Role of gut microbiota in infectious and inflammatory diseases

1The human gut microbiota is a community of microorganisms that includes viruses, bacteria, archeas, fungi and protozoa, and the microbiome is the collective genomes of microorganisms, their metabolites, and proteins in a specific environment. In humans, the intestine harbors the greatest number of microorganisms and the greatest number of species in relation to other places in the body. They consist of over 1,500 species, which colonize the digestive tract within minutes of birth, establishing a symbiotic or mutualistic relationship with epithelial and lymphoid tissue. The intestinal microbiota is predominantly composed of bacteria, containing especially the phyla Firmicutes, Bacteroidetes, Actinobacteria and Proteobacteria (Figure 1), being the most microorganisms found in the colon. These microorganisms produce a variety of metabolites from the anaerobic fermentation of exogenous dietary components and endogenous compounds generated by microorganisms and host. The generated metabolites, such as short-chain fatty acids (SCFAs), interact with host cells and influence immune responses. Therefore, this is a dynamic and complex ecosystem that helps the proliferation, growth, and differentiation of epithelial cells to fight against infections and stimulate the immune system.

2There is mounting evidence indicating that the gut microbiome plays an important role in modulating host physiology, with studies linking gut microbiome composition and functions to differential inflammatory, neurological, and even behavioral activities. The intestinal microbiota has several functions, including protection against pathogens by colonization of the mucosal surface and production of antimicrobial substances, aiding in digestion and metabolism, controlling the proliferation and differentiation of epithelial cells, changing insulin resistance and affecting its secretion, influencing brain-intestinal communication and thus influencing host neurological functions. Thus, disturbances in the intestinal microbial population can result in an imbalance of the homeostasis, promoting the development of pathologies. Several intrinsic factors can influence the composition and function of the gut microbiota, such as birth form, age, host genetics and innate and adaptive immunity. Extrinsic factors such as diet, lifestyle, geographic region, presence of allergens or pathogens and antibiotic therapy can also determine the type of microorganism found. Dysbiosis is a term used to describe a quantitative and/or qualitative change in the composition of the microbiota. Dysbiosis can be caused by many of daily activities, such as dietary patterns, hygiene habits, physical activity, and medication use. When there is a dysbiotic state, the functioning of the microbiota is affected and can induce a disease state. In this review, we provide an overview of the current understanding of the role of the gut microbiota in the regulation of the immune system and the modulation of serum cytokines in the most common and/or most studied autoimmune and inflammatory diseases, and in viral and mycobacterial infections.

3The human gastrointestinal tract is the main site of interactions between microorganisms and the host’s immune system. In this interaction, the microbiota contributes to the physiological functions of the host while the host provides nutrition and habitat. The gut microbiota is essential not only for the degradation and fermentation of feed, but also for defense against pathogens, either by competing for nutrients and adhesion sites, or by secreting antimicrobial peptides. Experiments conducted in germ-free animals (GF) have demonstrated that colonization of the microbiota early in life is necessary for the proper development of the immunity. In the lack of gut microbiota, the immune system of the intestinal mucosa is underdeveloped, with, for example, reduced number of functional regulatory CD4+ CD25+ T cells, resulting in a reduced capacity to fight pathogenic bacteria. In addition, the balance between proinflammatory interleukin (IL)-17-producing effector T helper (Th17) cells and Forkhead box P3 (Foxp3+) regulatory T (Tregs) cells in the gut requires signals from gut bacteria, and those signals are dependent on gut microbiota composition. For instance, GF animals colonized with Bacteroides fragilis had the balance between Th1 and Th2 cells restored, thanks to the production of polysaccharide A. Polysaccharide A is a bacterial product that influences T cell activation through interaction with Toll-like Receptor 2 (TLR2). It inhibits Th17 differentiation and favors Treg activity, thus favoring immune tolerance. Resident bacteria, especially Clostridia-related species, have been associated with development of Th cells and induction of Treg cells.

4The intestinal microbiota produces a diverse repertoire of metabolites from food by modifying host products and by de novo synthesis. Among them, short-chain fatty acids (SCFAs) are the most described in the regulation of the immune system. SCFAs result from fiber fermentation in the colon and include acetic acid, butyric acid, and propionic acid, which cross the intestinal epithelium and interact with host cells, influencing immune responses. In addition to their metabolic functions, these substrates have several regulatory functions. SCFAs are inhibitors of histone deacetylases (HDACs) and ligands for G protein-coupled receptors (GCPRs), also called free fatty acid receptors (FFAR). SCFA-guided inhibition of HDACs tends to promote a tolerogenic and anti-inflammatory cell phenotype that is essential for maintaining immune homeostasis.

5Studies with exposure of peripheral blood mononuclear cells (PBMCs) and neutrophils to SCFAs showed inhibition in the production of the pro-inflammatory cytokine tumor necrosis factor (TNF) and in the activation of nuclear factor-κB (NF-κB;; ). SCFAs also influence peripheral T cells, especially regulatory T cells, through HDAC inhibition. reported that inhibition of HDAC9 increased the expression of Foxp3+ and number of Treg cells, improving suppressor function of Foxp3+ Treg cells under homeostatic conditions and amplified attenuation of Treg cell-mediated colitis in mice. Some SCFAs such as butyrate and propionate also modulate antigen presentation by inhibiting dendritic cell development through inhibiting HDACs and interacting with FFAR.

