Gut Microbiota and Inflammatory Bowel Disease

Abstract

Inflammatory bowel disease (IBD) is a chronic and relapsing inflammatory disorder that includes Crohn’s disease and ulcerative colitis. Ulcerative colitis involves the distal colon, proximal colon, and cecum and can lead to ulcerations and bleeding. Crohn’s disease appears as patched lesions in the gastrointestinal tract and inflammation, stenosis, or fistulas. IBD affects millions of people worldwide and has been associated with high morbidity and mortality. Our intestine is colonized by trillions of microorganisms (including bacteria, viruses, fungi, and protozoa), which constitutes the microbiota. Reduction of bacteria with anti-inflammatory capacities and increase of bacteria with inflammatory capacities are observed in patients with IBD when compared with healthy individuals. Microbial balance is needed for the development of a healthy gut and a symbiotic microbiota without problems. Any disturbance in that balance leads to dysbiosis and the host may become more susceptible to disease. Some alteration in the microbiome is protective or causative; thus, we selectively will review IBD disease, pathogenesis, and potential roles of some members of microbiota in IBD. In this chapter, we also explain the therapeutic approaches targeting microbiota (probiotics, prebiotics, postbiotics) and the relationship between gut microbiota imbalance, and how defects in this dysbiosis can lead to disease.

1. Introduction

Inflammatory bowel disease (IBD), including ulcerative colitis (UC), Crohn’s disease (CD), and indeterminate colitis, is a chronic and relapsing inflammatory disorder of the gastrointestinal tract [1, 2]. More than 1 million residents in the United States and 2.5 million individuals living in Europe are estimated to be suffering from IBD [2]. The incidence of IBD has been rapidly increasing in newly industrialized countries in Asia, the Middle East, Africa, and South America over the last two decades [3, 4]. IBD has been associated with high morbidity and mortality, low quality of life, and financially demanding medical care [5]. The causes of this disease are multifactorial, the two main types: UC and CD, have similar clinical and pathological presentations and can cause irreversible impairment of the structure and function of the gastrointestinal tract [6]. These diseases are characterized by a relapsing behavior, manifested by alternating phases of inactive states in which there is no intestinal inflammation and active states that present inflammation or any other disease symptoms [7]. Although the main biological processes involved in the development of both conditions are different [6]. CD can affect any part of the GI tract, especially the terminal ileum, associated with inflammation, stenosis, and/or fistulas [7, 8].

CD occurs in patients between the ages of 15 and 35 years, affects the mucosal layer of the colon, and causes abdominal pain, diarrhea, and fever, fistula, lesions in the rectum or intestine, and other symptoms. CD damages the small intestine; therefore, malnutrition is very common in CD [9]. Despite the UC, rectal bleeding is less common in CD patients and more than 50% of patients with CD suffer from folate and vitamin D deficiency, while more than 50% of people with UC suffer from iron deficiency [10].

UC disease is a mucosal inflammation that can only affect the large intestine, i.e., the colon, and the inflammation generally starts in the distal colon, going forward through the proximal colon until the cecum and can lead to ulcerations and bleeding [11]. About 25% of UC patients are diagnosed before the age of 18 years, because this disease affects adolescence [9]. There are different diagnostic tests for UC including clinical, endoscopic, histologic, and radiological tests although approximately 8.5% of IBDs are unclear [12, 13]. UC is the initial subtype of IBD, and the term IBD includes the characteristics of both CD and UC. It has long been difficult to distinguish between these two diseases, but now there is a clinical definition for both. Both diseases can affect specific parts of the lives of patients, such as school, job, social life, and family life Figure 1 [9].

Figure 1.

The effective agents in development of inflammatory bowel disease.

The concept of IBD pathogenesis is based on the theory of a disrupted intestinal barrier and a dysregulated immune response in a genetically susceptible host. IBD presents defects in the detection and control of the gut microbiota, associated with unbalanced immune reactions, genetic mutations that confer susceptibility to the disease, and complex environmental conditions such as a Westernized lifestyle [7, 14]. There is a strong clustering in families and with certain ethnicities. Other studies showed 15–50 times increased relative risk for siblings of a CD patient to also develop CD. The ethiopathology of IBD is multifactorial and is characterized by the interaction between genetic, microbial, environmental, and life style factors, which influences the immune responses and leads to the gut inflammation. Gut microbiota is important for the development and maturation of the immune system and reduced microbial diversity and its dysbiosis observed in IBD patients (Figure 1).

