Gut Microbiota Characteristics in Ulcerative Colitis and other Gastrointestinal Diseases

different gastrointestinal diseases. Gut microbiota changes in different gastrointestinal diseases provides an insight into the possible role of gut microbiota in the development of different GI diseases. However, the main question is “are these changes a cause or a result of a disease process”. Moreover, trying to alter gut microbiota with a therapeutic intent is the best way to prove such a causal relationship where improvement of the disease process, after gut microbiota modulation, is a strong indicator of gut microbiota role in the pathogenesis of this disease.


INTRODUCTION
The term microbiota refers to the collective assembly of different microorganisms from different kingdoms (Prokaryotes, Eukaryotes) with their niche of activities including their cellular components, genetic materials, metabolites all embedded in their host environment [1].It has been proposed, recently, that the human being is a holobiont encompassing own human cells and microbiota members with their different metabolic functions which intersect with the human metabolic and immunological functions [2].
Traditionally, the gut microbiota numbers have been estimated at 10 14 cells compared to own human cells of 10 12 [3].Due to the huge numbers of microbiota inhabiting our body, these microbiota niches have been referred to our second genome [4].
Under normal circumstances, gut microbiota exerts many physiological functions.This involves augmenting the host metabolism through the expression of many metabolismrelated genes lacking in the human genome [5].In this regard, most of the energy consumed by the colonic epithelial cells is provided by the gut microbiota as short chain fatty acids (SCFA) through digestion of unabsorbed carbohydrate [6].Moreover, gut microbiota has a recognized role in the immune system regulation and programming [7,8].A traditional role that the gut microbiota Ellehleh et al., Afro-Egypt J Infect Endem Dis 2021;11(4):320-330 https://aeji.journals.ekb.eg/ has long been known for is the protection against invasion and colonization by different pathogens [9].One interesting recent application of this property is the production of the antibacterial microcins to bind siderophores produced by some pathogens and target these pathogens via siderophore receptor uptake acting exactly as Trojan horses [10].
Although the gut microbiota shows daily variation due to many environmental effectors including diet, medications, smoking etc [11], it is a resilient community which can maintain its homeostasis continuously to maintain a symbiotic effect with the host environment [12].
However, in disease states, particularly when prolonged, a state of dysbiosis ensues which seems to exceed the mere association to have detrimental effect on the host and disease progress [13,14].
Of particular interest is the gut microbiota changes in different gastrointestinal pathologies given the direct contact of the microbiota communities in the gut with the GI mucosa and related immune system.In this article, we will review gut microbiota disturbance patterns encountered in some of the most common GI diseases.

Gut Microbiota in Clostridium difficile infection (CDI)
A healthy gut microbiota is known to confer resistance against C. difficile infection.

Gut microbiota in IBD
Although the 2 phenotypes of IBD, namely, Crohn's disease (CD) and Ulcerative colitis (UC) share many pathogenic features including genetic, immunologic, and even epidemiologic features, the role of gut microbiota in the pathogenesis of both diseases seem to be different in terms of diversity, microbiota compositions and functional pathways as would be evident below.In this regard, it has been frequently shown that gut dysbiosis is deeper and more evident in CD compared to UC.This can have both diagnostic and therapeutic implications.