6Furthermore, by regulating the activity of hypoxia-inducible factor (HIF), butyrate and propionate are associated with the maintenance of intestinal homeostasis. HIF is the main regulator of oxygen homeostasis in response to hypoxia. It is a transcription factor formed by a heterodimeric protein, composed of α and β subunits. The β subunit, also called the aryl hydrocarbon receptor nuclear translocator (ARNT), is not influenced by oxygen and is stably expressed. The α subunit, composed of three subunits (HIF-1α, HIF-2α, HIF-3α), is directly regulated by the presence of oxygen. In a situation of tissue normoxia, HIF-1α is continuously synthesized and degraded through the 26S proteasome system. In contrast, under hypoxic conditions, HIF-1α stabilizes and bound to HIF-1β, initiates transcription of its target genes. In the intestine, these target genes are basally regulated to maintain the epithelial barrier and include genes crucial for cellular energetics, barrier function, mucin production, microbial defense, and xenobiotic clearance. Therefore, HIF-1α stabilization maintains the structure of the epithelial barrier, stimulates CD4+ T cells and IL-22 production and, increases the expression of MUC2, MUC3 and intestinal trefoil factor (ITF), which is essential for the epithelial restoration of the colon. Thus, SCFAs play an important role in regulating the host–microbe interaction, modulating the HIF, which directly influences this crosstalk.

7In addition to SCFAs, other metabolites produced by the gut microbiota have important immunomodulatory functions, such as indole derivatives, which are derived from tryptophan, and polyamines, originated from dietary arginine. Indole derivatives promote the integrity of the enteric epithelium and the defense against microorganisms, inducing the multiplication of intestinal goblet cells, and the secretion of antimicrobial peptides, and mucins. Tryptophan derivatives also promote the differentiation and function of anti-inflammatory macrophages, Treg cells and IL-22 producing innate lymphoid cells 3 (ILC3). IL-22 acts in the maintenance of intestinal epithelial cells (IECs), regulates the equilibrium of the commensal microbiota and protects against infection by Citrobacter rodentium. In mice, ILC3s induce fucosylation, which is an important glycosylation mechanism in IECs. This induction may be dependent on commensal bacteria, using IL-22, and independent of these bacteria, requiring lymphotoxin. The absence of intestinal fucosylation leads to increased susceptibility to Salmonella typhimurium infection. Therefore, ILC3s play an important role in modulating the intestinal microenvironment through the regulation of epithelial glycosylation, protecting against infection by pathogenic bacteria. Polyamines, such as putrescine, are found in many cells and play a role in gene transcription, translation, proliferation, and cell death. Polyamines are essential for host cell functions; for example, intestinal epithelial cells depend on these molecules to maintain high proliferation rates. They assist the development and maintenance of the intestinal epithelium and the inhabiting immune cells.

8Most evidence suggests that intestinal microbiota metabolites and antigens can influence the immune system. Therefore, dysbiosis, characterized by alterations in the microbiome resulting in an imbalance in the microbiota, can contribute to the development of some immunological and inflammatory pathologies, both at the intestinal level, such as the well-documented Inflammatory Bowel Disease (IBD; ), and in other regions of the body, such as in rheumatoid arthritis (RA; ). Indeed, many organs distant from the intestine, such as the skin, brain, and lungs, which are not in direct contact with the intestinal microbiota, can be affected by dysbiosis and its repercussions in the immune point of view. This suggests that the gut microbiota actually has the capacity to interact with the immune system in a systemic manner. For this, the gut microbiota needs to send microbial signals that are transmitted through the intestinal epithelium. These signals can be structural components of the bacteria or the metabolites themselves produced by the gut microbiota that can diffuse through the circulation and directly affect distant organs or by signaling nerves or hormones in the gut.

9The gut microbiota is mainly composed of the phyla Bacteroidetes and Firmicutes, which comprise approximately 90% of the microbial population in humans. Bacteroidetes vary in relative abundance among individuals, but they normally make up half of the gut microbiome. The members of this phylum reside especially in the distal intestine, where they function in the fermentation of indigestible carbohydrates. The predominant genera of Bacteroidetes in the human gastrointestinal tract are Bacteroides, Prevotella and Porphyromonas.

10Pro- and anti-inflammatory cytokines play an important role in regulating the host’s immune response to the intestinal bacteria’s own compositional variations and, therefore, in maintaining intestinal balance. For example, interleukin-10 (IL-10) production by Tregs is essential in maintaining intestinal homeostasis, as it prevents excessive inflammation. Lactobacillus rhamnosus and Lactobacillus reuteri have been shown to induce IL-10 production by Tregs. Interleukin-17A (IL-17A), produced by Th17 cells, is an important mediator of innate and adaptive immune response, but can also contribute to inflammation and tissue damage. Some members of the Bacteroides, such as B. fragilis, have been shown to induce Treg differentiation from CD4+ T cells, and thus decrease IL-17A production. On the other hand, Prevotella spp. have been associated with an increase in IL-17A production in CD4+ T cells (Figure 2; ). Interleukin-22 (IL-22), also produced by Th17 cells, and innate lymphoid type 3 (ILC3) cells and is involved in defense against extracellular pathogens. IL-22 production is also associated with epithelial regeneration and repair. Akkermansia muciniphila, a common human gut bacterium, has been shown to induce IL-22 production by ILC3 cells. Interferon gamma (IFN-γ) production is a typical response of Th1 cells and is associated with protective immunity against intracellular pathogens. Supplementation with different species of Lactobacillus increased IFN-γ production by T lymphocytes, macrophages, and dendritic cells. Interleukin-12 (IL-12), which is a key factor in the polarization of CD4+ T cells to the Th1 phenotype, can also be modulated through the gut microbiota. Several strains of Lactobacillus also have been associated with an increase in IL-12 production. Therefore, the intestinal microbiota can modulate and be modulated by cytokines produced in the intestine. Directly and indirectly influencing host immune responses in states of health and disease. However, the impact of the different compositions of the intestinal microbiota on the modulation of cytokine production and consequent inflammatory response needs to be better elucidated.

11The immune system is a collection of cells, tissues and organs that work together in complex ways to protect the body from invaders. It is composed of several blood cells such as dendritic cells (DCs), T cells and B cells, lymphoid organs such as bone marrow, and lymph nodes, and molecules as antibodies, complement and cytokines. The function of the immune system is to eliminate infectious microorganisms and cancer cells, and to aid repair tissue after injury, thus contributing to the maintenance and reestablishment of homeostasis. In autoimmune diseases, the balance between pathogen recognition and self-attack prevention is compromised. As a result, control of inflammation is lost and continued activation of the immune system occurs even in the absence of infection.