More than 200 IBD-associated susceptible genes have been identified, some of which are known to be involved or implicated in mediating host responses to gut microbiota [14]. This has evoked the possibility that gut microbiota is implicated in the pathogenesis of IBD [3]. Microbial factors have been historically proven to be indispensable for the onset of IBD, and advances in high-throughput sequencing have enabled us to elucidate the gut microbiome in IBD. IBD can be caused by determined infection of an enteric pathogen such as Mycobacterium avium subspecies paratuberculosis, Clostridioides difficile, Helicobacter pylori, Campylobacter concisus, Fusobacterium nucleatum, and adhesion-invasive Escherichia coli. An excess of translocation of intestinal bacteria across the intestinal barrier, the imbalance between beneficial and detrimental commensal bacteria can cause IBD [15, 16]. Some bacteria including AIEC can be considered as both a persistent pathogen and detrimental commensal bacteria [17].

Therefore, this chapter covers the origins, causes, diagnosis, and treatment strategies of this complex disease.

2. IBD and immunity system

Epithelial layer integration permits the gastrointestinal bacteria to communicate with the immune system [18]. The mucosal layer is the first physical barrier on the mucosal surface and is produced by the polymerization of gel-forming mucins secreted by Goblet cells. The second defense barrier against bacterial attack is the intestinal epithelium, which makes up of enterocytes and particular epithelial cells called Goblet and Paneth cells [19]. Intestinal epithelial cells prevent the influx of antigens and the attack of pathogens and commensal microbes [18]. Intestinal epithelial cells (IECs) also express toll-like receptors (TLRs) and nucleotide oligomerization domain receptors (NODs), which are pathogen-sensitive innate immune receptors. IECs then make chemokines and cytokines to engage immune cells [18]. TLR signaling pathways helps the epithelial barrier to remain intact and produce 12 and interleukin 6 [18, 20]. The epithelial barrier impairment causes intestinal permeability to increase, which has been shown in CD and also in UC, and this might be a main pathogenetic mechanism in IBD [19]. TLR acts as pro/anti-inflammatory gene activation inducer and controls the adaptive immune responses [21, 22].

Intestinal immune cells including innate immune cells and adaptive immune cells significantly involve in immune responses in IBD [23]. Macrophages, TLRs, and NOD-like receptors (NLRs) are essential for developing tolerance to certain pathogens and promoting wound treatment. Binding to pathogene receptors leads to the activation of different signaling pathways and the production of proinflammatory cytokines, chemokines, and antimicrobial peptides. The antigen-presenting cells (APCs) link innate immunity and adaptive immunity by secreting cytokines and presenting antigens to the T cells [24]. Fine gut-resident macrophages, described by a lack of CD14 expression, manifest decreased response, proliferation, and chemotactic activity. The gut-resident macrophages have increased phagocytic activity and secretion of cytokines in IBD patients, causing dramatic inflammation [25]. After microorganisms’ invasion, innate immunity activates after a few hours [26]. Macrophage cells kill specific pathogens, such as peptides and lipopolysaccharides. In IBD acute phase, the number of macrophages in the intestinal mucosa increases dramatically, and a large number of T cells and costimulatory molecules such as CD40, CD80, and CD86 are involved in the inflammatory process and intolerance of commensal microbes and immune activity [27].

Malfunction in TLR signaling can induce an intestinal inflammatory response with various clinical phenotypes, including the IBD. A considerable target of the TLR signaling is the activation of the transcription factor NF-kB, which regulates the expression of a variety of genes responsible for controlling the innate response, such as IL-1, IL-2, IL-6, IL-12, and TNF-𝛼 [28, 29]. Table 1 shows the cytokines and cellular sources involved in immune response in IBD. Both IL-1 and TNF-𝛼 share numerous pro-inflammatory properties responsible for the development of IBD [30]. Dendritic cells are professional antigen-presenting cells that activate T cells and induce adaptive immune responses, describing key players in the cross talk between innate and adaptive immunity [38].

