Published: December 2018
Authors: F. De Luca, and Y. Shoenfeld

Summary:

“The microbiome is represented by microorganisms which live in a symbiotic way with the mammalian.

Microorganisms have the ability to influence different physiological aspects such as the immune system, metabolism and behaviour.

In recent years, several studies have highlighted the role of the microbiome in the pathogenesis of autoimmune diseases. Notably, in systemic lupus erythematosus an alteration of the intestinal flora (lower Firmicutes/Bacteroidetes ratio) has been described.

Conversely, changes to the gut commensal and periodontal disease have been proposed as important factors in the pathogenesis of rheumatoid arthritis. At the same time, other autoimmune diseases (i.e. systemic sclerosis, Sjögren’s syndrome and anti‐phospholipid syndrome) also share modifications of the microbiome in the intestinal tract and oral flora.

Herein, we describe the role of the microbiome in the maintenance homeostasis of the immune system and then the alterations of the microorganisms that occur in systemic autoimmune diseases.

Finally, we will consider the use of probiotics and faecal transplantation as novel therapeutic targets.”

Introduction:

“The human body is densely populated by commensal and symbiotic microbes, the majority of the constituent microorganisms being bacteria. These microbes occupy different habitats such as gut, skin, vagina and oral.

Not only are the types and abundance of microbes different in different organs, but these may also differ in different individuals. The genome of these microorganisms and their ecosystems constitute a microbiome.

Factors such as diet, environment, host genetics and mode of delivery may be the reason behind the wide microbial diversity.

1. The presence of the microbiome and microbial products regulate the development and function of the immune system in the host. Furthermore, other physiological aspects of the mammalian (metabolism, behaviour) are affected by commensal microorganisms

2. Recently, many scientists have focused on the importance of the commensal bacteria in the pathogenesis of several diseases, including autoimmune diseases. The aim of this review is to describe the main alterations of the microbiome that occur in autoimmune diseases.”

Microbiome and Autoimmune Diseases:

“Autoimmune diseases (AIDs) result from an individual’s immune system attacking self‐tissues, with an estimated incidence of approximately 3–5% worldwide.

The pathogenesis is not understood completely, but environmental factors (life‐style, diet, drugs, infections) and certain genetic backgrounds have been proposed.

The human microbiome might be a major player in autoimmunity, as the loss of immune tolerance can be caused by microbial composition changes.

Microorganisms can elicit the immune response against the host if the mechanisms of tolerance fail for several reasons…

Evidence from neuroscience research suggests that the microbiome is essential for development and maturation of the central nervous system, as well for behavioural and cognitive functions.

Communication between the central nervous system and gut is bidirectional, and is referred to as the ‘gut microbiota–brain axis’. The gut can interact with the brain through several pathways and through commensal metabolism, such as short‐chain fatty acid (SCAFs), 5‐hydroxytryptamine (5‐HT) and gamma‐aminobutyric acid (GABA).

Multiple sclerosis (MS) is an autoimmune disease characterized by the invasion of the central nervous system by immune cells (i.e. CD4 and CD8 T cells, B cells and activated monocytes), resulting in the demyelination of neurones and subsequent pathology…”

Rheumatoid Arthritis:

“RA is a chronic autoimmune disease characterized by inflammation and pain of the joints with varying degrees of systemic involvement in the presence of rheumatoid factor (RF) and anti‐citrullinate peptide antibodies (ACPA).

Although the genetic background plays an important role, other environmental risk factors, such as tobacco use and infection, have shown strong evidence for the pathogenesis of the disease…

Recently, alteration of microbiota has attracted the attention of many researchers. Several studies have found an association between periodontitis and RA.

The chronic oral inflammation caused by oral bacteria and leucocyte infiltration with progressive destruction of the alveolar bone seems to share the same pathogenetic mechanisms with RA:

(i) accumulation of leucocyte infiltration; (ii) release of inflammatory cytokines and mediators such as prostaglandin E2 (PGE2), tumour necrosis factor (TNF)‐α, interleukin (IL)‐1b, IL‐6, IL‐12, IL‐17, IL‐18, IL‐33, granulocyte–macrophage colony‐stimulating factor (GM‐CSF), monocyte (CSF (M‐CSF), receptor activator of nuclear factor kappa‐Β ligand (RANKL), matrix metalloproteinases (MMPs) and nitric oxide (NO)…

The majority of microorganisms present in our body are harboured in the human gut, thus affecting the balance between pro‐ and anti‐inflammatory immune responses.