12Autoimmune and inflammatory diseases are characterized by dysregulated immune response, with production in abnormal amounts of autoantibody-producing B cells, autoreactive T cells, and augmented production of pro-inflammatory cytokines. Genetic and environmental factors including geographic location, immunological disorders and viral infections favor the development of autoimmune diseases. Furthermore, dysbiosis of the intestinal microbiota has been associated with these pathologies through several mechanisms, which can impact the regulation of the human immune system (Table 1). For example, molecular mimicry (when self-antigens and foreign antigens share similar sequences or structures) impacts on the permeability of the intestinal mucosa and may be associated with initiation and amplification of disease progression. While certain microbiota compositions could prevent autoimmunity in genetically susceptible individuals, disturbances or alterations in this composition may trigger the autoimmune process.

13Inflammatory bowel disease (IBD) is a group of complex multifactorial inflammatory diseases that affect the gastrointestinal tract. It comprises two main classes: ulcerative colitis (UC) and Crohn’s disease (CD), which have different clinical, endoscopic, immunological, and histopathological characteristics. UC is the most common form of IBD, which affects more than 5 million individuals worldwide. Its inflammation is limited to the mucous layer, causing superficial damage restricted to the wall of the rectum and colon. CD is characterized by irregular transmural inflammation that extends through the intestinal wall into the serous layer, and it affects mainly the terminal ileum, but it can affect any part of the gastrointestinal tract.

14Both diseases are characterized by an imbalance between anti and proinflammatory signals and the displacement of leukocytes to the intestinal epithelium. However, the T cells populations involved in the immune responses seem to be different depending on the disease, which may explain the different phenotypes observed in clinical practice. UC is thought to occur due to an imbalance of intestinal immunity related to Th2 cytokines, while CD is associate to a Th1 and Th17 cytokine profile. In CD, differentiation into Th1 and Th17 occurs by induction of cytokines IL-12, IL-18, IL-23 and transforming growth factor beta (TGFβ) produced by macrophages and other antigen-presenting cells (APCs; ). In UC, increased secretion of IL-5, which is Th2 specific, is related to more effective activation of B cells and stimulation of immune responses when compared to the Th1 response observed in CD. Although the exact mechanism of causing IBD remains unknown, it is broadly accepted that the pathogenesis of the disease involves the interaction of genetic susceptibility and environmental factors in the microbiome, which, through an impaired intestinal epithelium, will lead to excessive immune activation, responsible for the clinical observed in patients. Thus, genetically susceptible subjects are thought to produce a disordered immune response to their gut microbiota, leading to chronic inflammation and repetitive damage to the intestinal mucosa.

15IBD is one of the diseases most associated with dysbiosis of the gut microbiota. Patients with IBD show loss of microbial diversity and stability and an increase in Proteobacteria and certain members of Bacteroidetes. Among the components of Proteobacteria, adherent/adhesive Escherichia coli strains have been associated with IBD. Adherent invasive E. coli was associated with CD, while diffusely adherent E. coli was associated with UC. Adherent invasive E. coli is able to adhere to the intestinal mucosa, invade and replicate within IECs, translocate through the intestinal barrier and move to deeper tissues. Furthermore, adherent invasive E. coli survives within macrophages, induces TNF-α production, and promotes granulomatous inflammatory response. Diffusely adherent E. coli, on the other hand, is able to adhere to the colonic mucosa and induce inflammatory responses characterized by induction of cytokine secretion, including IL-8, TNF-α and IL-1β and by promoting increased intestinal permeability. These data suggest that E. coli strains may play a key role in the pathogenesis of IBDs.

16Unlike E. coli, Akkermansia muciniphila has been shown usually reduced in the intestine of patients with IBD, resulting in an increase in the overall population of mucosal bacteria. IBD patients also have a lower abundance of Lactobacillus spp., Bifidobacterium spp., and F. prausnitzii resulting in reduced SCFAs concentrations when compared to healthy individuals. Through its ability to produce butyrate F. prausnitzii performs anti-inflammatory activity. Butyrate improves intestinal barrier function and regulates the balance between Treg and Th17 cells. Furthermore, Regner et al. reported that intestinal intraepithelial lymphocytes (IELs) and cytokines produced by these cells correlated with the relative abundance of various bacterial taxa. IELs from individuals with UC and CD produce different cytokines when compared to controls. In UC, IELs secrete increased amounts of IL-1β, while in CD there is increased secretion of IL-17A, IFN-γ and TNF-α (Figure 3; ). IELs are T cells that are in close contact with gut bacteria and can be influenced by differences in gut microbiota components. Together, these data suggest that dysbiosis in IBD patients could lead to the loss or impairment of microbial functions necessary to maintain intestinal epithelial barrier integrity, possibly causing increased inflammatory responses and spread of pathogens to intestinal tissues. However, is still unknown if these changes are a cause or consequence of IBD.

17Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by a constant immune response that results to chronic inflammation and destruction of cartilage and bones. It is a serious chronic disease that affects about 1% of the world’s population, being more common in women than in men. The mechanisms involved in the etiopathogenesis of the disease are complex and encompass both innate and adaptive immune responses, involving APCs, generation of autoreactive T cells and production of autoantibodies, such as rheumatoid factor. In addition, an association of the intestinal microbiome with the development and progression of RA has been demonstrated. An altered gut microbiota has been associated with loss of tolerance to autoantigens and in the increase of inflammatory episodes that cause damage to the joints. Furthermore, patients with RA have a reduction in the diversity of the gut microbiota when compared to controls and this is correlated with duration of illness and levels of autoantibodies produced.