Pro-inflammatory
Cytokines	Cellular Sources	Principle function	Role in immune system
IL-1, IL-1β	Mϕ, IECS, Monocytes	Influence on the T cell and secretory cytokines	Innate immune response [30, 31, 32]
IL-2	Th-cells	T & B cells proliferation IFN-γ production	Adaptive immune response [31]
IL-6	DCs, Mϕ	Differention of Th17, Treg cells and activating STAT-3 signaling pathway	Innate immune response [31, 33, 34, 35]
IL-12	DCs, Mϕ	Promoting the differentiation of Th1 and Th17 cells	Innate immune response [36, 37]
IL-13	Th2 cells	Intestinal permeability inducing and activating of B cell	Innate immune response [38]
IL-17	Th17 cells	Inducing and promoting of secretory cytokines	Adaptive immune response [39, 40]
IL-18	Mϕ	Provoking the secretion of pro-inflammatory cytokines	Innate & adaptive immune response [32]
IL-22	Th17 cells	Inhibiting pathogens of intestinal and repairing of intestinal tissue	Innate immune response [41]
IL-23	Mϕ	Provoking the production cytokines	Innate immune response; [36]
TNF-α	Mϕ, DCs, Th-cells	Promoting the production cytokines and Th-cells proliferation	Innate immune response [31, 42]
INF-γ	Th-cells	Activating NF-κB signaling pathway and activating of Mϕ	Adaptive immune response [43]
Anti-inflammatory
IL-4	Th2-cells	Th2-cells differentiation and inhibiting the production of cytokines of Th1cells	Adaptive immune response [31]
IL-10	DCs, Mϕ, Treg cells	Inhibiting the production of cytokines Th1 cells	Adaptive immune response [31, 44]
TGF-β	DCs, Treg cells, T cells	Treg and Th17 differentiation and restraining of Th-cells	Adaptive immune response [31, 34, 35]

Table 1.

The pro-inflammatory agents’ contribution in immune response in IBD.

Abbreviations: Mϕ: Macrophage, IECS: Intestinal epithelial cells, DCs: dendritic cells, STAT-3: signal transducer and activator of transcription, NF-κB: nuclear factor kappa B.

The other IBD risk variants in other genes are involved in IL-12 and CCR6, chemokine receptors preferentially expressed on IL-17 producing cells [19]. IL-23/IL- 17 axis has a key role in this cross talk and the IL23R gene encodes a specific subunit of the IL23 receptor that has been identified and largely replicated in independent cohorts of patients with both CD and UC [45]. Other clinical studies have found that the intestinal mucosa and lamina propria of IBD patients contain much higher levels of Th17 cells, IL-17, and IL-23 compared with the healthy controls [24].

Appositive of the innate immune response, the adaptive immune system is very specific, it presents long-lasting immunity. Key players of the adaptive immune response are T cells. Th0 cells can become activated and either differentiate into Th1 or Th2 or Th17 cells [19, 38]. However, a dysregulated T cell response with abnormal development of activated T cell subsets causes inflammation because of an excess release of cytokines and chemokines, which have multiple pathogenic impacts on components of the immune system. Figure 2 shows the immune response in IBD. The levels of T-cell-derived cytokines detected in IBD mucosa, different studies have associated CD and UC with different subtypes of pro-inflammatory immune responses. Therefore, the innate immune response is as important as the adaptive immune system in inducing gut inflammation in these patients [19, 24, 38].

Figure 2.

The role of immune response on progress IBD.

Genome-wide association studies and immunological studies have mentioned that IBD pathogenesis is related to mucosal innate immune responses, including classical Th1 response in CD patients and Th2 type-like response in UC patients [45, 46].

In mouse model studies, induction of CD caused increase of IFN-𝛾 expression in their spleen and local intestinal mucosa [43]. CD evolution is generally mediated by CD4+ Th1 and Th17 cells, and IFN-𝛾 is a major cytokine declared in this disease [47]. Deficiencies of IL17-A and IL17-B in experimental models showed both pro-inflammatory and tissue-protective effects against colitis depending on the model used [19, 48]. However in mucosa of IBD patients, IL-17A cells regulate and induce a number of pro-inflammatory molecules [38].

Regulatory T cells (Treg) produce the anti-inflammatory cytokines (IL-10, TGF) and exert an effective anti-inflammatory action in experimental colitis. Treg are reduced in peripheral blood of patients with active IBD in comparison with quiescent IBD patients and control subjects [49, 50]. In contrast, Treg are increased in the intestinal mucosa of IBD patients, and their function is normal. An intact TGF signaling, which is impaired in inflamed IBD mucosa because of upregulation of the inhibitory molecule Smad7, is needed for Treg function [19]. Treg cells, expressing the transcription factor forkhead box P3 (FOXP3), have a negative immunomodulatory character in immune tolerance and a crucial role in the pathogenesis of IBD [24, 51, 52].