Gut microbiota in ulcerative colitis
Both experimental and human studies demonstrate gut microbiota disturbances.In human studies, "Diversion colitis" might be one early indication of the importance of gut microbiome in maintaining a healthy gut homeostasis and that its absence or disturbance might be responsible for colitis [26].Also, the historical use of probiotics for treatment of UC, albeit with no significant effect, was another indication of the role gut microbiota perturbation in the pathogenesis of UC Gut microbiota can explain the effect of some factors predisposing to IBD pathogenesis and flares.An example of this would be the effect of dietary iron which leads to an increase of some iron-dependent species including the pathogens E. coli and Klebsiella which in turn can promote an inflammatory sequalae with IBD flare [32].In addition to the dysbiosis frequently observed in patients with UC, the physiological interactions between gut microbiota and gene expression were shown to be significantly disturbed in UC with lower number of detected correlations between mucosal transcriptional profiles and gut microbiota in UC patients and their unaffected discordant twins compared to healthy controls.Transcriptional profile related to oxidative stress was increased in UC [44].
While primary sclerosing cholangitis (PSC) is strongly related to UC [45] and although they share common features in the gut microbiota patterns, PSC was shown to be associated with an increase of some bacterial species independent of UC such as Rothia, streptococcus, Enterococcus, Clostridium, Veillonella and Hemophilus.On the other hand, some species were more abundant in UC compared to PSC-IBD as Fusobacteriaceae [33].
Another cross-sectional study involving patients with PSC (with or without UC) and UC-alone patients showed similar results.Although all patient groups had a decrease in microbiota diversity compared to healthy controls, patients with PSC had unique microbiota profile which allowed their differentiation from both healthy controls and patients with UC with no hepatic disease.PSC patients had significantly higher abundance of Veillonella.Interestingly, the presence of associated UC had no significant effect on the gut microbiota pattern observed in PSC patients [46].Furthermore, experimental studies could also provide an insight into the role of gut microbiota in the development of UC.Germ free mice (GF) were shown to not develop colitis even with genetic modifications known to induce spontaneous colitis such as IL-

Gut microbiome in irritable bowel syndrome (IBS)
Irritable bowel syndrome is one of the most common digestive disorders world-wide with a global prevalence estimated at 9.2% based on Rome III criteria and 3.8% according to the Rome IV criteria as shown in a systematic review that involved 92 different adult populations [55,56].Some early studies have even estimated a probability of getting a diagnosis of IBS at 30% among those presenting with gastrointestinal symptoms at their GPs [57].The underlying pathophysiology of IBS is not completely understood with many theories have been proposed involving many factors [58].
The first indication of the role of gut microbiota in IBS was the condition termed post-infectious IBS which develops after acute gastroenteritis with associated gut microbiota alteration [59].The gut microbiota composition and its contribution to the evolution of IBS has gained a lot of attention recently with the development of next generation sequencing and better understanding of the gut microbial environment.
In a cross-sectional study on IBS patients, the distribution of gut microbiota enterotypes was found to vary significantly according to IBS subtype, where the Bacteroides enterotype (lowest in Methanobacteriales abundance) was more common in IBS-diarrhoea predominant and IBS-mixed subgroups compared to healthy subjects who had the highest prevalence of Prevotella enterotype.Interestingly, Prevotella prevalence among the study groups had negative correlation with IBS severity.A microbial signature of 90 microbiota members, selected by machine learning, had the ability to differentiate The beneficial role of Bifidobacterium and Lactobacillus in patients with celiac disease might be ascribed to augmenting epithelial barrier function, reducing translocation of pathogenic bacterial species into the gut mucosa and modifying the immune response in the duodenum [68].This is in addition to the previously mentioned role of these species in the favourable digestion of gluten [65].
Assessment of the duodenal microbiota in children with celiac disease has shown significant decrease of the beneficial Lactobacilli and Bifidobacteria along with an increase of the pathogenic Escherichia coli compared to healthy controls [69].Gut dysbiosis has been shown in patients with celiac disease who had lower abundances of Fecalibacterium Prausnitzii, clostridium histolyticum, lituseburense and Bifidobacterium along with higher Prevotella & Bacteroides compared to healthy controls.This was associated with impaired immunological response as shown by significantly lower IgA coating of both Prevotella and Bacteroides in those patients [70].
Assessment of fecal microbiota in patients with celiac disease, consistently showed dysbiosis that coincided with that seen in duodenal mucosal biopsies where patients with celiac disease showed higher abundances of staphylococcus, Clostridium leptum, E. coli and Bacteroides compared to controls who had higher Bifidobacterium.Interestingly, a gluten free diet led to a partial improvement of these dysbiotic features where staphylococcus and E. coli returned to normal levels after treatment [71].However, a gluten free diet for more than 2 years failed to completely restore the gut microbiota composition where still a treated cohort of children with celiac disease exhibited higher Bacteroides, Shigella, Salmonella & Klebsiella and lower Bifidobacteria & lactobacillus compared to healthy controls [72].Interestingly this study identified some fecal metabolites as markers of celiac disease including ethylacetate, octylacetate, some SCFA and some amino acids.
Persistence of symptoms in patients with celiac disease despite a gluten free diet has been associated with alterations of duodenal microbiota with higher proteobacteria and lower Bacteroidetes & Firmicutes found in those symptomatic treated patients compared to healthy controls [73].