18Some individuals with early rheumatoid arthritis (who have not treated with antirheumatic drugs) have a greater relative abundance of Prevotella copri and a decrease in the number of Bacteroides in the gut. A study in China identified that RA patients had an increase in the abundance of Lactobacillus salivarius in the gut, teeth, and saliva. In contrast, Haemophilus spp. were decreased in these patients at all sites evaluated. In another study, patients with RA also had decreased intestinal microbial diversity, which correlated with antibody production and illness duration. RA patients showed an increase in the relative abundance of Collinsella aerofaciens and Eggerthella lenta and a decrease in Faecalibacterium. In in vitro experiments, the genus Collinsella increased intestinal permeability and induced IL-17A expression, suggesting that the expansion of the microorganisms of this genus increases proinflammatory conditions, thus being an arthritogenic candidate in the human intestine (Figure 3;;;; ). The reduction in the abundance of Faecalibacterium may be associated with a reduction in the production of butyrate, a final metabolite of fiber breakdown that presents an anti-inflammatory property, maintaining the integrity of the intestinal epithelium.

19Intestinal microbiota involvement appears to vary in different subsets of RA patients. However, despite the discrepancies found in different studies, P. copri, L. salivarius, and Collinsella are predominant in recent early RA and may be associated with its pathogenesis. Differences in patient characteristics, such as genetic background, environmental exposures and different treatment regimens may explain the variety of candidate arthritogenic bacteria.

20Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that affects multiple structures in the body. It is characterized by persistent inflammation in organs and presents several clinical manifestations, including skin rash, neurological disorders, glomerulonephritis, and severe vasculitis. SLE is more frequent in women, being triggered by the interaction between different factors, such as genetic predisposition, hormonal changes, environmental factors, and epigenetics. Despite this, the exact etiology and pathogenesis of the disease remain unknown.

21Several immunological alterations have been reported in human and animal models of SLE, including autoreactive B and T cells, abnormal levels of pro-inflammatory cytokines and impaired immune complex clearance. This loss of self-tolerance plays a fundamental role in the occurrence and development of the disease. Ineffective elimination and/or excessive formation of neutrophil extracellular traps (NETs), characterized by fibrous networks made up of nuclear and granular components that protrude from the membrane of activated neutrophils, is involved in the pathogenesis of SLE. In addition to this mechanism, Th1, Th2, and Th17 cell dysfunction have been related to the occurrence and development of the disease. Under normal circumstances, Th1 and Th2 cells maintain an immune balance. However, the imbalance between these cells contributes to the pathogenesis of the disease. As for Th17 cells, IL-17 produced by these cells, associated with B-cell growth factor, positively regulates the differentiation and survival of B cells, stimulating humoral immunity to produce antibodies. Thus, SLE is characterized by intense production of autoantibodies, deposition of antigen–antibody complex and activation of the complement system in tissues, leading to the accumulation of self-reactive monocytes, neutrophils, and lymphocytes.

22The failure in immunological tolerance characteristic of SLE can be also promoted by dysbiosis or aberrant intestinal immunity. Despite differences in dysbiosis patterns in the disease, studies have reported a reduction in the Firmicutes/Bacteroidetes ratio compared to healthy controls. As an example, in a Chinese population, in fecal samples from patients with SLE, a decrease in bacterial richness, a reduction in the Firmicutes/Bacteroidetes ratio and an increase in the relative abundance of Bacteroides was identified. In addition, an abundance of other genera has been demonstrated in individuals with SLE: Rhodococcus, Eggerthella, Klebsiella, Prevotella, Eubacterium, and Flavonifractor.

23Dysbiosis may also be associated with the activity or remission phase of SLE, since affected individuals seem to exhibit characteristic patterns of dysbiosis in the intestinal microbiota in parallel with disease activity. Lupus activity was positively associated with the genera Streptococcus, Campylobacter and Veillonella and the species S. anginosus and V. dispar, while the genus Bifidobacterium was negatively correlated with disease activity. Streptococcus and Veillonella genera appear to have pro-inflammatory effects. Streptococcus combined with Veillonella obtained from the human intestine inhibited the production of IL12p70 and increased the response of TNF-α, IL-8, IL-6, and IL-10 (Figure 3; ). Furthermore, through molecular mimicry, some Streptococcus species induce the activation of B cells and specific CD4+ T cells through antigen presentation. Therefore, these genera can interfere with the mucosal immune system and induce cross-reaction with host tissue, potentially being involved in enhancing the host’s immune response in SLE.

24There is increasing evidence that gut health exerts profound effects upon non-gastrointestinal diseases, including those of the skin. Intestine and skin are immunological barriers and constitute the environment for physiological microbiota. The concept of gut–skin axis has been implicated in the pathogenesis of many chronic inflammatory diseases. It suggests that the gastrointestinal system directly affects the skin homeostasis and allostasis through interactions between the immune, metabolic, and nervous systems. Gut dysbiosis has been implicated in many dermatologic conditions.

25Intestinal microbiota dysbiosis has been shown in psoriatic patients and it correlates to the severity and status of the disease. Moreover, psoriatic patients showed less diversity in gut microbiota when compared to controls. It was hypothesized that the differential plenty of bacteria may be the reason for the gut dysbiosis in psoriasis instead of the number of bacterial species. A link between gut dysbiosis and butanoate metabolism and butyrate production has also been proposed, since it has been implicated in the regulation of various inflammatory factors, including TNF-α, IL-10, and Il-1𝛽. It has been hypothesized that the presence of Escherichia coli could be related to psoriasis, since it was increased in intestinal flora of psoriatic patients. E. coli is known to be responsible for the production of TNF-α and other proinflammatory cytokines and also have been related to the etiology of IBD (discussed above), which is known to be related to psoriasis. Although the immunological and inflammatory responses in psoriatic patients seem to be affected by intestinal dysbiosis, the composition of the microbiota profile still needs more investigation since the results are heterogeneous.