3. IBD and gut microbiota

IBD is obviously related to gut dysbiosis that impairs host-microbe and immune homeostasis [53]. The human gut includes trillions of commensal bacteria per gram of gut lumen content. These bacteria can be nutritious and provide the intestinal epithelium [38, 54]. The gut microbiota leads to intestinal homeostasis due to our physiological procedure and metabolites [55]. There are different phyla, including Bacteroidetes, Firmicutes, Proteobacteria (Escherichia and Helicobacter), and Actinobacteria that include fungi, protists, and viruses (Table 2) [56, 57].

Increased	Decreased
Bacteria	Fusobacterium species	Bififidobacterium species
	Pasturellaceae Bacteroides species
	Proteobacteria (adherent invasive Escherichia coli)	Clostridium XIVa, IV
	Ruminococcus gnavus Faecalibacterium prausnitzii
	Veillonellaceae Roseburia species
	Suterella species
Fungi	Candida albicans	Saccharomyces cerevisiae
	Candida tropicalis
	Clavispora lusitaniae
	Cyberlindnera jadinii
	Kluyveromyces marxianus
Viruses	Caudivirales

Table 2.

Microbiota changes associated with inflammatory bowel disease.

Ecological factors, such as as host diet, hygiene, antibiotic consumption, and lifestyle, induce immune responses that change the intestinal microbiota and damage the mucosal barrier [38, 58]. Gut microbiota plays an important role in the pathogenesis of IBD and impacts energy metabolism host, immune homeostasis, development and maintenance of mucosal integrity [24]. Table 3 shows the effect of gut microbiota in inflammatory bowel disease and its interdependence with the immune response.

Depleted	Immune Association
SCFA producing bacteria (F. prausnitzii, Roseburia, Eubacterium)	Produce SCFA plays a major role in modulation of inflammation, regulation of immune responses, maintenance of barrier integrity in the gut, enhanced expansion of the Treg population, and skew of human dendritic cells to prime IL-10-secreting T cells [59, 60, 61].
Bacteroides fragilis	Produces lipid antigens controlling homeostatic iNKT cell proliferation and activation [62].
Bifidobacterium	Inhibits intestinal inflammation by acting on Treg cells [63].
Mbb. smithii	Weak association with pro-inflammatory mechanisms [64].
Enriched	Immune association
E. coli (adherent invasive)	Invades intestinal epithelial cells replicate in macrophages and induce granulomas [65].
Clostridiaceae; (class)Clostridiales	Clostridium difficile could induce the expansion of regulatory Tcells (Treg) and to mitigate intestinal inflammation [66].
Proteobacteria (Salmonella, Yersinia, Desulfovibrio, Vibrio Helicobacte)	Associated with a pro-inflammatory state as revealed by quantification of common pro-inflammatory interleukins. The inflamed gut appears to provide a favorable environment for the expansion of this phylum [67].
R. gnavus	Secretes a complex glucomannan polysaccharide inducing TNFα secretion by dendritic cells [68].
Fusobacterium	Especially F. nucleatum, which is a well-recognized proinflammatory bacterium and it may secrete Outer Membrane Vesicles (OMVs) activate epithelial TLR4 to drive inflammation [69, 70].
C. albicans	Interacts with mucosal innate immune cells through the pathways associated with Dectin-1 in macrophages [71].
Bacteriophages (Caudovirales and Microviridae)	role in physiology of intestinal or change the bacterial in gut microbiota via predator-prey relationships [72]. Enterobacteria are the hosts of Microviridae [73].
Eukaryotic viruses	Infect of intestinal and develop host susceptibility to IBD by immune response via inflammatory mediators, and inducing alterations in the composition of the commensal bacteria [74].
Eukaryotic viruses	Infect host cells may increase host susceptibility to IBD by supporting a long-standing immune response through inflammatory mediators, as well as by inducing alterations in the composition of the commensal microbiota [74]
M. stastmanae	This leads to the substantial release of proinflammatory cytokines in monocyte-derived dendritic cells [64].

Table 3.

Gut microbiome in inflammatory bowel disease and its associations with the immune system [7].

