CMPH

Summary

The definition of an autoimmune disorder is a condition in which the body’s immune system mistakenly attacks its own healthy tissues and cells. The assumption is that something is wrong with the immune systems targeting. The theory is that the immune system is overactive and targeting healthy cells. This paper will demonstrate that there is nothing inherently wrong with the immune system, and the body is fighting a chronic infection due to dysbiosis. During an infection, the body’s immune system will kill healthy cells. Perhaps the term “Autoimmune Disease” is a misnomer, and the immune system is just fighting an infection caused by dysbiosis.

Bacteria, fungi, and viruses are found in the mouth, esophagus, stomach, and intestinal tract. Most bacteria are commensal. Bacteria is found in the blood, and the synovial fluid. Arthritis sufferers typically have dysbiosis. H Pylori is found in arthritic patients in the synovial fluid. When the gut is leaky, or there is an ulcer or bleeding gums, bacteria escape into the body, seeking food and a place to hide. When the body is under attack from a pathogenic virus, the immune system reallocates resources and energy to focus on the immediate threat posed by the virus. Fewer resources are allocated to treating bacterial infections. During a viral attack, the bacteria may enter the synovial fluid and hide in the cracks in the cartilage, which have developed due to wear and tear, triggering an inflammatory response from the immune system. During the immune response, the cartilage matrix is destroyed due to the actions of Nutrifilles, Natural Killer Cells, Killer T Cells, and the Complement System, which attempt to rid the body of bacteria and fungi.

Psoriatic and rheumatoid arthritis may be a normal immune response to the dysbiosis of the synovial fluid. In healthy individuals, bacteria are present throughout the body, including in the bloodstream and synovial fluid. Perhaps arthritis is a case of the wrong bacteria entering the synovial fluid, causing dysbiosis in the synovial fluid. The infiltration of bacteria causes an immune response, and the macrophages are drawn to the area, releasing cytokines. Cytokines trigger inflammation, and neutrophils and dendritic cells are drawn to the area, thereby exacerbating the inflammation. As the improper bacteria bury through the cartilage, the macrophages and neutrophils follow them deeper and deeper. Bacteria and fungi are seeking microcracks to hide in. Neutrophils deploy their Neutrophil Extracellular Traps (NETs). The NETs kill bacteria and fungi, and also damage the cartilage, creating more crevices and hiding places for other bacteria. The blood and the synovial fluid are not in a sterile environment. Each has its biosphere.

Intestinal tract infections, gum infections such as gingivitis, and acid reflux disease can all contribute to the potential for a leak into the bloodstream. During a viral infection, cytokines are released drawing macrophages and neutrophils to the area of viral infection and away from a small bacteria infection in the synovial fluid. Further neutrophils will apoptosis after 24 hours further diminishing the bacterial infection fight. In their brilliant paper, Berthelo et al. details that DNA from gut microbiota can be found in the synovium of osteoarthritis and rheumatoid arthritis sufferers. Furthermore, they point out that bacterial DNA is found in the blood, and bacteria are also found in the crevices of the cartilage [3]. Berthelot et al [22] summarize the microbiome that exists and opens the door to the diversity that exists from the shoulder to the knee. Here I propose that Metabolic syndrome is the underlying disease. Its contributing factor is a poor diet, which results in dysbiosis and elevated levels of triglycerides and glucose in the blood, allowing bacteria and fungi to thrive. We should treat the gut biome along with the arthritis. A diet that focuses on whole foods and plant-based sources of protein has also been reported to be beneficial in the maintenance of arthritis and remission. For example, one controlled case series of 22 arthritis patients demonstrated a remission rate of 92% when placed on the plantbased diet [34].

How Can Bacteria Enter the Body?

Periodontal Disease

A high percentage of people with (RA) Rheumatoid Arthritis have periodontal disease, often cause by the bacterium Porphyromonas gingivalis [1]. Inflamed and bleeding gums create a constant entry point for these bacteria to leak into the bloodstream.

Acid Reflux in The Esophagus (GERD)

Many bacteria can cause Gastroesophageal Reflux Disease (GERD), particularly Helicobacter pylori (H. pylori). Additionally, changes in the gut microbiome, including shifts in specific bacterial populations, have also been linked to the development and exacerbation of (GERD) [16]. The resulting acid reflux can damage the esophagus, allowing the bacteria in that region to enter the bloodstream [26].

Ulcers in the Stomach

Damage to the stomach lining can cause bacteria to enter the bloodstream. Helicobacter pylori (H. pylori) is particularly common [17]. H. pylori-infected patients with RA exhibited notably higher levels of the anti-Cit-K1 antibody both in serum and synovial fluid than uninfected patients with RA. Additionally, the serum anti-Cit-K1 antibodies whereas positively correlated with Cit-K1 expression. In short, people with high levels of Helicobacter pylori had a higher incidence of arthritis [18].

