*2.6.1.2 Propionic acid (PA)*

PA is found naturally in dairy products secondary to the natural fermentation by Propionibacterium and also may be added as food preservative. PA produced in the intestine by the fermentation process of different compounds determined by anaerobic flora comprises a much higher proportion compared with the amount delivered with food [99]. The effects of PA reside in [11, 100]:

	- inhibits lymphocyte proliferation
	- activates the synthesis of anti-inflammatory resistin in adipose tissue
	- inhibits TNF-α release by neutrophils and endothelial cells
	- represents the most potent ligand of GPCR43, a receptor exposed to immunocites, proving a strong relationship with the immune system

#### *2.6.1.3 Acetic acid (AA)*

There are discordant results concerning AA, some research suggesting stimulation of the proliferation of neoplastic tissue, others inhibition of the neoplastic tissue during hypoxia, and even onset of metabolic syndrome and obesity [101, 102].

### *2.6.1.4 Adjuvant treatment with SCFA in IBD*

Vernia et al. [103] used enemas twice daily for a period of 6 weeks vs. placebo group; they obtained statistically significant decreases in intestinal bleeding and urgency, as well as an improved patient self-evaluation score compared with placebo. The study of Lührs et al. [104] compared the efficiency of a butyrate enema versus a placebo, used twice daily for a period of 8 weeks. They showed that study patients presented a significant reduction in the number of macrophages with NF-kB expression and also a decreased number of neutrophils in crypt and epithelia and of lymphocytes and plasma cells of the lamina propria, proved in bioptic specimens, in correlation with the disease activity. Another study performed a randomized, prospective evaluation of corticosteroid enemas and mesalazine enemas vs. SCFA enemas in patients with distal UC (proctosigmoiditis), proving similar recovery rates between these three groups [105].

The study of Hamer et al. [93] using rectal enemas with sodium butyrate vs. saline for 20 days in patients presenting distal UC in clinical remission demonstrated minor effects induced by butyrate on colonic inflammation and oxidative stress. They proved the effect of BA on colonic glutathione levels. Another randomized trial [106] investigated sodium butyrate enemas for 2 weeks vs. placebo in patients with distal UC non-responsive to conventional treatment. The authors found a significant decrease in the number of stools, blood discharge, endoscopic score of severity, and histologic score of inflammation in patients treated with SCFA enemas. Scheppach et al. [107] compared enemas of combined SCFA, butyrate, or saline placebo in patients with active distal UC twice daily for 8 weeks showing a trend toward a beneficial effect of SCFA enemas. Some other studies were not able to prove the efficiency of treatment with SCFA enemas [108, 109]. They were able to show that only patients with colitis dating back less than 6 months responded significantly more to SCFA vs. placebo. In conclusion, the results of most studies using SFCA are inconsistent.

## *2.6.2 Tryptophan (Trp)*

Tryptophan represents a fine regulator of inflammation involved in the adaptive immunity, mucosal barrier, and intestinal homeostasis. Gut microbiota metabolizes tryptophan, through this influencing serotonin and the immune system. Most products of the bacterial metabolism of tryptophan represent ligands for the aryl hydrocarbon receptor (AhR) that mediate the expression of genes responsible for the metabolism of xenobiotics (i.e., dioxins, drugs) metabolized by the cytochrome P450. Tryptophan metabolites such as AhR ligands are essential in the gut mucosal protection against inflammation and for maintaining intestinal homeostasis by helping mucosal barrier integrity and acting on many immune cell types. The metabolism of Trp generates some bioactive postbiotic derivatives, including indole acetate and propionate indole. Host enzymes involved in Trp metabolism (IDO1 enzyme) have a positive effect on clinical activity of IBD [110–114].

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

In patients with IBD, it was suggested that pro-inflammatory cytokines initiate the conversion of Trp to its metabolites. A very small amount of ingested Trp is conversed to serotonin, which acts not only on the CNS but also on the digestive tract, influencing gut vasodilation, motility, secretion, and absorption processes. Trp and its metabolites represent potential therapeutic targets in IBD. In this regard, trials using the administration of Lactobacillus, which produces AhR agonists, were able to demonstrate a decrease of colonic inflammation in animal models [115, 116].

#### **2.7 Antibiotics**

Antibiotics may have an insecure effect on the gut microbiota homeostasis, leading to an increase in Enterobacteriaceae and reduction in Clostridia, representing a possible pre-IBD state [117]. Moreover, IBD patients treated with antibiotics have an increased risk of developing an overgrowth of pathogenic microbes (e.g., Clostridioides difficile), fungi (e.g., candida), and bacteriophages [118]. Antibiotics have been widely used, in both pediatric and adult IBD especially in situations (pouchitis, perianal disease, abdominal abscesses), but even in luminal disease. Suggested potential mechanisms for the role of antibiotics in IBD patients include [119, 120]:


In most of the cases, antibiotics are used empirically, without identification of a specific microbial target. A case series [121] with very early-onset IBD patients refractory to other conventional treatments, mean age of 1.6 years, demonstrated that oral administration of Vancomycin ± Gentamycin can induce sustained remission.