For example, Clostridium cluster IV and XIVa were less abundant in IBD patients than in healthy controls [55]. Bacteroides genus is obligate anaerobe bacteria and consists a large amount of the normal gut microbiota. B. fragilis decreases in IBD patients and promotes the quantities of anti-inflammatory cytokines against colitis [24, 75]. The overgrowth of Enterobacteriaceae, Pseudomonas-like bacteria, and Escherichia coli promotes the intestinal inflammation and alters the composition of the microbiota in most colitis models and IBD patients [58, 76, 77]. Faecalibacterium prausnitzii secret anti-inflammatory cytokines, which reduce in the intestine of IBD patients [24, 55]. Fusobacterium and Ruminococcus gnavus have also been increased in CDI patients [78]. In a recent study performed on IBD patients, a functional gut microbiome dysbiosis and impaired microbial transcript were seen. Facultative anaerobes were raised at the expense of obligate anaerobes [79]. Other different studies showed that the diversity of gut microbiota was either decreased or equal in IBD patients versus controls. F. prausnitzii, Eubacterium rectale, and Akkermansia were decreased, and Actinomyces, Veillonella, and E. coli were increased in patients with UC (Table 3) [80].

Other possible pathogens in the exacerbation of the IBD disease are Mycobacterium avium subspecies paratuberculosis, Clostridium difficile, Listeria monocytogenes, and Campylobacter concisus, as well as viruses, including cytomegalovirus, Epstein-Barr virus, and measles virus [17, 81]. In addition, a number of pathogenic parasites may involve in the progression of this disease. Overexposure of immune system in the presence of too many bacterial materials could also cause the loss of immunological tolerance to the bacteria, which are generally considered the normal flora in the gut [81]. Some of the individual bacterial species that associate with human IBD are reviewed here.

3.1 Clostridioides difficile

C. difficile is an obligate anaerobic Gram-positive spore-forming bacterium, which is prevalent in nature and also colonizes the human intestinal tract [81, 82]. C. difficile leads to diarrhea and colitis, frequently in persons who have been treated with antibiotics for other medical complications [81, 83, 84].

C. difficile can produce toxins type A and B, and IBD patients with C. difficile infections (CDI) appear severe clinical symptoms, such as abdominal pain, diarrhea, bloody stools, and leukocytosis [85, 86].

CDI causes relapsed IBD, and IBD patients in remission had a significantly higher presence of toxigenic C. difficile in their intestinal tract as compared with healthy controls [87]. UC patients have a high risk of CDI in comparison with healthy population or CD patients.

The two toxins encoded by tcdA and tcdB genes lead to the disruption of epithelial cytoskeleton and tight junctions, which contribute to the CDI [81, 88, 89]. A reduction in butyrate-producing bacteria and increase in lactic-acid-producing bacteria were seen in CDI status. Overrepresentation of Akkermansia may be a predictive marker for the development of nosocomial diarrhea, which can result in a worse CDI prognosis [82]. Activation of the production of multiple inflammatory cytokines such as IL-8, TNF-a, IL-1, and tumor necrosis factor (TNF-a) could damage the intestinal epithelial cells and trigger IBD in CDI patients [90]. Reduced bile salts happen in the colon of patients with IBD leading to spore germination of C. difficile [86, 91]. Patients with IBD present common infections such as gastrointestinal infections of C. difficile, Salmonella, Shigella, and Campylobacter jejuni [81, 92].

3.2 M. avium subspecies paratuberculosis

M. avium species is commonly present in the environment and comprises four subspecies, including M. avium subspecies avium, M. avium, M. avium subspecies hominissuis, and M. avium subspecies silvaticum [93]. M.avium causes production of some inflammatory cytokines in IBD patients [86]. In IBD patients, the increase in metalloprotease leads to dysregulation in immune system and large level of inflammatory cytokines [94, 95]. Combination of multiple antibiotics including rifabutin, clofazimine, and clarithromycin, adds up to ciprofloxacin, metronidazole, or ethambutol, which are used for treatment of patients with positive different species of M.avium [96]. Also antibiotics such as nitroimidazoles and clofazimine are effective in the treatment of CD [97].

3.3 Helicobacter pylori

Helicobacter species are Gram-negative bacteria. H. pylori is an important pathogen that isolates from gastrointestinal tract of humans and animals. H. pylori infection has been reported in IBD patients and shows a protective effect in IBD [98, 99]. H. pylori increases the expression of forkhead box P3 (FOXP3) with stimulating of the regulatory T cells production, reduces the production of inflammatory cytokines, and finally, decreases inflammation [100, 101]. H. pylori with cytotoxin-associated gene A (CagA+) genotype, in IBD patients, diverts TH1 response to TH2 response that has anti-inflammatory task [102].