26The relationship between atopic dermatitis and gut microbiota was also studied. Various observational studies showed different results regarding the diversity and the composition of the gut microbiota in atopic dermatitis patients. Lower intestinal bacterial diversity has been associated with an increased risk of atopic disease. This dysbiosis results in a reduction of short-chain fatty acids production, like acetate, propionate, and butyrate. They are known to be potent anti-inflammatory in many diseases, including atopic dermatitis, through inhibition of Th2 and activation of regulatory T cells. These changes can cause a disruption in the integrity of the gut epithelial barrier, leading to an increased intestinal permeability and favoring toxins and gut microorganisms to penetrate the body circulation and contribute to skin inflammation. When these reach the skin, a strong Th2 reaction may be induced, causing further tissue damage. The use of probiotics was also studied, and some results point to an improvement on the severity of the atopic dermatitis. Its role is based on their ability to balance the intestinal microbiota, protecting the gut barrier function, and decreasing the production of the pro-inflammatory cytokines IL-4, IL-5, IL-13, and TNF-α, which are closely related to atopic dermatites.

27Microbial diversity is significantly decreased in acne patients when compared to controls. A decrease in Lactobacillus, Bifidobacterium, Butyricicoccus, Coprobacillus, and Allobaculum was found in patients with acne. Lactobacillus and Bifidobacterium are probiotic genera that balance the intestinal microbiota and also strengthen the intestinal barrier. Furthermore, the influence of dietary habits in acne supports the existence of gut-skin axis. Similar results were seen in rosacea patients, which present with similar quantity of bacteria, but a reduced richness on the composition. Acidaminococcus, Megasphaera e Lactobacillales were genus more prevalent in rosacea patients, while Peptococcaceae, Methanobrevibacter, Slackia, Coprobacillus, Citrobacter e Desulfovibrio were reduced when compared to controls. Another study found increased abundance of Rhabdochlamydia, Bifidobacterium, Sarcina, CF231, Ruminococcus in rosacea patients and reduced quantity of Lactobacillus, Roseburia, Megasphaerae, Acidaminococcus, Hemophilus, Citrobacter and Clostridium.

28In patients with hidradenitis suppurativa (HS), a reduction diversity was observed when compared to controls. One of the greatest differences were high degrees of Ruminococcus gnavus and Clostridium ramosum, which have already been related to Crohn’s disease. Different compositions in intestinal microbiota between HS patients and controls have also been demonstrated, with lower abundance of Firmicutes phyla. However, that was a pilot study and further investigation is still needed to corroborate these results. On the other hand, no differences in diversity were observed in another recent study, although there were some bacterial features differences. One interesting finding was the presence of Robinsoniella in 59% of HS patients and in none of the healthy controls. The gut dysbiosis described in these studies leads to an increased production of inflammatory cytokines such as TNF-α, IL-1β, and IL-6 by the intestinal epithelia which is followed by an increase in circulating inflammatory cytokines namely IFN-γ, and TNF-α. These cytokines end in an inflammatory process in the skin that involves MMP expression and are directly related to HS lesion formation. It is also known that as HS, other diseases like psoriasis and IBD run with increased IL-17, and also present with gut microbiota alterations.

29In alopecia areata (AA), two studies failed to demonstrate differences in diversity between patients and controls. However, at the genus level, abundance of Blautia, Pseudomonas, Collinsella, Megasphaera, and Dorea was found in AA patients. Other study found an elevated presence of Holdemania filiformis, Lachnospiraceae, Erysipelotrichaceae, Parabacteroides johnsonii, Bacteroides eggerthii, Clostridiales vadin BB60 group, Eggerthellaceae and Parabacteroides distasonis, while in controls, Phascolarctobacterium succinatutens, Clostridiales family XIII, Dorea longicatena, Phocea massiliensis, Turicibacter sanguinis, Streptococcus thermophilus and Flavonifractor plautii in patients with AA were notably more abundant. Moreover, improvement of AA symptoms was reported after fecal microbiota transplantation, reinforcing the association between intestinal microbiome composition and AA pathogenesis. It is hypothesized that the gut microbiota could also interfere with wound healing by interfering with healing factors like tissue oxygenation levels, blood pressure, inflammation, and the immune system. Nevertheless, little is known about the intestinal microbiota composition in patients with chronic ulcers.

30The impact of the gut microbiota is being studied in several other skin conditions, like vitiligo, lichen sclerosus, seborrheic dermatitis, and skin cancer, including the response to immunotherapy, like in cutaneous melanoma. Although the relationship between the gut microbiota and these diseases is already established in most of them, there is still a gap to be filled in order to better understand its impact and mechanisms. The knowledge of such influence could shed some light on potential therapeutic allies, like probiotics, diet, and even fecal microbiota transplantation.

31As with each infection, each pathogen can induce a different immune response, as the process of activating these responses takes place. In a viral infection, the main cells involved in the process of fighting the virus are cytotoxic cells, which may be linked either to innate immunity (NK) or to adaptive immunity (CD8+), always with the fundamental antiviral action of the cytokine IFN-γ.

32It is well known that a healthy commensal microbiota is critical to protecting the host against a several of infections, either by direct elimination or by indirect suppression, inside or outside the intestine. The mucosal epithelium is the main entry route for many pathogens, which can cause an important dysbiosis by affecting the intestinal mucosal barrier. During viral infection in mucosal tissue, viruses may encounter the host’s commensal microbiota. Depending on the profile of this microbiota, it is possible that it is beneficial to the host, defending it from infections, as well as it is possible that it creates an environment conducive to viral infection (Table 2;; ).

33The commensal microbiota may help to promote viral infection by, for instance, facilitating viral gene recombination, thus allowing an increase in viral infectious capacity. The microbiota also may influence viral infection through other indirect mechanisms, such as stimulating the creation of immunoregulated environments through the production of IL-10 by Treg cells and the inhibition of cytokines such as IFN-γ and TNF-α, which disrupts the immune system’s ability to act properly to fight the viral infection.

