*2.3.2 Side effects of probiotics*

The meta-analysis of Dore et al. [47] on the incidence of side effects related to the use of probiotics in IBD patients that included nine trials (826 patients) demonstrated a higher percentage of side effects in the group of patients treated with probiotics; this effect was remarked only in patients with UC, but not with CD. These studies referred to more digestive side effects, abdominal pain occurring significantly more often in patients using probiotics. Later (2020), the same group performed a retrospective cohort study on IBD patients, 100 taking probiotics (VSL#3, Lactobacillus reuteri, and a mixture of S. thermophiles and L. acidophilus, B. breve and B. animalis ssp. Lactis) and 100 controls, showing that the incidence of adverse effects (need for systemic steroids, hospitalization, and surgery) was lower in patients taking probiotics (more than 75% of the duration of IBD) and especially in UC patients [48].

Probiotics are commonly considered as safe agents, reducing the adverse effects of the IBD, but we have to keep in mind that exceptionally, in immunosuppressed patients, bacterial translocation and sepsis may develop.

## *2.3.3 Probiotic engineering in the treatment of IBD*

The use of probiotics helps the transition from a pro-inflammatory to an antiinflammatory state at the gut level. Nowadays, the strains currently available as probiotics are represented by the Bifidobacterium species, Enterococcus faecium, Lactobacillus strains, Saccharomyces boulardii, Bacillus species, and Pediococcus, which have been demonstrated to be associated with the beneficial health effects [27, 49, 50]. Probiotic engineering determines the formation of bacterial strains with more powerful properties to target the enteric pathogens and to specifically intervene in IBD. These types of probiotics have the capacity to synthesize in situ a one or multitude of desired therapeutic biomolecules able to act on gut inflammation and avoid the side effects and complications associated with current treatment. This strategy uses bacteria or yeasts genetically engineered with the genes for some therapeutic agents that are acting as anti-inflammatory agents [22, 51].

One of the strategies used in probiotic engineering used a xylan-inducible system in Bacteriodes ovatus, which was able to induce some important biomolecules for the maintaining of gut integrity [52].

Many cytokines have been involved in IBD. Lactococcus lactis has been engineered to produce anti-inflammatory cytokine IL-10 [53]. IL-10 treatment proved to be promising in animal models of IBD and also in clinical trials using IBD patients [49]. Results of two trials performed by IBD Cooperative Study Group demonstrated an improvement of the disease in 23.5% of patients receiving IL-10 vs. placebo [54–58]. IL-27 is known to play a crucial role in infectious diseases, autoimmunity, and cancer in many organs and systems, including the digestive tract. In an animal model, treatment with IL-27 was able to diminish experimental colitis. Moreover, in colitis mouse models, engineered IL-27-producing L. lactis demonstrated to be more efficient than both the IL-10-producing L. lactis and systemic administration of IL-27 [59–61].

Interleukin 35 (IL-35) is an anti-inflammatory cytokine from the IL-12 family and plays an important role in immune suppression. IL-35 plays a pivotal role in the development and the function of both regulatory B (Bregs) and T cells (Tregs). IL-35 functions as a new anti-inflammatory factor for IBD and other immune diseases. Therapeutic potential of recombinant IL-35 protein was assessed in DSS-induced colitis mouse model. Recombinant IL-35 protein could slow down the pathologic process in mouse model. Trefoil factors (TFF) and anti TNF-α nanobodies (single domain antibody fragments) represent other therapeutic agents that have been constitutively expressed in L. lactis and tested in DSSinduced colitis in mice [49]. The former have protective and reparative properties on the intestinal epithelium. The peptides produced *in situ* by L. lactis were considerably more effective at healing colitis than the oral or rectal administration of the purified TFF [49].

One recent study engineered E. coli Nissle 1917 to produce an extracellular matrix including all three trefoil factors in order control inflammation. Tumor necrosis factor (TNF) is a pro-inflammatory cytokine secreted in IBD, and antibodies for this cytokine are used nowadays as a treatment for IBD, but associated with some side effects and disadvantages. Oral administration of nanobody-secreting L. lactis leads in local delivery of anti-mTNF nanobodies in the gut and was associated with a significant reduction of inflammation in a mouse model of DSS-induced colitis. This way of administration has been proved to prevent the systemic side effects of anti-TNF through localized delivery [62].

## *2.3.4 Probiotic engineering in vaccinations*

Traditional oral vaccinations may fail to resist in the harsh gastric environment and, sometimes, they are unable to act on the most important immune structures that induce immunity. Furthermore, there is the possibility of reversion to a virulent state of the attenuated microbes [63]. On the other hand, engineered probiotics have the following advantages:


But we have to take into considerations several disadvantages related to safety concerns. Bioengineered probiotics represent microbes and are genetically modified organisms (GMO) [66]; therefore, they pose some challenge for the approval of administration. Moreover, patients may be skeptic about their safety and their effects on the environment. To prevent bacterial gene transfer and survival in the natural medium, specific guidelines and containment strategies as well as specific engineering methods can be developed.

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