Helicobacter species are more detected in intestinal biopsies of patients with CD and UC than controls, although this difference was not significant [103]. Molecular studies detected non-pylori Helicobactor by Helicobacteriaceae family-specific PCR in 3% of IBD patients and 8% controls [104].

3.4 C. concisus and Fusobacterium nucleatum

Most strains of campylobacter colonize in the intestinal tract, but the colonization of C. concisus is in the oral cavity [105]. C.concisus is associated with IBD in the adult patients [106]. The virulence factors of C. concisus infect the lower parts of the intestinal tract [86]. Zonula occludens toxin (Zot) is expressed through a CON-Phi2 prophage and leads to the permeability of the epithelial cells and formation of IBD. This mechanism is similar to the Vibrio cholerae toxin [107]. C. concisus breaks the intestinal epithelial barrier and leads to apoptosis in human intestinal epithelial and intestinal inflammation [108]. The invasive strains of C. concisus enable them to survive in harsh conditions such as in anaerobic conditions [86].

F. nucleatum is an anaerobe bacterium that colonizes the oral cavity and intestinal tract [81]. It is abundant in intestinal tract of UC and IBD patients, and the quantity was linked with disease severity [109]. F. nucleatum leads to the damage of intestinal epithelium and promotes intestinal inflammation by inducing autophagic epithelial cell death [86].

3.5 Adherent-invasive E. coli

Adherent-invasive E. coli (AIEC) is a commensal human gut bacterium and is associated with ileal CD in the adult population. AIEC strains can adhere to and invade intestinal epithelial barrier assessed [110]. AIEC strains have various mechanisms and virulence factors, which are involved in the pathogenesis of IBD patients [86]. Several factors such as type 1 pili adhesion FimH and carcinoembryonic antigen cell adhesion molecule 6 are associated in promoting inflammation [111]. AIEC strains induced production of cytokines such as IL-8, TNF-a, and IL-6 in both epithelial cells and macrophages. Replication of AIEC in macrophages did not cause macrophage death, but increased production of TNF-a and IL-6 [81, 112].

4. Therapeutic approaches targeting microbiota (probiotics, prebiotics, postbiotics, and antibiotics)

Probiotics are live microorganisms, which allocate great health advantages for the host organism when used in an appropriate quantity [113]. Probiotics induce anti-inflammatory effects, enhance or renew barrier work, promote the growth of beneficial bacteria, and inhibit the growth of pathogens [114]. Probiotics rebalance the gut microflora shifting from pro- to anti-inflammatory state [115]. Prebiotics are substrates that are selectively utilized by probiotics allocating health benefits [17]. Inulin is a prebiotic that retains microbial population, helps the epithelium barrier function, and inhibits from pathogens translocation [116]. This process leads to the treatment of functional symptoms in IBD. Postbiotics are bioactive molecules produced by probiotics [117]. There are many reports that showed some probiotics and prebiotics can be beneficial in treatment and prevention of IBD in both human and mice models [118].

In CD, evidence for prebiotics and probiotics is commonly dissatisfactory and antibiotics have moderate effects [66]. The most common strains that are used as beneficial probiotics are Bifidobacterium species, Enterococcus faecium, Lactobacillus strains, and Saccharomyces boulardii, Bacillus species, and Pediococcus [115]. The theoretical risks of probiotics on animal models of IBD in different studies are described that include systemic infections, harmful metabolic activities, extreme immune stimulation in susceptible patients, gene transfer, and gastrointestinal adverse effects [119]. Some traditional probiotics, such as the probiotic cocktail VSL# 3 (containing a mix of four lactobacilli, three Bifidobacteria, and one Streptococcus strain), have shown limited effect in treating CD and UC, by reducing active inflammation and recurrence [17, 66].

