Advances in Research on the Relationship Between Intestinal Flora and Myasthenia Gravis Running Title: Correlation of Intestinal Flora and Myasthenia Gravis

Human intestinal flora refers to a large and diverse microbial population present in the digestive tract of the human body, which plays a significant role in the establishment of human immune homeostasis and the normal function of the immune system. Myasthenia Gravis is an autoimmune disease of the neuromuscular junction, mainly involved in the antiacetylcholine receptor antibody, cellular immune dependence, and complement. At present, studies have found that the intestinal flora of Myasthenia Gravis is different from that of healthy people. Probiotic therapy has been shown effective in the experimental autoimmune Myasthenia Gravis animal models. This article reviews the relationship between intestinal flora and Myasthenia Gravis, to provide new ideas for further study of the pathogenesis and clinical treatment of Myasthenia Gravis.


INTRODUCTION
Myasthenia Gravis (MG) is an autoimmune disease of the neuromuscular junction mainly mediated by anti-acetylcholine receptor (AChR) antibody, cellular immune dependence, and complement, which often manifests as morbid fatigue of part or whole-body skeletal muscle 1 .
The specific etiology and pathogenesis of this disease are still unclear, and there is no effective treatment to cure it. At present, studies have shown that the disorder of intestinal flora can cause a variety of autoimmune diseases 2, 3 . Many scholars have found that there are significant differences between intestinal flora and healthy people in MG patients, and probiotics have been shown effective in the treatment of experimental autoimmune myasthenia gravis (EAMG) animal models. This article reviews the relationship between intestinal flora and myasthenia gravis.

Intestinal flora concept
The human intestinal flora refers to a large and diverse microbial population present in the digestive tract of the human body. It contains at least 10 14 Bacteria in the human gastrointestinal tract, and the total weight is about 1 kilogram 4 . The number of genomes encoding the protein is More than 100 times more human genomes [5][6][7] . Among the approximately 200 common bacteria in the human gut, the most important genus are Bacteroides, Clostridium, Faecalibacterium, Eubacterium, Ruminococcus, Peptidococcus, Peptidostreptococcus, and Bifidobacterium 8-10 . These major intestinal bacteria are associated with type 1 diabetes, obesity, inflammatory bowel disease, Alzheimer's disease, Parkinson's disease, neuromyelitis optica spectrum disorders, chronic urticaria, Crohn's disease, multiple sclerosis, myasthenia gravis, Irritable bowel syndrome, gestational diabetes and many other human diseases   , see table 1 for details.The number, composition, and state of the intestinal flora are always changing dynamically. Even in the same individual or different individuals, or individuals in the same family, the diversity of the flora is very different 34 . It is generally believed that the intestines of newborns are sterile, after birth, various microorganisms enter the gastrointestinal tract through the mouth, anus, and colon, and the microbiota in the newborn is relatively stable to about one year old 35 . As the age changes, the intestinal flora in the human body will also change. Studies have shown that with the increase of age, the beneficial function of the age-related intestinal flora decreases, and the probability of inflammation and disease in the body increases, especially for older people over the age of 90, the chances of their occurrence are greater 36 .
Under normal circumstances, the intestinal flora and the host interact with each other to form a relatively stable dynamic balance, which plays a vital role in the digestion, absorption, metabolism, and immune regulation of the human body. When the proportion is imbalanced, displaced, and the body's immunity is low, the balance of intestinal micro-ecology is broken, which triggers immune disorders and successively causes various diseases of the body [37][38][39] .

Intestinal flora and human immunity
With the development of the Human Microbiome Project (HMP) 40 people's research on the intestinal flora has been deepened, and it has been found that the intestinal flora is closely related to human health. The intestinal flora is even considered to be "another organ" of our body. The establishment and the perfection of the immune system are almost simultaneous.
Our growth and development have always accompanied their interaction with our immune system. The composition and metabolites of intestinal microbes not only promote the development of the host's immune system but also regulate the body's immune system. The interaction between the intestinal flora and the immune system is two-way. The result is to maintain homeostasis; that is, the body's immune system can both immune to the gastrointestinal symbiotic microbes and respond appropriately to protect the body from pathogens 34

Correlation between intestinal flora and MG
The cause of MG has both environmental and genetic factors and the specific factors that cause susceptibility to remain challenging to determine. It is known that changes in the intestinal flora can affect the body's various physiological functions by regulating the body's immune system.
Whether the changes in the intestinal flora are related to the pathogenesis of myasthenia gravis has caused many scholars to think and pay attention. German Moris et al. 47  Desulfovibrio is increased. Dongxu Qiu et al. 48 compared the fecal microbiota of MG patients with age and gender-matched healthy controls, the pedigree of intestinal microflora, the changes in short-chain fatty acids (SCFAs), and found that they were associated with healthy people.
In comparison, the intestinal microflora of the MG group changed in the relative abundance of the bacterial taxonomic group, and the bacterial richness decreased sharply, especially in the Clostridium genus. The absolute amount of the healthy control group was three times higher than that of the MG group; the content of SCFAs in the MG group was significantly lower than that in the healthy control group. In addition, they also found that intestinal flora imbalance is

Possible mechanisms of intestinal flora and MG
The gastrointestinal tract is a complex ecosystem that contains a large number of microorganisms that are symbiotic with the host and affect human nutrition, metabolism, and regulatory T cells (Treg) in peripheral blood leukocytes 60 . Therefore, we hypothesized that the decrease in the number of Foxp3 + CD4 + Treg cells caused by the disorder of the intestinal flora and the abnormal function might lead to the occurrence of MG or the aggravation of symptoms, and the specific mechanism remains to be further studied. (See Figure 1 and Figure   2 for details.)

Treatment of intestinal flora and MG.
It by the disorder of intestinal flora and dysfunction may lead to the occurrence of MG or the aggravation of symptoms. At present, scholars have found that probiotic therapy can effectively alleviate the symptoms of EAMG. Therefore, we can start from the gut microbiota and focus on discovering the biomarkers of MG that may be present in the gut flora, which will help to diagnose MG better and better understand the relationship between gut flora and MG. In the future, using probiotic therapy to regulate intestinal flora may also be an effective treatment for MG.