34On the other hand, intestinal microbiota is fundamental for the maturation of the immunological system and can also cooperate with it to prevent and fight infections. For instance, commensal populations can induce the immune system to produce antiviral products, such as IFN. Among the different viral infections positively and negatively affected by the intestinal microbiota, and which are capable of also altering it, viral hepatitis (mainly HBV and HCV) and SARS-CoV-2 have been highlighted in the literature and will be discussed in further detail.

35Viral hepatitis occurs due to infections of hepatitis A B, C, D, and E viruses, which are considered a public health issue, mainly in low and middle-income countries. Hepatitis type B virus (HBV) and Hepatitis C virus (HCV) are considered the most important etiological agents of hepatitis, whose infection can result in serious liver problems, including liver cirrhosis (LC), hepatocellular carcinoma (HCC) and liver failure. These clinical conditions can usually progress slowly and silently through various clinical stages as long these liver viruses have ways of preventing their detection by the host’s immune system, a characteristic called viral escape. Hepatitis A and E viruses, on the other hand, cause acute infection that can resolve independently of any intervention, unless the infected individuals are in an immunocompromised condition.

36Dysbiosis of the intestinal microbiota can be exploited by viral hepatitis as an escape mechanism of the immune system. and showed that the level of Bacteroides was lower in patients with hepatitis B compared to healthy people. suggested that cirrhosis could impact the dysbiosis process, leading to a worsening of the patient’s clinical condition. The intestinal microbiota also can be greatly affected during the different stages of HCV infection. During the asymptomatic phase, an increase in bacteria of the genera Prevotella, Succinivibrio, Catenibacterium, Megasphaera and from the Ruminococcacea family has been observed, as well as a reduction in bacteria from the genera Bacteroides, Dialister, Bilophila, Streptococcus, Parabacterioides, in addition to the following bacterial families: Enterobacteriaceae, Erysipelotrichaceae and Rikenellaceae. Studies have indicated evidence of dysbiosis since the onset of HCV infection, such as increased concentration of bacteria from the Enterobacteriaceae family and bacteria from the genus Bacteroides. Different studies have suggested HCV infection-related dysbiosis, can be intensified by the increased presence of bacteria from the phylum Proteobacteria Firmicutes and Bacteroidetes. However, in dysbiosis related to chronic HBV infection, changes occur in the concentration of bacteria of the Enterococcus genus and the Enterobacteriaceae family, which may be increased.

37In chronic HCV infection, bacteria from the Firmicutes phylum and Ruminococcaceae and Lachnospiracea families may occur, while in chronic HBV infection, Bifidobacteria, from the genus Bifidobacterium, and the intestinal Lactobacilli, from the genus Lactobacillus, seem to be less present due to dysbiosis process in chronic infection. On the other hand, in the development of cirrhosis (due to HCV infection), there may be an increase in the proliferation of bacteria from the genera Enterobacteriaceae, Staphylococcaceae, Veillonellaceae and Bacteroides, in addition to the phylum Proteobacteria.

38According to, the dysbiosis observed in chronic HBV infection is similar to that found in cirrhosis, with an increase in bacteria from the Enterococcus, Faecalibacterium and Gemella genera, and from the Enterobacteriaceae family, in addition to a decrease in Bifidobacteria and Lactobacilli in the intestinal microbiota. However, in the evolution to Hepatocellular Carcinoma, the dysbiosis caused by HCV seems to be distinct from the dysbiosis found in cirrhotic patients and chronic patients, as only the species Streptococcus salivarius and the families Streptococcaceae, Lactobacillaceae and Enterobacteriaceae seem to be elevated, while only Ruminococcaceae and Lachnospiraceae would have a reduction.

39The dysbiosis process may be accompanied by liver inflammation, allowing the evolution to cirrhosis and hepatocellular carcinoma due to action of pro-inflammatory cytokines with a Th1/Th17 profile. Dysbiosis in patients with cirrhosis and hepatocellular carcinoma can strongly affect the permeability of the mucosal tissue, allowing the induction of the innate immune system of the liver. Thus, it is possible that the liver damage found in these patients is not only due to the antigen-specific cellular immune response in response to viral action, but also due to pathogen-associated molecular patterns (PAMPs), which also can trigger an innate immune response and, eventually, tissue damage. For example, patients chronically infected with HBV may have a reduction in the presence of Lactobacilli and Bifidobacteria in their intestinal microbiota. Both bacterial families are rich in unmethylated CpG DNA, which directly triggers the CpG DNA-TLR9 pathway and the immune response to the liver virus. Unmethylated CpG DNA are recognized as PAMPs by TLR9, which is expressed in several mononuclear cells, stimulating the innate and adaptive immune response.

40Infection by SARS-COV-2, which causes the pathology called Covid-19, is still under intensive investigation due to its unique characteristics. In addition to COVID-19 being a respiratory viral infection, different clinical pictures, and a major feature of the infection’s aggravation is the cytokine storm and the development of an intense inflammatory response.

41The pathophysiology of this infection is directly related to this intense inflammatory response. Thus, the severity of the disease is often not only related to the viral infection, but also to the exacerbated immune response of the host. Patients with severe COVID-19 exhibit elevated levels of inflammatory markers such as IL-6, IL-8, C-Reactive Protein (CRP) and lactate dehydrogenase (LDH). SARS-CoV-2 utilize the angiotensin-converting enzyme receptor 2 (ACE2) to penetrate the host’s target cell. ACE2 is highly expressed not only in the respiratory tract but also in various other tissues, including the gastrointestinal tract. This important aspect of infection is further evidenced by the fact that ACE2 is important in controlling inflammation and the intestinal microbiota. After virus entry, various inflammatory signaling pathways are activated within cells and inflammatory products are released. Among these products, type I Interferons (IFN-I) are essential in the first line of defense, creating an antiviral environment that makes it difficult for the perpetuation of the virus. However, SARS-COV-2 has the ability to evade the immune system by inhibiting the production of IFN-I.