The Cochrane systematic review of Townsend et al. [122] assessed the efficacy and safety of antibiotic administration for induction/maintenance of remission in CD. There were 13 RCTs included, comprising 1303 patients. Comparisons included ciprofloxacin/rifaximin/metronidazole/clarithromycin/cotrimoxazole vs. placebo, ciprofloxacin plus metronidazole vs. methylprednisolone, ciprofloxacin, metronidazole and budesonide vs. placebo with budesonide, ciprofloxacin vs. mesalazine, ciprofloxacin plus adalimumab vs. placebo with adalimumab, ciprofloxacin plus infliximab vs. placebo with infliximab, clarithromycin and antimycobacterial vs. placebo, and metronidazole plus cotrimoxazole vs. placebo. All antibiotics were pooled as a class vs. placebo, and antibiotics plus anti-TNF vs. placebo with anti-TNF. There was an uncertain effect of individual antibiotics on CD patients due to imprecision. Considering antibiotics as a class, 55% of the patients treated with antibiotic failed to achieve remission at 6–10 weeks vs. 64% of placebo group; 41% of the patients with antibiotic failed to achieve a clinical response at 10–14 weeks vs. 49% of placebo group (RR 0.77). The effect of antibiotics on relapse and on serious AE was unclear. They do not seem to increase the risk of AEs. The most frequent adverse events included gastrointestinal distress, upper respiratory tract infection, abscess development, headache, change in taste, and paresthesia. When antibiotics were combined with anti-TNF, 21% of patients on associated therapy failed to achieve a clinical response/remission

at week 12 vs. 36% of placebo patients (RR 0.57, low certainty evidence); 77% of the combined group had an AE compared with 83% with placebo (RR 0.93). In active CD, evidence suggests a modest benefit provided by antibiotics that may not be clinically significant. In this context, more research is needed to establish the efficacy and safety of antibiotic treatment for maintenance of remission in CD patients.

In the future, due the development of microbiome evaluation techniques, by assessing the specific gut microbiome from patient stool samples before treatment, we will be able to select the right IBD candidates for antimicrobial treatment [123] in order to target specific pathobionts or to favorable modulate microbiome/ metabolome.

#### **2.8 Fecal microbiota transplantation (FMT) for the treatment of IBD**

The study of Zhang et al. [124] investigating the role of FMT in an UC mouse model induced by dextran sulfate sodium demonstrated that FMT intervention decreased disease activity index levels and the histopathological changes, reduced the expression of colonic cytokines and oxidative stress, restored the gut microbiota, and increased the concentrations of gut SCFAs.

The systematic review of Imdad et al. [125] included four studies (277 participants), which assessed the efficiency of FMT for the treatment of UC, most of the subjects presenting mild-moderate forms of disease; authors did not find any eligible trials for the treatment of CD. Three of the studies administered FMT *via* the rectal route and one study *via* the nasoduodenal route. Combined data suggest that FMT increases the percentage of clinical remission by twofold in patients with UC compared with control group, 37% (52/140) of FMT patients vs. 18% (24/137) of control subjects achieving remission (RR 2.03). One of the studies reported that none of the patients receiving FMT relapsed at 12 weeks vs. 20% of control (RR 0.28). It was inconclusive whether there is a difference in serious adverse event (SAE) rates between the FMT and control groups, including worsening of the disease needing intravenous steroids/surgery, infections (e.g., Clostridium difficille, cytomegalovirus), small bowel perforation, and pneumonia. Common adverse events included digestive symptoms, upper respiratory tract infection, fever, headache, and dizziness. At 8 weeks, 49% (68/140) of FMT patients vs. 28% (38/137) of controls achieved clinical response (RR 1.70). Also, 30% (35/117) of FMT vs. 10% (11/112) of control subjects (RR 2.96) achieved endoscopic remission.

The systematic review and meta-analysis of Fang et al. [126] investigated the efficacy and safety and protocol of FMT for IBD, including a total of 596 pediatric and adult patients, out of which 459 received FMT. Data showed that patients with moderate-severe attacks of disease could develop significantly higher remission rates with FMT vs. patients with mild-moderate attacks. Also, in case of UC patients, FMT determined significantly higher clinical remission rates vs. placebo (28% vs. 9%, P=0.0003). The authors conclude that FMT represents an efficient and safe therapy for IBD patients (both pediatric and adult). In this meta-analysis, the type of donor stool (fresh/frozen), route of delivery, and antibiotic pretreatment proved to have no impact in patients with IBD. Due to these results, they considered FMT as a potential rescue therapy, possibly even an initial therapy for IBD.

Sokol et al. [127] performed a randomized, single-blind and sham-controlled pilot study of FMT in adults with colonic/ileocolonic CD who were enrolled while receiving oral corticosteroid in active disease. After achieving clinical remission, patients were randomized to receive either FMT or sham transplantation, while receiving a
