**2.2 Prebiotics and dietary fiber**

Prebiotics are defined by the International Scientific Association for Probiotics and Prebiotics (ISAPP) as a "substrate that is selectively utilized by host microorganisms conferring a health benefit" [11, 12].

The most commonly used fibers in patients with digestive diseases are nondigestible soluble fibers that are fermented by the bacteria from the colon, leading to an increase in the concentration of some healthful bacterial metabolites such as short-chain fatty acids (SCFA). Soluble fiber, such as inulin, fructooligo- (FOS) and galactooligo-saccharides (GOS), lactulose and derivatives of galactose and β-glucans, proved to be efficient for the gut health, by both modulating gut microbiota and by exerting anti-inflammatory properties. These fibers can be naturally found in a huge number of products of plant origin and also added in different food products for nutritional and health purposes [6]. They increase the volume of the intestinal contents (by binding to water) and maintain the correct pH. Prebiotics increase the number of beneficial bacteria from the gut microbiome (i.e., the Lactobacillus, Bifidobacterium, and Bacteriodes families) and inhibit the pathogens [13, 14]. Also, they have a beneficial influence on the metabolism of lipids (lowers serum cholesterol level), glucose, and proteins, and increase the absorption of calcium, iron, and magnesium [11].

In order to be categorized as a prebiotic, a product must meet several conditions [12]:


#### *2.2.1 Clinical studies on prebiotics in IBD*

Research data demonstrate that prebiotics determine the change of gut microbiota spectrum and bacteria metabolites, but there are still few data published regarding prebiotics in IBD.

Benjamin et al. [15] performed a randomized, double-blind, placebo-controlled study, assessing the effect of FOS administration on active CD. The study was performed on 54 patients with CD and 49 controls; patients with active CD were randomized to receive FOS or placebo for a period of 4 weeks. Data showed a clinical worsening of the CD patients receiving prebiotics.

The results of another study showed that oral lactulose had no beneficial effect in active IBD (clinical, endoscopic, or histopathological activity), but it improves significantly the QoL in UC patients [16]. The multicenter clinical trial of Kanauchi et al. using germinated barley foodstuff (GBF) treatment in patients with mild-tomoderate active UC for 24 weeks showed significant improvement of clinical activity [17]. A research assessing the administration of inulin enriched with FOS in the same type of patients for 2 weeks demonstrated a significant reduction in the value of stool calprotectin [18].

Another study assessed the effect of GFB treatment for 12 months in inactive UC patients, revealing a lower rate of relapse [19]. A randomized, placebo-controlled study investigated the efficiency of ispaghula husk supplementation for 4 months in patients presenting inactive UC. They found a significantly higher rate of clinical improvement in the intervention group vs. placebo (69% vs. 24%) [20]. The study of Fernandez-Benarez investigated the effect of Plantago ovata seeds on three different groups of inactive UC (105 patients)—treated with mesalamine alone, Plantago ovata seeds with mesalamine, and Plantago ovata seeds alone for a period of 12 months, finding similar remission rates for all groups, but significant increase in stool butyrate levels in the groups treated with Plantago ovate [21].

To date, results of prebiotic research in patients with IBD are conflicting. Although the administration of prebiotic agents may be associated with some adverse digestive side effects in active IBD, their administration in early childhood for a proper development of gut microbiome and later prevention of IBD onset should be taken into consideration.

#### **2.3 Probiotics**

The human intestine is colonized by 10–100 trillion commensal bacteria that are involved in the digestion process, modulation of immune response, and other functions. Nowadays, due to excessive use of antibiotics, stress conditions, and hygiene, we encounter gut dysbiosis. Lactic-acid-producing bacteria (LAB) include the biggest part of the microbiome, which produce lactic acid as a result to the anaerobic digestion of saccharides. Lactobacillus spp. are the most important group of bacteria found *Efficiency of Treatment Targeted on Gut Microbiota in Inflammatory Bowel Diseases… DOI: http://dx.doi.org/10.5772/intechopen.108664*

in fermented food (e.g., pickles, soured milk, kefir) and are considered to be beneficial for humans [22, 23].

Probiotics are live organisms that are beneficial for the gut by modulating the immune response—increase the IgA production and enhance the host immune system`s defenses—and are able to compete with pathogens [24, 25]. Their favorable actions on human gut are the following [26–29]:


The beneficial effect of probiotics was known through antibiotic-based therapy [30, 31] to decrease blood cholesterol level [32], the treatment of local infections [33], and others. In case of IBD patients, there is an abnormal activation of the immune system due to chronic intestinal inflammation. Prebiotics modulate the immune system in the mucosa layer of the intestine, by stimulating the production of antibodies, promoting phagocytosis and NK activity, determining T cell apoptosis, enhancing anti-inflammatory cytokines while reducing the pro-inflammatory ones.

#### *2.3.1 Clinical studies and meta-analysis with probiotics in IBD*

The randomized double-blind study by Tamaki et al. [24] performed in patients with mild/moderate UC demonstrated a reduction in clinical activity assessed by Ulcerative Colitis Activity Score (UCDAI), though not reaching statistical significance, in 28 patients treated with Bifidobacterium longum 536 vs. 28 patients in the placebo group, after 8 weeks of follow-up. They observed a statistically significant improvement in rectal bleeding and endoscopic activity assessed by Mayo scale.

