Question

Describe in 2 pages at least how gut flora can be related to immune system disorders.

Answer 1

The human gut harbors a complex community of microbes that affect many aspects of our health. Known as the gut microbiota, these bacteria help with metabolism and maintaining a healthy immune system.

The lining of the intestine forms a barrier that is crucial to containing gut microbes. If the lining is breached and a gut microbe is able to get into the bloodstream and nearby organs, it can cause disease. Despite the fact that the body has many ways to prevent the breach, microbes sometimes get through.

Bacteria and Cancer in the Gut

Cynthia Sears, a professor of medicine at Johns Hopkins and member of its Kimmel Cancer Center, studies the role of the microbiome in causing colon cancer in mice and humans. Colon cancer seems to stem from an interaction among the microbiome, the immune system and epithelial cells that line the colon.

Sears’ lab is using mice to study one kind of human colonic bacteria that may be a bad actor, enterotoxigenic Bacteroides fragilis (ETBF). ETBF makes three types of a protein called the Bacteroides fragilis toxin (BFT); one of which, BFT2, has greater carcinogenic potential and is common in humans. The protein sets off a huge array of actions in the epithelial cells that line the colon. In certain mice, it can cause inflammation and cancer of the colon. Sears’ group is now trying to figure out what the receptor is that enables the protein to interact with epithelial cells. Finding that, she says, “may open our eyes to how cancer begins in the colonic epithelial cells.”

One of the actions set off by ETBF in the colon is called TH17 inflammation. This is largely thought to be useful for fighting off bacteria and fungi, but it can also turn against the body and cause cancer in the colon. Using mice, Sears’ group is trying to understand exactly what the TH17 response does to cells in the colon to promote cancer development.

No one species has been found to always cause colon cancer in humans. Instead, carcinogenesis may have to do with a shift in the ecology of the gut—that is, in the makeup of the bacterial community.

Scientists have suspected since the 1970s that bacteria contribute to colon cancer. But, as sequencing has gotten cheaper, it’s become much easier to ask questions about exactly what kind of role bacteria play in the disease. “Whether they’re the reason it starts or whether they contribute to the growth of tumors over time, I think, is a question that remains to be clearly answered,”

* Functions of the Gut Microbiota

1. Metabolic role

• Salvages calories

• Produces short-chain fatty acids

• Produces arginine and glutamine

• Synthesizes vitamin K and folic acid

• Participates in drug metabolism (eg, activates 5-aminosalicylic acid from sulfasalazine)

• 2. Deconjugation of bile acids

• 3. Prevention of colonization by pathogens

• 4. Immunologic effects

• Stimulates immunoglobulin A production

• Promotes anti-inflammatory cytokines and down-regulates proinflammatory cytokines

• Induces regulatory T cells

The Normal Gut Microbiota: An Essential Factor in Health

Basic Definitions and Development of the Microbiota

The term microbiota is to be preferred to the older term flora, as the latter fails to account for the many nonbacte-rial elements (eg, archea, viruses, and fungi) that are now known to be normal inhabitants of the gut. Given the relatively greater understanding that currently exists of the role of bacteria, in comparison with the other constituents of the microbiota in health and disease, gut bacteria will be the primary focus of this review. Within the human gastrointestinal microbiota exists a complex ecosystem of approximately 300 to 500 bacterial species, comprising nearly 2 million genes (the microbiome).¹ Indeed, the number of bacteria within the gut is approximately 10 times that of all of the cells in the human body, and the collective bacterial genome is vastly greater than the human genome.

At birth, the entire intestinal tract is sterile; the infant’s gut is first colonized by maternal and environmental bacteria during birth and continues to be populated through feeding and other contacts.² Factors known to influence colonization include gestational age, mode of delivery (vaginal birth vs assisted delivery), diet (breast milk vs formula), level of sanitation, and exposure to antibiotics.^3,4 The intestinal microbiota of newborns is characterized by low diversity and a relative dominance of the phyla Proteobacteria and Actinobacteria; thereafter, the microbiota becomes more diverse with the emergence of the dominance of Firmicutes and Bacteroidetes, which characterizes the adult microbiota.^5–7 By the end of the first year of life, the microbial profile is distinct for each infant; by the age of 2.5 years, the microbiota fully resembles the microbiota of an adult in terms of composition.^8,9 This period of maturation of the microbiota may be critical; there is accumulating evidence from a number of sources that disruption of the microbiota in early infancy may be a critical determinant of disease expression in later life. It follows that interventions directed at the microbiota later in life may, quite literally, be too late and potentially doomed to failure.

Following infancy, the composition of the intestinal microflora remains relatively constant until later life. Although it has been claimed that the composition of each individual’s flora is so distinctive that it could be used as an alternative to fingerprinting, more recently, 3 differ-ent enterotypes have been described in the adult human microbiome.¹⁰ These distinct enterotypes are dominated by Prevotella, Ruminococcus, and Bacteroides, respectively, and their appearance seems to be independent of sex, age, nationality, and body mass index. The microbiota is thought to remain stable until old age when changes are seen, possibly related to alterations in digestive physiology and diet.^11–13 Indeed, Claesson and colleagues were able to identify clear correlations in elderly individuals, not only between the composition of the gut microbiota and diet, but also in relation to health status.¹⁴

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Introduction

The microbiota consists of a multispecies microbial community living within a particular niche in a mutual synergy with the host organism. Besides bacteria, the microbiota includes fungi, archaea, and protozoans (1, 2), to which viruses are added, which seem to be even more numerous than microbial cells (3). The gastrointestinal tract (GIT), with its epithelial barrier with a total area of 400 m², is a complex, open, and integrated ecosystem with the highest exposure to the external environment. The GIT contains at least 10¹⁴ microorganisms belonging to >2,000 species and 12 different phyla, the associated microbiome containing 150- to 500-fold more genes than the human DNA (1, 4–7). The GIT microbiota exhibits a huge diversity, being individually shaped by numerous and incompletely elucidated factors, such as host genetics, gender, age, immune system, antropometric parameters, health/disease condition, geographic and socio-economical factors (urban or rural, sanitary conditions), treatments, diet, etc. (8, 9). Recent metagenomic data demonstrated that the majority of component species is not present in the same time and in the same person, but, however, few species are abundant in healthy individuals, while other species are less represented (4, 7). In addition to the distribution along the digestive tract segments, the GIT microbiota of the three distinct transversal microhabitats, i.e., floating cells in the intestinal lumen, cells adherent to the mucus layer and respectively to the surface of the epithelial cells, is also different (3).