Leaky Gut

Inflammation of the intestinal tract can cause gaps to form, allowing commensal bacteria to penetrate the intestinal wall. Moreover, evidence for microbial maternal transmission is increasingly widespread across animals. An imbalance in gut bacteria, called dysbiosis, can occur when different foods, chemicals, toxins, or poorly digested foods can cause an imbalance of microbes. The result of dysbiosis is inflammation and a leaky gut, which allows microbes to enter the bloodstream. Peyers patch in the intestine are the early warning cells for the intestine. These cells monitor the types of bacteria in the gut [24]. Cytokines damage tight junctions in the epithelial cells in the gut [38]. Everyone has experienced eating food that causes gas and bloating. This is a bloom of different types of bacteria. The intestinal microbiota is far more complex than currently imagined. An unhealthy diet and stress can impact the biome. Several researchers suggest that there may be over 1,000 species of bacteria, as well as an unknown number of viruses and fungi. With a leaky gut even, fungi can penetrate the bloodstream. To controld fungi mycoviruses are diverse and can infect a wide range of fungal species, including both pathogenic and non-pathogenic fungi. They can cause a variety of effects in their fungal hosts, ranging from asymptomatic infections to severe disease [15].

The Intestinal Biome

The innermost first layer is the mucus layer, which allows friendly microbes to adhere and nourish themselves. These beneficial bacteria communicate with our immune system, triggering an immune response when pathogenic bacteria and viruses are present. Beneath the mucus layer, Intestinal Epithelial Cells (IECs) form a physical barrier through tight junctions, which is essential for a healthy person. The intestinal flora can downregulate and upregulate regulatory T cells (T_reg cells) to modulate the immune response. Peyer’s patches continuously sample gut bacteria [24]. Cytokines are released by many of the immune cells like toll receptors, macrophages, neutrophils, dendritic cells will loosen tight junctions [38]. The intestinal flora can cause food cravings and mood changes. It does invite the question of who is working for whom; are we just legs and arms for the bacteria?

Diet and a Healthy Intestine Biome

Foods such as fermented foods (yogurt, kimchi, sauerkraut), whole grains, beans, leafy greens, and onions can promote a healthy gut microbiome, which is crucial for digestion, nutrient absorption, and overall well-being. These foods provide food for beneficial bacteria and fiber that nourish the gut microbiome. High-Fiber foods: Beans, lentils, leafy greens, asparagus, onions, and legumes are excellent sources of fiber and provide prebiotics that support a healthy gut microbiome. Bone broth provides collagen, which helps repair the gut lining. Garlic and onions act as prebiotics, while berries and other fruits contain polyphenols that protect the gut microbiome.

The Blood is not Sterile

In Castillo’s paper, it is illustrated that even in healthy individuals, a bacterial biome exists. They point out that blood microbiome exists in domesticated animals. They assert “that the presence of foreign microorganisms in human blood does not necessarily equate with infection or a diseased state [4]. In 1969, Tedeschi reported the presence of active bacteria in the blood of healthy individuals [2]. Bacteria from the skin and oral cavities can enter the bloodstream when the barriers between these environments are compromised. There are commensal bacteria that both occupy space and provide essential nutrition. Moreover, the microbiome can also self-regulate to some degree, some bacteria kill pathogenic bacteria, and certain viruses (bacteriophages) are excellent way to infect and kill pathogenic bacteria in a very target specific way [35]. Diet can also regulate the microbiome when the body has too much sugar or other nutrients, bacteria and fungi can bloom. Similar to an algae bloom in a lake that receives excessive runoff of fertilizer [27].

Synovial Fluid is Not Sterile it has its own Biome

The common understanding was that synovial fluid was sterile. New research shows that this is not the case. The paper by Hammad, et al.’s paper [6], showed that “Bacterial 16S rRNA genes were detected in 87.5% RA patients and all healthy control subjects” and “Utilising PCR bacterial 16S DNA was detected in synovial fluid of 14 of 16 patients with RA (87.5%) and 9 out of 9 healthy control subjects. The presence of fungi was detected in 12 of 16 (75%) RA samples and 8 out of 9 (89%) healthy control samples.” The author proposes that bacteria from the oral cavity or gut have found their way to the synovial fluid via the bloodstream [6]. The immune system views most bacteria and viruses as hostile beyond the skin barrier. Some bacteria are commensal in other areas of the body, such as the synovial fluid. Betaproteobacteria dominated Osteo-arthritis, and the control group had Actinobacteria and Clostridia. There are commensal bacteria everywhere, and the immune system is working diligently to distinguish between those that belong and those that do not. The biom is very complex and a common bacterium in one location might be more pathogenic in another. For example, the common bacteria in the mouth can be pathogenic in other parts of the body. Further viruses can be commensal. For example: specific viruses like bacteriophages can target specific pathogenic bacteria, acting as a very potent antibiotic that does not harm commensal bacteria. It is estimated that 40% of the bacteria in the ocean are infected with a virus [24]. Before the age of antibiotics, phages were used for the antibiotic properties [35].