Some clinical trials showed that Lactobacillus rhamnosus administration in gastroenteritis children did not have better outcomes than those who received placebo [120]. Although a multi-strain probiotic (including L. rhamnosus, Lactobacillus plantarum, Lactobacillus acidophilus, and E. faecium) is related with lower intestinal inflammation in UC patients, but not in CD patients [121]. Besides the mentioned traditional probiotics, Akkermansia muciniphila and their supernatants that contain postbiotics significantly reduced the severity of colitis [17]. F. prausnitzii produce barrier improving immunosuppressive SCFAs, stimulate Tregs to produce IL-10, which have protective effects on the intestine [66]. In mice models, administration of A. muciniphila or its postbiotic reduced the infiltrating macrophages and CD8+ in clolon and inhibited colitis [122, 123].

These helpful microbes and their metabolites should be investigated as therapeutic determinants in treatment of IBD. Dietary substrates such as oligosaccharides and fiber are prebiotics that selectively increase the quantities of SCFA-producing commensals, blocking the AIEC epithelial adherence, and the virulence products of intestinal pathogens in IBD [66].

Probiotic engineering with emerging technologies such as as CRISPR-Cas system can be used to produce to treat untreatable chronic inflammatory conditions [115]. With increasing our knowledge about viable bacterial strains and synthetic biology tools, we can identify and characterize extra probiotic bacterial strains as potential candidates for probiotic engineering [124].

Antimicrobial agents and IBD have a complex relationship. They have hazardous influences on the homeostasis of the host microbiota, leading to a population shift described by increased Enterobacteriaceae and decreased Clostridia abundant, which is regarded a possible pre-IBD condition [125]. Also, IBD patients treated with antibiotics are at high risk of forming an overgrowth of pathogenic microbes including C. difficile, candida, and bacteriophages [126].

In addition, antibiotics are an integral part of the treatment repertoire in IBD, whereas before the period of immunomodulation and biologic therapy. The mechanisms of antibiotics in treatment of IBD are a direct effect on the gut microbiota, preferring flora that are linked with anti-inflammatory properties, e.g., Bacteroides and Firmicutes, and decreasing pathogenic microbes that are associated with inflammation, such as as Enterobacteriaceae, e.g., E. coli and Fusobacterium [75]. Furthermore, we can choose target-specific pathobiants or to manage individual microbiome in IBD patients by determining patient stool samples prior to treatment [124].

The immunological mechanisms of IBD have made great upgrades, provided novel tactics for IBD treatment. Biological agents induce and maintain clinical remission of IBD and promote mucosal curing. A number of biological agents that have been approved for the treatment of IBD are some of the TNF-α inhibitors such as Infliximab, Adalimumab, Certolizumab pegol, Glimumab, Etanercept, and Tocilizumab [24]. However 10–40% of IBD patients do not respond or lose their response to treatment over time [127].

4.1 Fecal microbiota transplantation (FMT)

FMT appears effective therapy for treatment of recurrent CDI and in UC or CD remission induction but remains strong and safe in the long term is not clear [128, 129]. A significant proportion of recurrent CDI patients have IBD, and FMT is moderately less successful in treatment of CDI from patients with IBD in comparison with patients without IBD [130]. Some issues could affect the FMT outcome in IBD treatment including donor choice; preparation of fecal material; clinical management, the high abundances of fungi or virus communities in donor stool or other essential necessities for implementing an FMT center [131, 132].

Recently, the field of IBD genetics has made enormous progress, and different relative molecular and cellular pathways exist. Fluctuations in specific gene loci promise therapeutics for IBD in the future. Besides, FMT, novel natural medicines, new antimicrobial agents, and combined treatment programs are also anticipated to break the IBD and therapeutically delay. The combined treatment strategies that use anti-inflammatory agents and anti-fibrotic drugs will provide great insights into the existing IBD therapeutics [17].

5. Conclusion

Correct interplay between gut microbiota and the host is essential for human health. Microbial balance is pivotal for host metabolic and immune functions as well as to prevent disease development. Disturbance in that balance generates dysbiosis making the host susceptible to certain diseases. Gut microbiota stimulates the immune system, and altered composition of this microbiota in early life can lead to an inadequately trained immune system that can overreact to commensal microbes and lead to inflammatory diseases. Recent research has provided striking findings supporting that the gut microbiome plays an important function in the etiopathogenesis of IBD.

The clinical and epidemiological evidences showed that the infectious pathogens have possible role in IBD progression, especially, Mycobacterium avium paratuberculosis, C. difficile, E. coli, and C. concisus. Also, some viruses such as cytomegalovirus, Epstein-Barr virus, and measles by different pathogenesis have been be associated with the higher IBD risk; however, H. pylori may reduce intestinal inflammation and protect against IBD.