Recent findings suggest that the microbial colonization of the GIT starts before birth, as revealed by the placental microbiome profile, being composed of members of Firmicutes, Proteobacteria, Tenericutes, Bacteroidetes, and Fusobacteria groups, which were found to share some similarities with the human oral microbiome (10). Also, the meconium of full term infants is not sterile, harboring 30 genera normally found in the amniotic fluid, vagina, and the oral cavity (8, 9, 11). We can assume that the bacteria reach these sites mainly from the vaginal tract, although selective translocation is also possible. Archaea were also detected in the vaginal microbiota of pregnant women, accounting for a mother-to-child transmission (12).

Vaginally born infants have a microbiota containing species derived from the vaginal microbiota of their mothers. Conversely, in the case of cesarean section delivered babies, the microbiota is similar to the skin microbiota and is rich in Propionibacterium spp. and Staphylococcus spp. (13).

It is generally accepted that the pregnancy period and the first 1,000 days after birth are the most critical timeframes for interventions and any modulation made at this point has the potential to improve child growth and development (14). Delivery mode seems to influence immunological maturation through microbiota development. Cesarean section delivered children were found to have a higher number of antibody-secreting cells (11).

Furthermore, the human milk is involved in the GIT microbiota and immune system development. In addition to its nutritional components, this natural functional food contains numerous bioactive substances and immunological components that control the maturation of the newborn intestine and the composition of the microbial community. Numerous studies revealed that breast-feeding has a protective role in infants, conferred by a complex mixture of molecules, including lysozyme, sIgA, alpha-lactalbumin, lactoferrin, but also free oligosaccharides, complex lipids, and other glycoconjugates (14). The proteolytic processing of glycoprotein k-casein, with the release of glycomacropeptides, prevents colonization of the gut by pathogens, through competition with the receptors of the gut epithelial cells in breast-fed infants. Lactoferricin is a potent antimicrobial agent, explaining the decreased infant death rate caused by gastrointestinal and respiratory infections in breast-fed infants (14, 15). Moreover, breast milk contains ~10⁹ bacterial cells/L (16) and prebiotic oligosaccharides (fructans) which stimulate the multiplication of Bifidobacterium spp. and Lactobacillus spp., while follow-on milk powder stimulates proliferation of enterococci and enterobacteria (17, 18). As the infant grows, solid foods are introduced, therefore the microbiota diversity increases, and the microbiota community evolves toward the adult-like state. Although some dominant enterotypes represented by Bacteroides, Prevotella, and Ruminococcus genera are recognized, however, the final composition of the adult microbiota is unique and the factors guiding this feature are still a matter of debate (19).

The very active microbial community has been shown to mutually interact with the host and to exert a lot of beneficial roles, explaining its tolerance by the host organism. The GIT microbiota is involved in energy harvest and storage, and, due to its particular metabolic pathways and enzymes, it extends the potential of the host metabolism. This property is believed to exhibit a potent evolutionary pressure toward the establishment of bacteria as human symbionts (11). The GIT microbiota influences the normal gut development, due to its ability to influence epithelial cell proliferation and apoptosis of host cells. Although the intimate interactions between microbiota and host cells are widely unknown, a major mechanism seems to involve short-chain fatty acids (SCFA), resulted from the fermentation of indigestible polysaccharides (fibers), such as butyrate, acetate, and propionate with an important anti-inflammatory role. SCFAs also support intestinal homeostasis in the normal colon, by aiding intestinal repair through the promotion of cellular proliferation and differentiation. However, SCFAs seem to inhibit the cancerous cells proliferation. Among the different SCFAs, butyrate has a paramount role in intestinal homeostasis due to its role as a primary energy source for colonocytes (20, 21). In addition, the GIT microbiota stimulates the nonspecific and specific immune system components development, just after birth and during the entire life and it acts as an antiinfectious barrier by inhibiting the pathogens’ adherence and subsequent cellular substratum colonization and by the production of bacteriocins and of other toxic metabolites. Moreover, the microbiota is predominantly composed of anaerobes which prevent the process of translocation of aerobic/facultatively anaerobic bacteria and the consecutive systemic infections in immunodeficient individuals. Importantly, some GIT microbiota representatives (Escherichia coli and Bacteroides fragilis) are involved in the synthesis of vitamins, such as B1, B2, B5, B6, B12, K, folic acid, and biotin. Also, the GIT microbiota has the ability to degrade xenobiotics, sterols and to perform biliary acids deconjugation (B. fragilis and Fusobacterium spp.) (19).

All these aforementioned effects are occurring when the microbiota community is characterized by an interspecies balance, known as eubiosis. Any perturbation of eubiosis, known as dysbiosis, could become a pivotal driver for various infectious and non-infectious diseases, each of them with specific microbiota signatures that can further trigger pathophysiologies in different organs (11).

Our aim was to review these physiological roles, focusing on one side the GIT microbiota contribution to the immune system development and education, and on the other side, to what is happening when eubiosis is replaced by the dysbiosis status; in this case the immunostasy is altered, the host becomes more susceptible to infections, both exogenous and endogenous; immunotolerance is affected and the immune system will react against the self-components (autoimmunity), or vary in intensity, being either over (allergic reactions and chronic inflammation) or less/inappropriately (immunodeficiency and cancer) activated.

Regulation of the Microbiota

Because of the normal motility of the intestine (peristalsis and the migrating motor complex) and the antimicrobial effects of gastric acid, bile, and pancreatic and intestinal secretions, the stomach and proximal small intestine, although certainly not sterile, contain relatively small numbers of bacteria in healthy subjects.¹⁵ Interestingly, commensal organisms with probiotic properties have recently been isolated from the human stomach.¹⁶ The microbiology of the terminal ileum represents a transition zone between the jejunum, containing predominantly aerobic species, and the dense population of anaerobes found in the colon. Bacterial colony counts may be as high as 10⁹ colony-forming units (CFU)/mL in the terminal ileum immediately proximal to the ileocecal valve, with a predominance of gram-negative organisms and anaerobes. On crossing into the colon, the bacterial concentration and variety of the enteric flora change dramatically. Concentrations of 10¹² CFU/mL or greater may be found and are comprised mainly of anaerobes such as Bacteroides, Porphyromonas, Bifidobacterium, Lactobacillus, and Clos-tridium, with anaerobic bacteria outnumbering aerobic bacteria by a factor of 100 to 1000:1. The predominance of anaerobes in the colon reflects the fact that oxygen concentrations in the colon are very low; the flora has simply adapted to survive in this hostile environment.