42SARS-Cov-2 has already been detected in fecal samples and there is evidence that this virus replicates in enterocytes, which could promote alterations in the intestinal microbiota in patients who developed COVID-19. identified persistent changes in the fecal microbiome of patients with COVID-19 during their hospital stay, compared to controls. These changes in the fecal microbiota were associated with fecal levels of virus and gravity of COVID-19. Furthermore, bacterial species of Bacteroidetes appeared to be negatively correlated with the severity of COVID-19. Species of the genus Bacteroides, such as B. dorei, were inversely correlated to the fecal viral load of SARS-COV-2, and it is possible that B. dorei induces suppression of ACE2 expression. On the other hand, Agathobacter, Fusicatenibacter, Roseburia, and Ruminococcaceae were less present in COVID-19 patients, being negatively correlated with CRP, procalcitonin and D-dimer levels. A reduction in the presence of bacterial with immunomodulatory activity, such as Eubacterium rectale, Faecalibacterium prausnitzii, and Bifidobacterium was observed. Conversely, CRP and D-dimer levels were positively correlated with the increased expression of Streptococcus, Rothia, Veillonella and Actinomyces bacteria. In summary, the composition of the intestinal microbiota in patients with COVID-19 has been correlated to the severity of the disease. Dysbiosis may remain present in the patient’s intestinal microbiota even after recovery from SARS-COV-2. The alteration of these bacterial groups was also associated with the elevation of the cytokines TNF-α, CXCL10 (C-X-C Motif Chemokine Ligand 10), CCL2 (C-C motif chemokine ligand 2) and IL-10. So, it is possible that this dysbiosis is related to the more severe version of the pathology of COVID-19, where there is an intense production of proinflammatory cytokines.

43Tuberculosis (TB) is an infectious disease caused by the alcohol-acid-resistant bacillus Mycobacterium tuberculosis and is considered one of the main neglected diseases in the world. It is a highly transmissible disease spread by aerosol droplets containing bacilli, usually during sneezing or coughing. It is believed that in most individuals the infection results in clinically asymptomatic latent tuberculosis infection. The bacillus predominantly infects the lungs, causing pulmonary tuberculosis. However, it can also invade extrapulmonary organs such as lymph nodes, bones, and meninges. Although 90%–95% of individuals infected with M. tuberculosis remain protected throughout their lifetime, 5%–10% of people develop active tuberculosis. Immune, host genetic and environmental predisposing factors, such as HIV infection and diabetes, have been associated with the disease. During active tuberculosis, symptoms include cough, fever, weight loss and hemoptysis.

44The gut microbiota has been reported as a host factor that may be associated with tuberculosis. Studies have shown remarkable differences between the gut microbiota of TB patients and healthy controls. reported a decrease in microbiome diversity, mainly associated with changes in the relative abundance of Bacteroides in the gut microbiota of Chinese patients with TB. In another study, an important decrease in the number and diversity of the microbiota was observed, with a remarkable reduction in SFCA-producing bacteria such as Roseburia inulinivorans, Bifidobacterium adolescentis, and Akkermansia muciniphila.

45divided patients analyzed by them according to time of diagnosis and treatment time into new tuberculosis patients and recurrent tuberculosis patients. New tuberculosis patients showed an increase in Actinobacteria and Proteobacteria, while recurrent patients showed a reduction in Bacteroidetes, containing several beneficial commensal bacteria in fecal samples. The phylum Proteobacteria contains several gram-negative bacteria and opportunistic pathogenic species. The lipopolysaccharide (LPS) component of the cell wall of these bacteria can trigger the activation of pro-inflammatory macrophages (M1) and other innate immune cells. M1 macrophages are characterized by high antigen presentation and expression of IL-12, IL-23 and TNF-α (X). Therefore, this group of bacteria can induce an inflammatory response locally and at distant sites if the epithelial barrier is disturbed. Since any damage to the intestinal barrier can cause microbial translocation into the blood and produce a sustained inflammatory response, it might also impact lung disease. In the same research, Prevotella and Lachnospira were considerably reduced in new and recurrent tuberculosis patients compared to healthy subjects (Table 3;;; ). Furthermore, Prevotella was positively correlated with the number of peripheral CD4+ cells in NTB and negatively correlated with RTB. Taken together, these data suggest that specific intestinal microorganisms may modulate the host immune system and be related to patient prognosis and outcome, especially in cases of impaired intestinal barrier.

46Leprosy is a chronic granulomatous mycobacteriosis with high infectivity and low pathogenicity, and, like tuberculosis, is considered one of the main neglected diseases. The disease is caused by Mycobacterium leprae and occurs in a variety of clinical forms that depend on the immune status of the host. The disease especially affects the skin and peripheral nerves, but it can also affect the eyes, upper respiratory tract mucosa, bones, and testicles. Classically, it is characterized with a Th1/Th2 paradigm, presenting a cytokine profile that varies according to the type of Th response. However, studies have also shown differences across the disease spectrum for Th9, Th17, Th25 and Treg lymphocytes.

47Leprosy has been associated with dysbiosis of the skin microbiota. Atypical human skin taxa were identified in leprosy lesions, with the genera Burkholderia, Pseudomonas and Bacillus being overrepresented, while the Staphylococcus genus, which is inhabitant and abundant in healthy people skin, was underrepresented in these lesions when compared to healthy controls. A study evaluated the constitution of the skin microbiome in lepromatous skin lesions (and matched adjacent uninjured areas) sampled from a cohort of Brazilian patients. The researchers found in both samples from infected leprosy patients (injured and uninjured tissue) less diversity compared to the skin of healthy individuals. This lower diversity could be imputed to the impact of the microorganism itself or to a systemic change resulting from the ongoing treatment regimen.