As mentioned above, the butyrate produced by intestinal bacteria could explain anti‐inflammatory properties through the differentiation of Treg lymphocytes.”

Discussion:

“The association between bacteria and autoimmune disease is well understood; alteration of microbiome ‘dysbiosis’ can induce autoimmune disease in people with certain genetic backgrounds and environmental factors.

Dysbiosis can be categorized into three different types: (1) loss of beneficial organisms, (2) excessive growth of potentially harmful organisms and (3) loss of overall microbial diversity.

Moreover, these three types are not mutually exclusive and can occur simultaneously 103. Besides, different commensal can increase or decrease in amount according to disease… Recently, studies have focused upon reversing the negative effects mediated by the microbiota during the disease state.

It is possible to restore the healthy flora through administration of (i) probiotics, Gram‐positive bacteria (i.e. Bifidobacteriaum spp., Lactobacillus spp., Lactococcus spp., Pediococcus spp. and other non‐pathogenic strains of E. coli); and (ii) faecal microbiota transplantation (FMT), which consists of engrafting a healthy microbiota into patient recipients to reintroduce or re‐establish a stable environment that influences both the endogenous microbes and the host.

The scientific literature is rich with studies concerning probiotic treatments in autoimmune disorder.

Recently, it has been demonstrated that in non‐obese diabetic (NOD) mice the oral administration of a Lactobacillaceae protects mice from T1D by suppressing IL‐1b and promoting the differentiation of CD103+ tolerogenic DCs in the gut.

Moreover, in a multi‐centre prospective cohort study, early probiotics supplementation has been shown to decrease the risk of islet autoimmunity in children with higher genetic risk of TDM1.

In 45 RA patients the administration of Bacillus coagulans has ameliorated pain and has improved disability, antagonizing microbes that may be contributing to an inflammatory response and producing short‐chain fatty acids such as butyric acid with anti‐inflammatory activities 108. In addition, the administration of L. casei reduces proinflammatory molecules (IL‐1β, IL‐2, IL‐6, IL‐12, IL‐17, IFN‐γ, TNF‐α and Cox‐2) in experimental arthritis.

Similarly, Lactobacillus spp. improves lupus symptoms, diminishes inflammation and restores the intestinal barrier, thereby increasing the expression of adhesion molecules in the gut.

Despite pharmacological drugs and the use of antibiotics that produce a negative impact on gut microbiota, there is a great deal of evidence that autoimmune diseases can be treated with antibiotics…

In conclusion, further studies will be required to investigate the relationship between mammalian and commensals in order to develop novel therapeutic targets…

Microorganisms can elicit the immune response against the host if the mechanisms of tolerance fail in several ways:

(i) epitope spreading consists of the development of autoimmune responses to endogenous epitopes following the release of self‐antigens during an inflammatory response, which is caused by a change in protein structure, i.e. changing of amino acid residue from arginine to citrulline.

This may result in an immune reaction not only against the original protein or in its citrullinated form, but also against other citrullinated proteins;

(ii) molecular mimicry is a mechanism by which infections can induce autoimmunity and occurs when foreign antigens share sequence or structural similarities with self‐antigens. The immune responses can be directed against peptides with similar charge distribution and overall shape.

(iii) Bystander activation occurs when microbial infection stimulates Toll‐like receptors (TLRs) and other pattern recognition receptors on antigen‐presenting cells (APCs) with the production of proinflammatory mediators which, in turn, may lead to tissue damage 29; and

(iv) prolonged infection with a virus, such as EBV or HCV, can induce constant activation and proliferation of T cells, resulting in the production of monoclonal and polyclonal antibodies as well as immune complexes, leading to loss of tolerance.”