At any given level of the gut, the composition of the flora also demonstrates variation along its diameter, with certain bacteria tending to be adherent to the mucosal surface, while others predominate in the lumen. It stands to reason that bacterial species residing at the mucosal surface or within the mucus layer are those most likely to participate in interactions with the host immune system, whereas those that populate the lumen may be more relevant to metabolic interactions with food or the products of digestion. It is now evident that different bacterial populations may inhabit these distinct domains. Their relative contributions to health and disease have been explored to a limited extent, though, because of the relative inaccessibility of the juxtamucosal populations in the colon and, especially, in the small intestine. However, most studies of the human gut microbiota have been based on analyses of fecal samples, therefore representing a major limitation. Indeed, a number of studies have already shown differ-ences between luminal (fecal) and juxtamucosal populations in disorders such as inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS).^17,18

In humans, the composition of the flora is influenced not only by age but also by diet and socioeconomic conditions. In a recent study of elderly individuals, the interaction of diet and age was demonstrated, firstly, by a close relationship between diet and microbiota composition in the subjects and, secondly, by interactions between diet, the microbiota, and health status.¹⁴ It must also be remembered that nondigestible or undigested components of the diet may contribute substantially to bacterial metabolism; for example, much of the increase in stool volume resulting from the ingestion of dietary fiber is based on an augmentation of bacterial mass. The subtleties of interaction between other components of diet and the microbiota are now being explored and will, undoubtedly, yield important information. For example, data indicating a potential role of certain products of bacterial metabolism in colon carcinogenesis have already provided strong hints of the relevance of diet-microbiota interactions to disease. Antibiotics, whether prescribed or in the food chain as a result of their administration to animals, have the potential to profoundly impact the microbiota.¹⁹ In the past, it was thought that these effects were relatively transient, with complete recovery of the microbiota occurring very soon after the course of antibiotic therapy was complete. However, while recent studies have confirmed that recovery is fairly rapid for many species, some species and strains show more sustained effects.²⁰

Host-Microbiota Interactions

Gut-commensal microbiota interactions play a fundamental role in promoting homeostatic functions such as immunomodulation, upregulation of cytoprotec-tive genes, prevention and regulation of apoptosis, and maintenance of barrier function.²¹ The critical role of the microbiota on the development of gut function is amply demonstrated by the fate of the germ-free animal.^22,23 Not only are virtually all components of the gut-associated and systemic immune systems affected in these animals, but the development of the epithelium, vasculature, neu-romuscular apparatus, and gut endocrine system also is impaired. The subtleties of the interactions between the microbiota and the host are exemplified by studies that demonstrate the ability of a polysaccharide elaborated by the bacterium Bacteroides fragilis to correct T-cell deficien-cies and Th1/Th2 imbalances and direct the development of lymphoid organs in the germ-free animal.²⁴ Intestinal dendritic cells appear to play a central role in these critical immunologic interactions.^24,25

How does the gut immune system differentiate between friend and foe when it comes to the bacteria it encounters?²⁶ At the epithelial level, for example, a number of factors may allow the epithelium to tolerate commensal (and thus probiotic) organisms. These include the masking or modification of microbial-associated molecular patterns that are usually recognized by pattern recognition receptors, such as Toll-like receptors,²⁷ and the inhibition of the NFκB inflammatory pathway.²⁸ Responses to commensals and pathogens also may be distinctly different within the mucosal and systemic immune systems. For example, commensals such as Bifidobacterium infantis and Faecalibacterium prausnitzii have been shown to differentially induce regulatory T cells and result in the production of the anti-inflammatory cytokine interleukin (IL)-10.²⁹ Other commensals may promote the development of T-helper cells, including T_H17 cells, and result in a controlled inflammatory response that is protective against pathogens in part, at least, through the production of IL-17.³⁰ The induction of a low-grade inflammatory response (physiologic inflammation) by commensals could be seen to prime the host’s immune system to deal more aggressively with the arrival of a pathogen.³¹

Through these and other mechanisms, the microbiota can be seen to play a critical role in protecting the host from colonization by pathogenic species.³² Some intestinal bacteria produce a variety of substances, ranging from relatively nonspecifc fatty acids and peroxides to highly specific bacteriocins,^33,34 which can inhibit or kill other potentially pathogenic bacteria,³⁵ while certain strains produce proteases capable of denaturing bacterial toxins.³⁶

The Microbiota and Metabolism

Although the immunologic interactions between the microbiota and the host have been studied in great detail for some time, it has been only recently that the true extent of the metabolic potential of the microbiota has begun to be grasped. Some of these metabolic functions were well known, such as the ability of bacterial disac-charidases to salvage unabsorbed dietary sugars, such as lactose, and alcohols and convert them into short-chain fatty acids (SCFAs) that are then used as an energy source by the colonic mucosa. SCFAs promote the growth of intestinal epithelial cells and control their proliferation and differentiation. It has also been known for some time that enteric bacteria can produce nutrients and vitamins, such as folate and vitamin K, deconjugate bile salts,³⁷ and metabolize some medications (such as sul-fasalazine) within the intestinal lumen, thereby releasing their active moieties. However, it is only recently that the full metabolic potential of the microbiome has come to be recognized and the potential contributions of the microbiota to the metabolic status of the host in health and in relation to obesity and related disorders have been appreciated. The application of genomics, metabolomics, and transcriptomics can now reveal, in immense detail, the metabolic potential of a given organism.^38–41

It is now also known that certain commensal organisms also produce other chemicals, including neurotrans-mitters and neuromodulators, which can modify other gut functions, such as motility or sensation.^42–44 Most recently and perhaps most surprisingly, it has been proposed that the microbiota can influence the development⁴⁵ and func-tion⁴⁶ of the central nervous system, thereby leading to the concept of the microbiota-gut-brain axis.^47–49

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GIT Microbiota and Immune System Development

The mucosal immune system is highly specialized, its functions are largely independent of the systemic immune system (15) and it undergoes major changes after bacterial colonization of the intestinal tract (22).