48Two main types of reactions can occur in leprosy patients, the reverse reaction and erythema nodosum leprosum (ENL). The reverse reaction is an acute inflammatory episode in the skin and nerves characterized by an accentuated of the cellular immune response against M. leprae. ENL is a systemic inflammatory process characterized by an increase in the levels of pro-inflammatory cytokines, such as TNF-alpha, IL-6, and IL-1B, derived from Th17 lymphocytes. Taking into account that the gut microbiota influences the homeostasis of various populations of T cells in the gut, including Tregs, Th1 and Th17, directing the pattern of local and systemic immune response, it is plausible to assume that the host’s gut microbiota may be associated to the variety of clinical responses present in leprosy and to the inflammatory state in leprosy reactions. However, so far there are no studies evaluating the role of the intestinal microbiota in leprosy and in the development of leprosy reactions.

49The microorganisms present in the human intestine play a key role in the process of development, maturation, and maintenance of the action of the body’s defense cells. They play a key role in host homeostasis under basal conditions. In addition to the competition with different pathogens for different niches, they induce protective responses through the modulation of inflammatory responses with the production of cytokines. Allied to the stimulation of protection against pathogens, the tolerance mechanisms promoted by a healthy intestinal microbiota, which involve the reduction of physiological impairment originated by interplay with microorganisms, constitute a strategy of equal significance for the conservation of the host’s health that enable the co-evolution of microorganism-host interactions. Despite this, small disparity in this interplay can have negative health implications and dysbiosis can lead to increased susceptibility to infections, as well as an imbalance in the host defense system, resulting in multifactorial inflammatory diseases.

50Evidence of the ways in which microbiota influences host physiology suggests that interplay between microbiota and cytokine pathways may be critical to sustaining host inflammation both in the gut and at extraintestinal sites. As an example, IL-17 can modulate, and be modulated by the composition of the microbiota. Mice with microbiota depleted by antibiotic have reduced levels of IL-17 in the lamina propria of the small intestine and mice with RA treated with antibiotics show reduced Th17 cells and IL-17 levels in the gut, reducing the consequences of arthritis. These data exhibited the relevance of the intestinal microbiota in modulating the production of IL-17 and associated the overexpression of this cytokine to the development of RA.

51In addition, in IBD, RA, COVID-19 and tuberculosis there is a reduction in the abundance of butyrate-producing bacteria. Especially Faecalibacterium species, which are diminished in three of these pathologies. As mentioned earlier, butyrate is an SCFA that plays a fundamental role in conserving the integrity of the intestinal mucosa and in the balance between Treg and Th17 cells. Thus, the change in the abundance of this bacterium could be related to a greater exposure of the host’s immune cells to intestinal bacteria, generating excessive activation of the immune system and an imbalance between T cells. Therefore, resulting in the intense inflammatory response involved in these diseases, whether autoimmune or infectious (IBD, AR and COVID;;; ). Taken together, these findings exemplify the importance and influence that the gut microbiota can exert on the host’s immune response.

52The microbiota-host cytokine relationship is a dynamic and complex process, where several factors can have a major effect on inflammation. The cytokine interaction patterns of the microbiota are stimulus-specific, cytokine-specific and cytokine and stimulus-specific, and are therefore disease-specific. In addition to the influence of the gut microbiome, environmental and host factors (genetic and non-genetic) also have an impact on cytokine modulation. Based on the data reviewed here, we can suggest that the gut microbiota has an important relevance in the outcome of infectious and inflammatory diseases by directing Th cell responses and by producing proinflammatory cytokines. Inflammatory diseases in which the intestinal microbiota has not been investigated, such as leprosy and its reactions, which are characterized by an intense increase in pro-inflammatory cytokines, may be at least in part related to alterations in the gut microbiota. Mainly because patients undergoing treatment for leprosy, for example, receive antibiotic treatment for up to 12 months. Therefore, it could lead to significant changes in the intestinal microbial community, with possible consequences for the modulation of immune responses and the development of inflammatory reactions. However, further studies are needed to clarify whether dysbiosis is the cause or consequence of the pathologies studied here and other diseases with an inflammatory background. Seeking to understand which changes in the intestinal microbiota or metabolites influence the variability of human cytokine responses in immunological diseases.

53As reviewed in this article, the gut microbiota has been associated with many diseases by inducing immune responses in different inflammatory conditions. Here, we provide a comprehensive overview of some of the possible cytokine modulation mechanisms by the microbiota already reported. However, it is fundamental taking into account that most studies use sequencing and analysis of 16S rRNA to infer to role of the microbiota in the health-disease interface. In order to obtain an in-depth view of the role of intestinal bacteria in the host’s immune system, it is essential that a greater number of studies assess, in addition to the composition, the metabolic patterns of the intestinal microbiota through metabolomic analyses. As highlighted here, microbial metabolites can directly or indirectly influence the pathophysiological states of the host, developing both pro- and anti-inflammatory effects. The future challenge will be to understand microbiota-metabolite-host interactions at the molecular level and in its entirety. A better understanding of these interactions can open perspectives for understanding and of biological pathways, as well as for adjuvant treatments based on probiotics containing immunoregulatory bacteria, prebiotics, which influence the growth of beneficial bacteria populations, or even a simple intervention in the diet.

54MM-F and GM contributed to the conception of the study, searching the literature, creating graphical illustrations, and writing the manuscript. DC contributed searching the literature and designed the tables. JP and RB contributed writing the manuscript. PS and TV contributed correcting the manuscript. FV contributed devising the concept, writing, and correcting the manuscript. All authors contributed to the article and approved the submitted version.

55This work was supported by Instituto Nacional de Genética Médica Populacional (INAGEMP; grant nos. CNPq 573993/2008-4 and FAPERGS 17/2551.0000521-0), Fundo de Incentivo à Pesquisa e Eventos (FIPE) of the Hospital de Clínicas de Porto Alegre (HCPA; grant no. 2019-0155), Coordenação Brasileira de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), and Fundação de Amparo à Pesquisa do Rio Grande do Sul (FAPERGS) (grant no. 19/2551-0001787-1).

56The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

57All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.