A single-center, randomized, double-blind and placebo-controlled study [34] in patients with UC in clinical remission compared a group of patients treated with Bio-Three (Streptococcus faecalis T-110, Clostridium butyricum TO-A, and Bacillus mesentericus TO-A), with a placebo group for a period of 1 year, demonstrated lower relapsing rate in the study group, but statistically significance was reached only at 3 months of study. Yilmaz et al. [35] performed a prospective open-label randomized control, single-center study that assessed the administration of fermented milk (400 ml of kefir daily) for 4 weeks. Their results showed a statistically significant reduction of the inflammatory syndrome, improvement of hemoglobin level, and results of good feeling score, in both CD and UC patients from the study group in comparison with controls. The randomized, placebo-controlled trial of Shadnoush et al. [36] on IBD patients remarked significantly higher amounts of Lactobacillus, Bifidobacterium, and Bacteroides in patients treated with yogurt vs. control group after 8 weeks.

A study compared effect of the treatment with mesalazine and a probiotic blend (Lactobacillus salivarius, Lactobacillus acidophilus, and Bifidobacterium bifidus BGN4) vs. mesalazine alone for 24 month in patients with moderate-to-severe UC demonstrated a statistically significant improvement in endoscopic activity and clinical symptoms in the first group vs. the group with aminosalicylates treatment, suggesting that the combined treatment could be a feasible alternative to steroid treatment [37]. Another study [38] compared a group treated with mesalazine and Bifico (containing Enterococcus faecalis, Bifidobacterium longum, and Lactobacillus acidophilus) vs. a group treated with mesalazine alone. After 40 days of treatment, a significant reduction in Enterobacteria, Enterococci, Saccharomyces, and Bacteroides and increases in Bifidobacteria and Lactobacilli, and also lower levels of CRP, fecal lactoferrin, alpha-1-antitrypsin and beta-2-microglobulin, IL-6, and higher level of IL-4 in the study group were noticed. The study of Su et al. [39] randomized patients with CD to two study groups, one treated with probiotics (Bifidobacterium and Lactobacillus) combined with sulfasalazine and prednisone and the other one treated with sulfasalazine alone, which were further compared with a healthy control group. Authors noticed a significant reduction in the pro-inflammatory cytokines, better therapeutic efficiency, and lower infection rate in the study group.

Bjarnason et al. [40] randomized 81 patients with UC and 61 with CD into two groups, one using multistrain probiotic agent named Symprove that contains Lactobacillus rhamnosus NCIMB 30174, Lactobacillus plantarum NCIMB 30173, Lactobacillus acidophilus NCIMB 30175, and Enterococcus faecium NCIMB 30176 with a second group of placebo. They noticed a statistically significant improvement in the level of fecal calprotectin in patients with UC treated with multistrain probiotic agent, without significant differences in other parameters. The multi-center, randomized, placebo-controlled study of Fedorak et al. [41] on 120 patients with CD who underwent ileocolonic surgical resection compared the study group treated with VLS#3 (an agent that contains viable bacteria, including four strains of Lactobacillus combined with three strains of Bifidobacterium and one strain of Streptococcus salivarius subspecies thermophilus) vs. a placebo group. After 1 year of follow-up, there were found lower rates of severe endoscopic recurrence and significant reductions in pro-inflammatory cytokine levels in the study group treated with VLS#3 vs. control group.

One study evaluated the effect of administration of the Bifidobacterium breve strain Yakult (BFM) found in fermented milk in patients with UC vs. placebo regarding the relapse-free survival and incidence of relapse, but they found no significant differences [42].

Asto et al. [43] performed a meta-analysis in which they evaluated 18 placebocontrolled studies (1997–2018), including 1491 patients with UC who were treated with prebiotics, probiotics, or synbiotics vs. placebo groups; although any significant effect in maintaining remission was not demonstrated, it could be concluded that probiotics are beneficial in achieving remission in the active phase of UC. The results of the meta-analysis of Zhang et al. [44] comprising 38 studies demonstrated that probiotics, prebiotics, and synbiotics are efficient in achieving and maintaining remission, and their use determined a reduction in UC disease activity index. Probiotics lead to an increase in the number of intestinal Bifidobacteria, and synbiotics were more efficient in comparison with probiotics and prebiotics.

The meta-analysis of Jia et al. [45] included 10 studies (1999–2013), most of them focusing on *E. coli* Nissle and VSL#3. The results demonstrated significant differences between *E. coli* Nissle vs. mesalazine in the remission rate, risk of recurrence, and

## *Efficiency of Treatment Targeted on Gut Microbiota in Inflammatory Bowel Diseases… DOI: http://dx.doi.org/10.5772/intechopen.108664*

occurrence of complications; also, statistically significant higher rates of remission and lower risk of recurrence were obtained with VLS#3 vs. control groups. Puvvada et al. [46] analyzed three RCTs, which examined the effect of probiotics on the QoL of patients with IBD (two of them with positive results). The authors concluded that probiotics have beneficial effects of the QoL of IBD patients.