Commensal microorganisms are required for the maturation of the immune system, which “learns” to differentiate between commensal bacteria (which are becoming almost quasi-self and tolerated antigens) and pathogenic bacteria (23, 24). Toll-like receptors (TLRs) from the membrane of the epithelial and lymphoid cells of the small intestine are involved in this differential recognition, being responsible for the normal development of the intestinal mucosal immune system. TLRs suppress the occurrence of an inflammatory response and promote immunological tolerance to normal microbiota components. The role of TLRs is to recognize different general microbe-associated molecular patterns (MAMPs) [containing various bacterial antigens (e.g., peptidoglycan components—muramic acid, capsular polysaccharides and lipopolysaccharides, flagellin and unmethylated bacterial DNA CpG motifs)] and to trigger the innate intestinal immunity (25, 26). Following stimulation, a complex cascade of signals is initiated, leading to the release of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB), which activates a variety of genes coding for chemokines, cytokines, acute phase proteins, and other effectors of the humoral immune response (27, 28). TLR activity decreases during the first weeks of life, potentially allowing the development of a stable gut bacterial community. Furthermore, TLR activation by antigens belonging to the normal intestinal microbiota is signaling the inhibition of inflammatory reactions, being thus essential to maintain intestinal homeostasis (29). Complementarily, NOD-like receptors (NLRs) recognize various microbial specific molecules and trigger the assembly of inflammasomes, which can act as sensors of damage-associated patterns. The NLPRP6 deficiency has been associated with an altered immune response (e.g., decreased IL-18 levels), dysbiosis, and intestinal hyperplasia (11, 30).

Gastrointestinal tract microbiota has been shown to modulate neutrophil migration and function (31) and to affect the differentiation of T cell populations into different types of helper cells (Th), respectively: Th1, Th2, and Th17 or into regulatory T cells (Tregs) (25). The Th17 cells are a subset of TCD4⁺ cells, which secrete multiple cytokines (IL-22, IL-17A, and IL-17F), with a significant impact on immune homeostasis and inflammation (32, 33). Unlike Th1 and Th2 cells, which have a stable secretory profile after differentiation, Th17 cells retain divergent cytokine expression profiles and functions (34). It has been shown that the administration of the purified capsular polysaccharide from the commensal bacterium B. fragilis suppresses the production of IL-17 and protects the colonic mucosa against inflammatory reactions initiated by bacterial antigens, stimulating TCD4⁺ lymphocytes to produce IL-10 (35). On the other side, the colonic environment also stimulates de novo differentiation and expansion of peripherally derived regulatory T cells from naïve CD4⁺ T cells (36). Tregs are key mediators of immune tolerance, limiting an inappropriately high inflammatory response (37), their dysfunction leading to autoimmune disorders (38).

sIgA has a crucial role in the local immune response, being considered the first line of defense against pathogens and toxins. sIgA production specific to different mucosal antigens is following their capture by Peyer’s patches M cells, transformation by underlying antigen-presenting cells [dendritic cells (DCs)], activation of T cells, and ultimately B cell class switch recombination in mesenteric lymph nodes (MLNs) and gut-associated lymphoid tissue. The commensal antigens induce the production of low amounts of sIgA through the modulation of their immunodominant epitopes, thus harboring an advantage for the colonization of the intestinal niche (11). A set of cytokines, including TGF-β, IL-4, IL-10, IL-5, and IL-6 stimulates IgA production. Some of these cytokines, notably IL-10 and TGF-β are crucial in maintaining the mucosal tolerance, therefore proving the link among sIgA production, immunity, and intestinal homeostasis (39).

In individuals with dysbiosis, immune responsiveness could be upregulated to promote the development of a more optimal status. This could be obtained through specific effects of sIgA, or less specific effects of innate immunity effectors (such as defensins) or local environment changes (i.e., diarrhea). In case of diarrhea, the host eliminates undesirable microbial communities in order to prepare niches for recolonization with more beneficial microbial populations, as a last resort to healing (14).

The host-commensal microbiota communication triggers antimicrobial responses from the epithelium including the release of several antibacterial lectins, including RegIIIc, α-defensins, and angiogenins (40, 41). These antibacterial effectors reduce the amount of potentially pathogenic microbes and provide protection against subsequent abnormal immune responses. For instance, Bacteroides thetaiotaomicron triggers the production of antimicrobial peptides which target other intestinal microbes. The microbiota of mice expressing a human enteric α-defensin, DEFA5, has no segmented filamentous bacteria (42), which are responsible for inducing IL-17-producing Th17 cells, which have been correlated with inflammatory bowel disease (IBD) and colorectal cancer.

Furthermore, aberrant microbial development during maturation of the innate immune system leads to defective immunological tolerance, which subsequently promotes exacerbated autoimmune and inflammatory diseases (e.g., allergen-induced airway hyperreactivity) (3). Microbial products may induce chronic stimulation of immune responses, leading to chronic, non-resolving inflammation and tissue damage, particularly after mucosal injury.

GIT Microbiota and Infections of Exogenous or Endogenous Origin

Microbiota–Pathogen Interactions

As also named “the last undiscovered human organ,” the intestinal microbiome has an impact on immune system development and differentiation. In addition, the microbiome holds a paramount role in the initiation and progression of infectious diseases (43).

Through the colonization of the mucosal entry sites of pathogens, microbiota could directly prevent the invasion by foreign microbes—a process known as colonization resistance (by competing with pathogenic bacteria in the gut for adhesion sites and nutrients, but also by releasing toxic molecules to counteract pathogen colonization), as well as indirectly, through the stimulation of the immune response. As stated above, the gut microbiota provides signals to stimulate the normal development of the immune system as well as the maturation of immune cells (44–46). The microbiota stimulates the secretory IgA response that is involved in inactivating rotaviruses, competes Clostridium difficile colonization, and neutralizes cholera toxin (47). Moreover, the signaling molecules released by the microbiota actively shape the host systemic immune response by regulating haematopoesis, and consequently potentiating the response to infection (48). Signals derived from the commensal microbiota trigger the development of granulocyte/monocyte progenitors in the bone marrow and hence affects tissue-resident innate immune populations which in turn promotes the early host innate response. In line with this, the absence of the microbiota derived signaling molecules cause alterations in tissue-resident myeloid populations prior to infection and leads to susceptibility to systemic infection by Staphylococcus aureus and Listeria monocytogenes (49).

The synergic interactions of the innate immune system and microbiota could be also exploited by pathogens to evade the antiinfectious mucosal barrier. A suggestive example is given by the oral bacterium Porphyromonas gingivalis, which escapes the host immune response via TLR2 signaling pathway modulation leading to dysbiosis and subsequent inflammation (50). Also, some viruses are able to interfere with the interplay between bacteria and the innate immune system (i.e., TLR4 signaling), for guaranteeing their efficient transmission (51). It has been proved that the antiviral host response is improved by antibiotic depletion of commensal microbiota. Intestinal antiviral innate immunity is the result of the induction of IL-18, interferon (IFN)-λ, or IL-22 pathways, which promote the expression of signal transducer and activator of transcription 1 (STAT1) and antiviral genes. Although IL-22 and IL-18 are both stimulated by commensal bacteria, IFN-λ expression is inhibited by the microbiota, hence enabling viral persistence. It has been also clearly demonstrated that interactions between gut epithelial cells and microbiota are crucial to maintain barrier defenses and gut homeostasis. For instance, the microbiota has a role in maintaining tight junctions’ integrity which limits Salmonella typhimurium invasion (52). On its turn, the intestinal pathogen S. typhimurium induces IL-22 production which targets commensal bacteria and liberates a colonization niche for the pathogen.