Role of neglected microbiota members (Mycobiota and Viromes)
Recently, the role of other players of the gut microbiota in different GI diseases has gained attention.Those include both the fungal communities (Mycobiota) and the viral component (viromes).
In UC, differences have been spotted between patients and healthy controls regarding core virome members including specifically the Caudovirales which become decreased at the time Enterobacteriaceae phages increased [74].Similarly, patients with CD have been shown to have differences in their virome community compared to healthy controls.Remarkably, CD patients have shown differences in their virome content from different GI segments [75].Also, an interaction between specific microbiota members and their lytic phages have been shown in CD [76].Moreover, CD patients have been shown to have fungal dysbiosis with an increase of their fungal/bacterial ratios associated with an increase of their Candida albicans and lower saccharomyces cerevisiae [77].
Still, these 2 aspects of the gut microbiota require further studies and assessment in both observational and interventional studies to elucidate their exact roles in the pathogenesis of different GI diseases.

Faecal Microbiota Transplantation (FMT); a possible treatment and a prove
Given the above-mentioned changes, gut microbiota modulation has developed as an appealing target for treating these disease processes with gastrointestinal diseases representing the best field to examine such a treatment modality given the direct contact of the gut microbiota with diseases gut mucosa.
These therapeutic modalities included the use of probiotics, antibiotics, and the rapidly expanding field of fecal microbiota transplantation which showed promising results in IBD [78][79][80][81][82][83][84][85].Also, FMT has shown a long success story in C. difficile infection which enabled complete cure with rare recurrence after single treatment [15].However, lack of standardization of the process is a major shortcoming before approval of FMT for different GI diseases.

Conclusions and future perspectives
The above-mentioned gut microbiota changes in different gastrointestinal diseases provides an insight into the possible role of gut microbiota in the development of different GI diseases.However, the main dilemma of a causal relationship persists with the main question is "are these changes a cause or a result of a disease process".This can be answered by conducting well designed longitudinal studies that explore the gut microbiota changes over time before disease onset in at-risk individuals and after disease onset both before treatment and after treatment.Moreover, trying to alter gut microbiota with a therapeutic intent is the best way to prove such a causal relationship where improvement of the disease process, after gut microbiota modulation, is a strong indicator of gut microbiota role in the pathogenesis of this disease.
Another area of interest which needs further studies is the role of gut Mycobiota and gut virobiota given the scarce literature exploring these microbiota members.

HIGHLIGHTS:
• Gut microbiota refers to the collective assembly of micro-organisms in a given host environment.
[27].A consistent depletion of the beneficial short chain fatty acid (SCFA) producing species as Fecalibacterium Prausnitzii in favour of the potentially pathogenic Enterobacteriaceae family (Escherichia/ Shigella) has been demonstrated in patients with UC [28, 29].These pathogenic bacterial members have the ability to induce a proinflammatory responses enhancing the development and progression of UC [30].This might be mediated through molecular mimicry or bacterial translocation with consequent activation of immune system [31].

[24].
[19] nested case-control study, lower microbiota diversity and reduction of the Clostridiales Incertae Sedis XI were identified as a risk factor for being infected with C. difficile in hospitalized patients on antibiotics[19].This shows the has been reported that patients with UC have gut dysbiosis manifested as a significant decrease of the health-associated species as Roseburia and Ellehleh et al., Afro-Egypt J Infect Endem Dis 2021;11(4):320-330 https://aeji.journals.ekb.eg/

•
It includes, in addition to the well characterized bacterial communities, different life forms of viruses and fungi.• Gut microbiota changes in different gastrointestinal diseases provides an insight into the possible role of gut microbiota in the development of different GI diseases.• Another area of interest which needs further studies is the role of gut Mycobiota and gut virobiota given the scarce literature exploring these microbiota members.