**3.3 Effects of inflammation on the intestine**

Due to its immaturity, the preterm neonatal intestine is at high risk for lesions caused by inflammation.

The risk factors for inflammatory lesions are represented by: immaturity of the mucosal barrier, immune cell dysfunction, low motility, reduced secretion of IgA and peptides with an antimicrobial role, high risk of dysbiosis and bacterial colonization.

Maternal chorioamnionitis determines a higher incidence of late sepsis in preterm newborns. The major intestinal consequence of maternal chorioamnionitis, chronic ischemia during pregnancy, antibiotic exposure is represented by necrotizing enterocolitis [19].

Pro-inflammatory mediators are important triggers in the development of the disease. Cyclooxygenase and platelet activating factors play a role in the inflammatory pathogenesis of NEC. The role of TLR4 receptors in NEC has been described. TLR4 recognize lipopolysaccharides and activate NF- κB, triggering the pro-inflammatory cascade. Enterocyte apoptosis is induced. The bacterial signal mediated by TLR4 causes mucosal lesions and allows the passage of bacteria into circulation. In mesenteric vessels, TLR4 will interact with bacteria, determining increased nitric oxide production, with severe vasoconstriction and reduced intestinal perfusion [20, 21].

The intestinal microbiota has an influence on immunity in both the intestine and the entire body.

Inflammation in NEC is caused by dysbiosis in the intestine and the exaggerated inflammatory response to this imbalance of the intestinal flora.

#### **3.4 Effects of inflammation on the kidney**

Nephrogenesis occurs until the gestational age of 34–36 weeks. The intrauterine inflammatory process will have an effect on renal function. Inflammation has an effect on the nephrogenesis process. Animal studies have demonstrated that the number of nephrons is up to 25% smaller in the case of exposure to hyperoxia and concomitant inflammation [22].

The reduced number of nephrons will have an impact on long-term renal function during childhood and adulthood, and it will favor the development of arterial hypertension at adult age.

#### **3.5 Effects of inflammation on the central nervous system**

Besides the impact on the pulmonary parenchyma, the inflammatory process in the intrauterine period also affects neurological development. Fetal inflammation,

as well as inflammation in the neonatal period due to infections can have consequences on the brain, causing lesions of the white matter, inducing periventricular leukomalacia, cerebral palsy, respectively.

The increased levels of IL-1 β, IL-6 and particularly TNF-α will exert a toxic effect on developing oligodendrocytes, but will also have a toxic effect at neuronal level. Experimental animal models have revealed the evolution of neurological lesions in time. MRI studies have evidenced long-term cerebral changes during adult life in animal models exposed to inflammation in the intrauterine period. Although there are no data about preterm infants exposed to inflammatory syndrome in the intrauterine period, it is important to consider the fact that some authors have reported cases of autism as an effect of persistent inflammation in the fetal period, or schizophrenia as an effect of latent inflammation [23].

Inflammation will induce lesions directly in the oligodendrocytes and neurons, but also indirectly, through the activation of microglial cells with the release of proinflammatory cytokines, followed by neuronal and oligodendrocytes damage [24].

The ELGAN study showed that a high level of inflammatory markers during the first month of life will entail a high risk of decrease in the intelligence quotient (IQ ) and executive functions [25].

The imbalance of the intestine – brain axis has an important role in neurocognitive development. Many studies describe the role of this imbalance. In its activity, endocrine, metabolic, immune and neural factors play an important role, but they have not yet been completely elucidated.