Generally, the antiinfectious barrier is efficient when the microbiota is complex and stable, in a eubiotic status. On the contrary, when dysbiosis occurs (due to different causes, e.g., poor colonization, antibiotherapy or an unbalanced, unhealthy diet, different pathological conditions leading to secondary immunodeficiencies), the microbiota loses its antiinfectious barrier potency and the host can be easily infected with different pathogenic microorganisms from the environment. In addition, some species of microbiota, enriched in the new condition of dysbiosis, can manifest their pathogenic potential by producing opportunistic infections. For example, antibiotics can be used for treating certain pathological GIT diseases, but the induced alteration of the intestinal microbiota could lead to metabolic disturbances, such as increased intestinal permeability, and may also increase susceptibility to infections [e.g., fungal and Clostridium difficile infections (CDIs)].

Recent findings proved a clear correlation between microbiome composition and risk of infectious diseases. For example, microbiota composition represents an infection risk for Plasmodium falciparum infection, and also a key factor for diverse vaccine responses (43).

Recent studies aiming to investigate the specific role of gut microbiota and immune system interactions in infectious diseases focused mainly on microbiome manipulation. This was achieved either by probiotics administration or fecal microbiota transplantation. Serious conditions which are prevalent in children, such as necrotizing and acute infectious diarrhea, but also antibiotic-associated diarrhea, CDIs and ventilator-associated pneumonia could be treated more efficiently by microbiota manipulation, with a better outcome, reduced mortality, and faster recovery rates. Since microbiota manipulation could control the balance between health and infectious disease, intestinal microbiota alteration by a pathogen or a pathobiont can lead to chronic diseases. In vivo studies demonstrated that the colonization of adherent-invasive Escherichia coli (AIEC, an E. coli pathovar involved in Crohn’s disease pathogenesis) during microbiota acquisition drove chronic colitis in mice (53). It seems that AIEC, Yersinia enterocolitica and probably other pathobionts, may promote chronic inflammation in susceptible hosts by producing gut microbiota alterations which lead to a higher capacity in activating innate immunity/pro-inflammatory gene expression (54). A recent study by Inoue et al. shed light on the impact of hepatitis C virus (HCV) infection on the gut microbiota. Unlike healthy individuals, HCV infected patients showed dysbiosis characterized by a decrease in Clostridiales and enrichment in Streptococcus and Lactobacillus genera. Microbiota alterations were present even in patients with mild liver disease, as revealed by the transient increase in Bacteroides and Enterobacteriaceae (55).

Gastrointestinal tract microbiota members can translocate from the digestive mucosa and reach the general circulation, indirectly by stimulating IL-12 production by splenic macrophages, DCs, which, in turn, regulates the Th1/Th2 balance toward a cell-mediated Th1 response (56). Studies have shown that the soluble products of Lactobacillus fermentum DSMZ 20052 determine the decrease of IL-8 levels by inhibiting the NF-kB pathway, thus alleviating the pro-inflammatory effect induced by Yersinia enterocolitica infection (57). Other studies support the activation of NF-kB signaling pathway with the subsequent activation of inflammatory genes by some probiotics. One of the hallmarks of NF-kB activation is the production of IL-6 (56). It has been shown that the colonization of the digestive tract of germ-free rats with Bifidobacterium lactis BB 12 strain stimulates the IL-6 synthesis (58).

Microbe–Microbe Interactions (Quorum Sensing)

All bacteria are able to communicate with each other by signaling molecules, which allow the bacterial cells to sense the environment, monitor population density and to adjust accordingly their gene expression. Through this type of communication, bacteria acquire an advantage crucial for dissemination and survival in highly competitive environments, which harbor hundreds of coexisting species (e.g., the oral cavity, the intestine). Depending on the involved members, intercellular communication is divided into two categories, based on the quorum-sensing (QS) mechanism. QS is a density-dependent molecular language responsible for the regulation of cellular phenotype/behavior as a response to environmental changes. The first type is the intraspecific cell-to-cell communication though specific QS molecules and the second mechanism consists of the interspecific communication based on an universal chemical “language,” which provides interspecific signaling between bacteria and eukaryotic/host cells. QS is orchestrated by small molecules, usually considered hormone-like organic molecules called autoinducers (AIs). AIs are represented by diffusible molecules called homoserine-lactones (Acyl-HSL) in Gram-negative bacteria and not diffusible peptidic molecules (AIP) in Gram-positive ones. A universal interspecies signal (“cross talk”) which contains AIs common for both Gram-positive and Gram-negative bacteria has been identified in 55 pathogens so far. These compounds depend on the microbial cellular density and hold a paramount role in various niches, especially in highly colonized sites, such as the gut and the oral cavity (59). This mechanism of communication regulates the expression of virulence genes in pathogens, with an important role in infection. For example, a relatively low virulence factors production by a limited population of bacteria may promote a robust host response that neutralizes these molecules, while the coordinated virulence factors gene expression by high-density bacterial populations can lead to higher secretion of extracellular factors (60, 61). The produced molecules have also an immunomodulatory effect, controlling the inflammatory response which can induce severe damaging of host tissues (62). Recent studies reported they may have also a therapeutic potential, for autoimmune diseases as immunosuppressive drugs (63). The QS mechanism allows bacteria to regulate the host colonization by commensal bacteria and to modulate the host response (64–66). Although the specific mechanism(s) through which AIs influence mammalian cells is unclear, a modified immune response was observed. For example, the 3-oxododecanoyl homoserine lactone (HSL-C12) induces apoptosis and Ca²⁺ release from endoplasmic reticulum stores. HSL-C12 has also been reported to modulate the inflammatory signaling (67), being immunosuppressive at or below 10 µM concentrations, but pro-inflammatory and proapoptotic at 20 µM and above (68). HSL-C12 acts through TLR- and Nod/Ipaf/caterpillar-independent signaling and activates multiple NF-κB-associated pro-inflammatory genes including IL-1α, IL-6, IL-8, Cox2, mPGES, PGE2, and MUC5AC in different cell types. The pro-inflammatory effects may be achieved through activation of MAPKs, extracellular-signal-regulated kinases, inhibition of peroxisome proliferator-activated receptor γ, or Ca²⁺ (69). In the presence of pro-inflammatory molecules, such as lipopolysaccharides (LPS) or TNFα, HSL-C12 may inhibit NF-κB signaling and expression of pro-inflammatory cytokines in macrophages and epithelial cells (69). In vivo experiments proved that direct injection of HSL-C12 in C57BL/6 mice lead to the expression of macrophage inflammatory protein-2 (MIP-2) (the mouse analog of the human cytokine IL-8) and also other cytokines. Significantly, higher concentration of MIP-2 was found in mice infected with QS active microbial strains than those inoculated with the QS-deficient bacteria (70).