How does Bacteria and Fungi get into the Synovial Fluid?

Bacteria, viruses, and fungi are always with us. Many species are commensal in one location, such as the intestine, and can be pathogenic in a different location, such as the synovial fluid. The Bacteria enter the synovial fluid through the bloodstream. The pore size of the cartilage is 6nm, the size of most bacteria is 100 to 4000nm, and the bacteria spores are 100nm. The only way bacteria can get into the synovial fluid is through the bloodstream. Microcracks can occur in the articular cartilage due to loading and extensive use. These micro-cracks can become filled with the wrong type of bacteria, which activates the dendritic cells as part of the innate immune system [3] [13]. Cytokines released from the immune cells destroy the tight junctions of epithelial cells, which is a characteristic of the classic leaky gut [38]. The immune system releases cytokines to activate macrophages and neutrophils, enabling them to deal with the infection. When sufficient bacteria are present in the synovial fluid, the macrophages are activated, releasing cytokines that induce inflammation and recruit dendritic

cells to sample the area. As the bacteria become more entrenched, larger quantities of cytokines are released, attracting additional neutrophils and exacerbating the inflammation. The neutrophils will kill the bacteria and surrounding somatic cells; the resulting DNA release from dying bacteria and somatic cells causes further inflammation and the release of additional cytokines. When attacked, bacteria become stressed and enter a mutation mode, signaling internal and external species to mutate. Many bacteria form biofilms, making it hard on the immune system. Next, the adaptive immune system is engaged. With the adaptive immune system engaged, the helper T-cells are active and activate the killer T-cells. A battle occurs between the immune system and mutating bacteria. If there is a wave after wave of bacteria from the leaky area, the bacteria and fungi will gain the upper hand, especially during a Cold and Flu Event. Most arthritis sufferers report an uptick in joint pain during a cold and flu episode [20]. The bacteria can mutate to evade and fend off the immune system because not enough resources are allocated to the attack. Since the synovial fluid has poor blood flow, there are few macrophages present, allowing bacteria to burrow deep into the cartilage. At some point, the immune system detects this through dendritic cells [13]. Pathogenic bacteria induce the natural killer cells to produce proinflammatory cytokines (IFNγ) from human lamina propria ILC3s, whereas commensal bacteria primarily elicit the production of protective cytokines (IL-22). This means the immune response is greater for pathogenic bacteria [37]. The ILC3s may also contribute to the relocation of intestinal bacteria from the intestine to the synovial fluid, as commensal bacteria are not typically viewed as pathogenic (Chart 1).

Chart 1: Dysbiosis Flowchart.

Rheumatoid Arthritis and the Immune Response

Macrophages are drawn to the synovial fluid because a noncommensal bacteria is present. They show clear signs of activation, such as overexpression of major histocompatibility complex class II (MHC-2) molecules, proinflammatory or regulatory cytokines, and growth factors. Synovial macrophages differentiate into stimulatory or inhibitory subpopulations, which in turn influence T-cell activity [10]. At the site of tissue destruction, macrophages express significant amounts of the inflammatory cytokines IL-1, TNF-α, and GM-CSF. The potential of macrophages to directly degrade cartilage matrix components is limited [10].

The lymphokine IL-17, produced in approximately 90% of RA synovial cultures but only in 16% of osteoarthritis cultures, strongly stimulates macrophages to produce IL-1 and TNF-α. The recent discovery of the gut microbiome in human cartilage, which differed between individuals with osteoarthritis and control groups, suggests that live bacteria from the gut microbiota may migrate between the gut and epiphyseal bone marrow. Subchondral microbiota could enhance cartilage healing and transform components of deep cartilage matrix into metabolites with immunosuppressive properties [8]. As the improper bacteria bury through the cartilage, the macrophages and neutrophils follow them deeper and deeper. Bacteria and fungi are seeking microcracks to hide in. Neutrophils deploy their Neutrophil extracellular traps (NETs). This kills bacteria and fungi, and also damages the cartilage, creating more crevices and hiding places for other bacteria. The release of bacteria DNA stimulates macrophages to release more cytokines, thus creating more inflammation. If a leaky gut is present, with an increase in bacteria and fungi, this process repeats itself, causing further cartilage damage and inflammation [33].