low-fermentation (LF), HF, and LF groups. The results showed that after 6 weeks, only patients in the FMT+LF group had a significant improvement in HOMA3-IR, while there was no difference in HOMA3-IR in the FMT+HF, HF and LF groups. Overall, the study confirms that FMT combined with low-fermented foods can effectively reduce insulin sensitivity in patients with obesity and metabolic syndrome, and has a high safety profile. There are also several clinical studies exploring the effects of FMT on T2DM.

Earlier research, published in the journal Gastroenterology, showed that six weeks after transplantation of intestinal flora from a lean, healthy donor, patients with diabetes experienced a significant increase in insulin sensitivity, accompanied by a significant increase in the abundance of butyrate producing bacteria. Another, larger study further confirmed the beneficial effects of FMT in improving insulin resistance. In other words, intestinal flora obtained from healthy donors and transplanted into T2DM patients can effectively improve the peripheral insulin resistance status of patients within 6 weeks, while reducing HbA1c and increasing plasma gamma-aminobutyric acid (GABA) water level. The study also confirmed individual differences in patients' response to FMT, with patients with low gut microbiota diversity at baseline having a better response to FMT, so the characteristics of a patient's gut microbiota are a key factor influencing treatment effectiveness.

三、Mechanism of MSCs and FMT alleviating clinical symptoms of T2DM

Existing evidence shows that MSCs and FMT can significantly improve the clinical therapeutic effect of T2DM patients, including but not limited to improving the insulin resistance status of patients, reducing the levels of HbA1c and fasting blood glucose, improving the function of patients' islet beta cells, and reducing the dosage of patients with hypoglycemic drugs. As mentioned earlier, factors such as insulin resistance, family genetics, obesity, and poor environment are all risk factors for T2DM, so interventions targeting different pathogenesis factors are a good strategy to fundamentally address T2DM related issues.

Mechanism of MSCs alleviating clinical symptoms of T2DM

The development of T2DM is related to many factors. Current studies have shown that macrophage polarization induced by inflammatory factors is an important cause of T2DM and related complications. Macrophages are a type of phagocyte located in tissues, derived from monocytes and precursor cells in bone marrow. Macrophages are highly heterogeneous, with different subtypes exhibiting different phenotypes and functions in the complex microenvironment in vivo, thereby regulating immune responses. According to the different activation state, function and secretion factors, macrophages can be mainly divided into pro-inflammatory M1 macrophages and anti-inflammatory M2 macrophages. Animal studies have found a significant increase in the number of anti-inflammatory M2 macrophages in a variety of tissues after MSCs infusion, suggesting that increased M2 macrophages are significantly associated with improved T2DM symptoms in mice. More specifically, the increased M2-type macrophages observed in the spleen may be transported to various damaged tissues to exert an anti-inflammatory effect. This suggests that MSCs may influence disease progression in T2DM patients by regulating the number of macrophages in immune organs.

Other studies have confirmed that MSCs can migrate to damaged tissues in T2DM patients and improve chronic systemic inflammation in T2D patients by secreting a large number of cytokines. In vitro studies have shown that MSCs can produce a large number of cytokines, such as insulin-like growth factor (IGF), basic long fiber growth factor (bFGF), vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF), during hypoxic conditions, and alleviate the sustained injury of damaged sites by inhibiting apoptosis and promoting angiogenesis. Therefore, it is believed that transplanted MSCs may migrate to the damaged pancreatic region, interact with the local microenvironment, and improve the state of damaged pancreatic cells and tissues. In addition, there are obligatory stem cells in the adult pancreas, which can differentiate into functional beta cells by activating differentiation factors under stress conditions. MSCs and their secretions may interact with the microenvironment by affecting the differentiation of pancreatic obligate stem cells and the regeneration of pancreatic islet beta cells, thereby reducing blood glucose, alleviating T2DM symptoms, and ultimately affecting the clinical prognosis of T2DM patients.

Mechanism of FMT in alleviating T2DM

Since the first study on the gut microbiota of T2DM was reported in 2010, it has now been shown that the abundance of Clostridium and Firmicutes is significantly decreased in T2DM patients, while the abundance of Proteus beta is significantly increased and correlated with plasma glucose content. Studies from germ-free mice have confirmed that gut microbiota is one of the important predispose factors of T2DM disease. Specifically, germ-free mice had significantly lower levels of insulin resistance and body fat than normal mice, and transplanting intestinal flora from diabetic mice to germ-free mice resulted in obesity and significant insulin resistance in the germ-free mice. These studies have explored the causal relationship between gut microbiota and diabetes, and existing studies have confirmed that FMT can reduce the release of inflammatory factors, improve the symptoms of T2DM in the long term, and reduce the occurrence of related complications.

The important mediators of intestinal flora also include bacterial metabolites and bacterial components, including short-chain fatty acids (SCFAs), bile acids, branched-chain amino acids (BCAA) and lipopolysaccharides (LPS). Existing studies have confirmed that these metabolites can affect the occurrence and development of T2DM through multiple pathways. SCFAs are metabolites produced by gut bacteria, including acetic acid, propionic acid and butyric acid, which are used by the body to metabolize dietary fiber. As one of the most extensively studied metabolites, SCFAs affects glucose metabolism and insulin sensitivity through pathways involved in maintaining the integrity of the intestinal barrier and stimulating intestinal hormone secretion. Bile acids promote muscle energy expenditure and intestinal cell secretion of glucagon-like peptide-1 (GLP-1) by activating mercaptan guanoside receptor-5 (TGR-5) to improve insulin resistance and glucose metabolism abnormalities.

Important role of intestinal flora in MSCs treatment

As mentioned earlier, MSCs infusion can significantly improve blood sugar levels, and improving insulin resistance status in diabetic patients is a key step in its effect. Considering that FMT can also affect the insulin sensitivity of patients through multiple pathways such as metabolism and immunity, the combination of FMT and MSCs in the field of diabetes treatment is logically reasonable from the mechanism. In other research areas, FMT has been confirmed to be associated with the treatment of MSCs. For example, the study published in 2021 confirmed that MSCs infusion inhibited enterococcus abundance and increased AKK bacterial abundance by regulating intestinal microflora distribution after hematopoietic cell transplantation, and finally increased the content of IL-17A and Occludin, promoting the repair speed of injured intestinal tract. Another, more in-depth study showed that hUC-MSC was able to reshape the diversity of the gut flora by regulating the secretion of immunoglobulin A, ultimately improving the symptoms of colitis. In disease models such as liver inflammation, acute lung injury and spinal cord injury, MSCs treatment has also been preliminatively demonstrated to be significantly associated with the restoration of the structure and diversity of the gut microbiota. Although most of these results come from animal models, and the causal relationship between the two has not been fully clarified, it still provides a series of valuable clues for researchers. In-depth study of the combined effect of MSCs and FMT and its application in T2DM may be one of the research trends in related fields.

四、Future outlook

In general, T2DM is a serious threat to human health. At present, a single treatment can not completely solve the clinical problems of patients, and comprehensive treatment is an important development direction. Both MSCs infusion and FMT are emerging treatments for T2DM in recent years, and both treatments have been proven effective and safe by a large number of clinical studies. Both MSCs infusion and FMT can affect the immune system, thereby regulating the inflammatory response during the development of T2DM disease. At the same time, both of them can improve insulin resistance status in T2DM. Therefore, there is reason to believe that the combination of the two is expected to further improve the clinical treatment effect of T2DM patients.