Quorum-sensing is also used by microbiota members in order to detect the presence of other similar microbes (71); their well-known antiinfectious barrier effect is to the result of the antagonistic relationships with pathogens; is well known that probiotic strains are able to produce antimicrobial molecules as well as small QSIs which are interfering with the QS mechanism and virulence expression of the pathogens (72–74). It seems that the antimicrobial eosinophil-derived neurotoxin, cathelicidins, defensins, AI2 signaling molecules hold paramount functions in intra- and interspecies communication.

Certain intestinal mammalian hormones mimic the action of bacterial signaling molecules, thus increasing the complexity level of the bidirectional communication between bacteria and the host (75). In this context, a particular field of the exchange of molecular information between the many microorganisms and the host (76) is represented by microbial endocrinology, defined by the ability of GIT microbiota to orchestrate a bidirectional communication with the central nervous system by producing and sensing neurochemicals that are derived either within the microorganisms themselves or within their host (77). Steroid hormones (adrenaline and noradrenaline), due to their ability to pass through the plasmatic membrane are involved in the inter-kingdom communication between microorganisms and their mammalian host (78, 79). Although bacteria do not express adrenergic receptors, some studies indicate that bacterial cells are responsive to adrenaline and/or noradrenaline (NA) and recent studies suggest they have an important impact in maintaining the homeostasis of gut microbiota (80). The existing data sustain that NA may work as a siderophore (81). It is believed that NA is involved in overexpression of enterobactin and in the iron chelating mechanism in E. coli, subsequently increasing the bacterial growth rate. On the other hand, gut microbiota can produce neurochemicals with hormonal activities that could extend beyond the gut, being involved in the modulation of anxiety, depression, cognition, pain, inflammatory, autoimmune, and metabolic diseases (82–87).

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The Gut Microbiota in Disease

Just as we are only now beginning to understand the key role of the flora in health, it has only been in very recent years that the true extent of the consequences of disturbances in the flora, or in the interaction between the flora and the host, has been recognized. Some of these consequences are relatively obvious. For example, when many components of the normal flora are eliminated or suppressed by a course of broad-spectrum antibiotics, the stage is set for other organisms that may be pathogenic to step in and cause disease.^1,2,32 The classic example of this is antibiotic-associated diarrhea and its deadliest manifestation, Clostridium difficile colitis. Similar perturbations in the flora are thought to be involved in a devastating form of intestinal inflammation that may occur in newborns and especially premature infants: necrotizing enteroco-litis. In other situations, bacteria may simply be where they should not be. If motility of the bowel is impaired and/or acid secretion from the stomach is drastically reduced, an environment conducive to the proliferation of organisms in the small intestine that are normally con-fined to the colon results; the consequence is the syndrome of small bowel bacterial overgrowth. In other situations, the immunologic interaction between the flora and the host is disturbed, and the host may, for example, begin to recognize the constituents of the normal flora not as friend but as foe and may mount an inappropriate inflammatory response, which, some believe, may ultimately lead to conditions such as IBD.^1,2,32 In other situations, damage to the intestinal epithelium renders the gut wall leaky and permits bacteria (in whole or in part) from the gut to gain access to the submucosal compartments or even to the systemic circulation, with the associated potential to cause catastrophic sepsis. This mechanism is thought to account for many of the infections that occur in critically ill patients in the intensive care unit, for example.

Most recently, qualitative changes in the microbiota have been invoked in the pathogenesis of a global epidemic: obesity.⁴¹ It has been postulated that a shift in the composition of the flora toward a population dominated by bacteria that are more avid extractors of absorbable nutrients—which are then available for assimilation by the host—could play a major role in obesity.⁴¹ Such studies rely on the application of modern technologies (genomics, metagenomics, and metabolomics) to the study of the colonic flora and have the potential to expose the true diversity and metabolic profile of the microbiota and the real extent of changes in disease. Rather than provide an exhausting survey of all the disease states that might be influenced by the microbiota, a brief overview of current information on the role of the microbiota in a few common diseases/disorders will be provided below.

Inflammatory Bowel Disease

There is a considerable body of evidence to support the hypothesis that the endogenous intestinal microflora plays a crucial role in the pathogenesis of IBD and its variants and related disorders.^50,51 Some of this evidence is time-honored, such as the predilection of IBD for areas of high bacterial numbers and the role of contact with the fecal stream in sustaining inflammation. Other evidence is more recent and includes studies described above that illustrate the key roles of the microbiota in host immune responses and the generation of inflammatory responses. This evidence is supplemented by experimental observations on the ability of strategies that modify the microbiota (eg, the administration of probiotics) to modulate the inflamma-tory response in experimental models of IBD.^52–58 Studies of the gut microbiota in IBD have revealed quantitative and qualitative changes,⁵⁹ including the intriguing finding in some studies⁶⁰ that a bacterium with anti-inflammatory properties, F prausnitzii, is less abundant in patients with IBD than in healthy individuals. The importance of microbiota-host interactions in IBD is further supported by the many studies of IBD genetics that have identified a host of changes in genes that code for molecules involved in bacterial recognition, host-bacteria engagement, and the resultant inflammatory cascade.⁶¹ On a more clinical level, the role of the microbiota is supported by the efficacy, albeit variable, of antibiotics in IBD⁶² and the suggestion, not always supported by high-quality clinical trials, that a number of probiotic organisms, including nonpathogenic Escherichia coli, Saccharomyces boulardii, and a Bifidobacte-rium, have efficacy in maintaining remission and in treating mild to moderate flare-ups in ulcerative colitis.^63–70 There are some preliminary data to suggest that fecal transplan-tation,⁷¹ a strategy used with considerable success in the treatment of resistant and recurrent C difficile infection,⁷² may be effective in ulcerative colitis.^73,74

A more convincing clinical illustration of the impact of modulation of the microbiota is provided by the example of pouchitis, an IBD variant that occurs in the neorectum in patients with ulcerative colitis who have undergone a total colectomy and ileo-anal pouch procedure. Here, VSL#3 (Sigma Tau Pharmaceuticals), a probiotic cocktail containing 8 different strains of lactic acid bacteria, has proven to be effective in the primary prevention and maintenance of remission of patients with pouchitis. In one study, remission was maintained in 85% of patients on VSL#3 compared with 6% of patients receiving placebo.⁷⁵

Irritable Bowel Syndrome

A variety of strands of evidence suggest a role for the gut microbiota in IBS⁷⁶ (Table 2). First and foremost among these is the clinical observation that IBS can develop in individuals de novo following exposure to enteric infections and infestations (ie, postinfectious IBS).⁷⁷ More contentious has been the suggestion that patients with IBS may harbor small intestinal bacterial overgrowth (SIBO).⁷⁸ More indirect evidence of a role for the micro-biota can be gleaned from some of the metabolic functions of the components of the microbiota. Thus, given the effects of bile salts on colonic secretion, changes in bile salt deconjugation could lead to changes in stool volume and consistency. Similarly, changes in bacterial fermentation could result in alterations in gas volume and/or composition. Further evidence comes from the clinical impact of therapeutic interventions, such as antibiotics, prebiotics, or probiotics, which can alter or modify the microbiota. Thus, the poorly absorbed antibiotic rifaximin (Xifaxan, Salix) has been shown to alleviate symptoms in diarrhea-predominant IBS,⁷⁹ and some probiotics (B infantis 35624 [Align][Procter & Gamble] in particular⁸⁰) have been shown to exert substantial clinical responses. The latter is of interest, given its demonstrated ability to modulate the systemic immune response in humans.^25,81 Also gaining currency is the suggestion that the colonic microbiota may demonstrate qualitative and/or quantitative changes in IBS.⁸²

^{other diseases}

Role of GIT Microbiota in Autoimmune and Inflammatory Diseases

The alteration of the complexity and eubiotic state of microbiota might promote intestinal and extraintestinal autoimmune and inflammatory disorders (type I diabetes, rheumatoid arthritis, ankylopsing spondilosis, IBD, pulmonary disease, atopy, non-alcoholic fatty liver disease, obesity, atherosclerosis, carcinogenesis, etc.) although the mechanisms involved are not well understood (3). Many researchers reported an opposite connection between the incidence of immune disorders and the infectious process. Within this line of thought, children under the age of 5 years living in developed countries are not exposed to many of the microbes, compounds and antigens they would have encountered a century ago. This lack of early immune stimulation by biotic factors that humans and their ancestors have evolved with may hinder the functioning of the immune system later in life and lead to hypersensitivity, autoimmune, or inflammatory diseases (88).

Type 1 Diabetes

Initially called juvenile-onset diabetes, type 1 DM (T1DM) is a chronic illness associated with high morbidity and premature mortality. This disease is caused by the patient’s inability to secrete insulin as a result of the autoimmune destruction of the pancreatic beta cells (89). Usually, T1DM occurs early in life, but recent studies reported that up to 50% of new-onset T1DM patients are older than 20 years (90). The major factor in the pathophysiology of T1DM is represented by autoimmunity. The genetically susceptible individuals (around 95% of patients with T1DM) harbor either human leukocyte antigen DR3-DQ2 or DR4-DQ8 haplotypes, or have the UBASH3A mutation, also known as STS2, located on chromosome 21, which are linked also with other autoimmune diseases, such as celiac disease (91, 92), viral infections (mumps, enterovirus, coxsackie virus B4, and rubella), but also toxic chemicals, exposure to cytotoxins or cow’s milk in infancy and may stimulate the production of antibodies against antigenically similar beta cell molecules. T1DM is associated with a low diversity of microbiota and with the expansion of distinct groups of bacteria (93, 94). However, human studies have not yet elucidated the causal relationship between the gut microbiome and pathogenesis of T1DM. Some models have linked the gut microbiome with the development of T1DM, respectively, the Hygiene Hypothesis, the Leaky Gut Hypothesis, the Perfect Storm Hypothesis, and the Old Friends Hypothesis. Based on the Leaky Gut Hypothesis, the increased permeability of the intestinal epithelium develops from loss of tight barrier function (95). Macromolecules derived from diet and microbial antigens are able to pass through the epithelial barrier and consequently trigger intestinal inflammation that could lead to pancreatic beta cell attack (95). The Old Friends Hypothesis sustains the role of commensal microbes which have evolved together with their host and highlights that loss of these commensal microbes may impact the host’s immune response regulation and homeostasis (96). On the other hand, the Perfect Storm Hypothesis reunites aspects from the Leaky Gut Hypothesis and the Old Friends Hypothesis advocating that a combination of both increased intestinal permeability an altered microbiota composition, and an impaired intestinal immune responsiveness interact together culminating in anti-islet autoimmunity (97). The Hygiene Hypothesis was formulated by David Strachan (1989) who, trying to explain the actual high incidence of allergic and autoimmune diseases, postulated that increasing T1DM incidences is the result of a diminished or a lack of contact with infectious agents due to elevated hygienic conditions (98). In a recent study by Maffeis et al. on children at risk of developing T1DM, increased intestinal permeability was correlated with microbiota alterations. Unlike healthy controls, children with T1DM risk exhibited high levels of Globicatella sanguinis, Dialister invisus, and Bifidobacterium longum (99). In addition, it was also reported that the Bacteroidaceae family is enriched in children with T1DM. Moreover, T1DM children exhibited a decrease of Bifidobacterium pseudocatenulatum and Bifidobacterium adolescentis (100). A subsequent study revealed that the microbiota of genetically predisposed infants from 3 months to 3 years old was characterized by an enrichment of Rikenellaceae, Ruminococcus, Streptococcus, and Blautia as well as by reduced alpha diversity (101).

Rheumatoid Arthritis

Recent studies found a correlation between rheumatoid arthritis, the enrichment of Prevotella copri and colitis susceptibility, suggesting that the inflammatory component of autoimmune diseases might be modulated by an impaired communication between the host and the microbiota (102). These data are also sustained by a recent study which characterized the gut microbiota of DBA1 mice after collagen induction arthritis (CIA) and found altered distribution of the microbiota. Mice susceptible to CIA harbored Lactobacillus as the dominant genus prior to the onset of arthritis. During disease progression, the operational taxonomic units (OTUs) of the Lachnospiraceae, Bacteroidaceae, and S24-7 families were significantly elevated in CIA-susceptible mice. Also, germ-free mice receiving microbiota harvested from CIA-susceptible mice presented an elevated induction of arthritis compared to those receiving microbiota from CIA-resistant mice (103).

Celiac Disease

Modification of the normal gut microbiota may have a role in the onset and/or progression of celiac disease. Species such as Staphylococcus epidermidis, Staphylococcus pasteuri, and Klebsiella oxytoca were enriched in duodenal biopsies harvested from patients diagnosed with active celiac disease. Species such as Streptococcus mutans and Streptococcus anginosus were reduced in patients with celiac disease compared to healthy people, independently of the inflammatory status. Fucosyltransferase 2 (FUT2) gene regulates the expression of ABH blood group antigens in mucus as well as other body secretions and also influences the composition of mucosa-associated bacteria. A mutation in FUT2 gene lead to decreased bacterial heterogeneity and abundance, including a lower quantity of Bifidobacterium spp., in the human gut. Fut2-deficient mice presented more susceptibility to Candida albicans colonization comparing to wild-type mice and Candida albicans infection is a culprit in the onset of celiac disease. Bifidobacterium spp. were shown to have a protective role against C. albicans colonization. Therefore, alteration of the microbiota due to mutation of FUT2 gene decreases colonization resistance and has a role in the pathogenesis of celiac disease (104).

Inflammatory Bowel Disease

Aberrant immune responses against commensal bacteria may promote the development of IBDs, such as ulcerative colitis and Crohn’s disease, providing experimental models for studying different aspects of the immune system-microbiota crosstalk, such as oxidative stress, microbial sensing, and antigen processing. Some alleles of the genes encoding for innate immunity mechanisms, i.e., ATG16L1, which is involved in autophagy; NOD2, which is connected to the activation of the immune system by peptidoglycans; and CLEC7A, linked with the recognition of fungi by DCs have been shown to predispose to IBD (105). Dysbiosis controls the pathogenesis of IBD, affecting over one million people in the United States and one-quarter million in the UK (106). The IBD pathogenesis involves the bacterial adherence to the gut mucosa and invasion into mucosal epithelial cells leading to the occurrence of an inflammatory response, mediated by the production of TNF-α by monocytes/macrophages. This chronic bowel inflammation affects the epithelial cell tolerance to intestinal bacteria leading to changes in intestinal microbiota composition with an increase in aerobic bacteria accompanied by a significant decrease in the fecal levels of butyric and propionic acid in IBD patients. However, despite the generally accepted involvement of LPS in triggering an inflammatory effect (2), the main species adhering to the mucosa surrounding the colon mucus layer are Bifidobacterium spp. and Clostridium coccoides, suggesting that IBD is not triggered by a microbial species, but by an unbalanced microbiota. The hydrogen peroxide-producing colonic bacteria have been also suggested as causative agents of IBD in young adults (107). The studies performed on a mouse model of colitis (dextran sodium sulfate-induced colitis) showed that the introduction of anaerobic, noncultivatable segmented filamentous bacteria stimulates Th17 development, while commensals such as Bacteroides fragilis or Clostridium species, facilitate the differentiation of regulatory T-cell and IL-10 production in the gut. In most cases of spontaneous colitis models, including the IL-10^−/− mouse, antibiotics or a germ-free state have been shown to prevent the development of colitis (24). The presence of Gram-positive bacteria, such as Lachnospirillaceae seems to be necessary for the infiltration of colitogenic macropahages and monocytes into the colon through induction of C–C chemokine receptor type-2 ligands, as revealed by the decrease of inflammatory reaction in mice treated with vancomycin (24). In humans, Faecalibacterium prausnitzii is one of the most abundant colonic bacteria found within the fecal mass but is also present in the adjacent mucosa, representing 5–20% of the total fecal microbiota of healthy individuals. Low counts of Faecalibacterium prausnitzii have been linked to several pathological disorders including Crohn’s disease (108).

Allergic Diseases

Allergic diseases affect more than half a billion people worldwide. The development of allergy is clearly associated with some genetic and molecular factors but environmental factors including the gut microbiota are also involved. Indeed, reduced microbial diversity in infancy was correlated with an increased risk for allergies later in life. The commensal microbiota was reported to provide protection against allergic airway inflammation and food allergy (109) since mice treated with antibiotics and germ-free mice developed an exacerbated disease. TLR2- or TLR4-deficient mice develop pulmonary damage after chronic intake of a high-fat diet, a feature that can be transmitted to wild-type mice by fecal transplantation (110).

Recent data proved that lower prevalence of bacteria such as Akkermansia, Faecalibacterium, and Bifidobacterium, along with higher abundance of fungi such as Rhodotorula and Candida in neonates may lead to allergy susceptibility by modulating T-cell differentiation (48).

Systemic Lupus Erythematosus (SLE)

Systemic lupus erythematosus is a systemic autoimmune disease with unknown etiology characterized by the presence of hyperactive and aberrant antibody response to nuclear and cytoplasmic antigens (111). The dysbiosys observed in SLE is characterized by an increase of the Bacteroides phyla and a decrease in the Firmicutes (112). Despite the fact that the role of microbiota in the development of SLE is poorly understood, it is suggested that the dysbiosis observed in the SLE patients could be related to this disease. In line with this, mouse models of lupus exhibited an accelerated development of the disease that was linked to increased levels of Lachnospiraceae and low levels of Lactobacillaceae (113).

Skin-Related Autoimmune Pathologies

Skin autoimmune diseases have also been linked to microbiome shifts. For instance, a recent study by Scher et al. compared the composition of gut microbiota in patients with psoriatic arthritis or with psoriasis to that of healthy controls (114). The gut microbiota signature of psoriatic arthritis and psoriasis groups exhibited decreased bacterial diversity and a reduced relative abundance of Ruminococcus, Pseudobutyrivibrio, and Akkermansia. Importantly, the microbiota profile of psoriatic arthritis was similar to that of IBD patients, therefore suggesting a link between the gut microbiota and this skin disease (114). In case of scleroderma, most patients suffer from GIT symptoms that may be due to changes in intestinal microbiota composition. Recently, Volkmann et al. (115) revealed that Firmicutes were highly abundant in systemic sclerosis patients compared to healthy controls, whereas Bacteroidetes were lower in one of the cohorts, compared to healthy controls (115).

Neurological Inflammatory Diseases

In the last decade, more studies proved that the gut microbiota has an impact on brain development and function. The studies compared germ-free and conventional laboratory rodents and the results suggest that the absence of microbiota alters anxiety-like behavior and also enhances the hypothalamic pituitary adrenal system stress reactivity. This abnormal behavior observed in germ-free animals was eradicated if the intestinal microbiota was restored in early life but not in the adulthood stage, suggesting the existe