**4. Nutritional supplements and antioxidants in AP**

Various supplements such as probiotics, glutamine, omega-3 fatty acids, and different formulations of enteral and parenteral nutrition have been studied with the aim of reducing inflammation and improving outcomes in AP [28]; however, their clinical benefit is still unclear.

### **4.1 Vitamins**

AP carries great oxidative stress and an acute systemic inflammatory response, [98] which is the reason why it is suggested that patients with AP have lower serum levels of anti-oxidant vitamins and may benefit from supplementation [99]. Vitamin A, vitamin C, vitamin E, selenium, and N-acetyl cysteine are important immunonutrients and have been inversely associated with AP [98]. It has been described that they may reduce inflammation and improve outcomes in SAP. Nevertheless, only a few small studies with varied doses and duration of vitamins have studied this effect with non-conclusive results: Musil et al. [21] found that plasma concentrations of vitamin A and vitamin C were significantly lower in AP patients compared with controls (P < 0.05) [100]. Recently, another study reported that vitamin D has been inversely associated with gallstone-related AP [98].

It has also been assessed the vitamin supplementation in combination with other antioxidants or in vitamin-only therapy and yielded mixed outcomes: In a multicenter randomized, double-blind, placebo clinical trial by Siriwardena et al. the use of intravenous combination of antioxidant therapy containing vitamin C, was not clinically justified to continue in AP [101]. Subsequently, another group comparing vitamin C (N-acetylcysteine) in combination with standard medical treatment in early AP suggested that antioxidant supplementation reduced the length of hospital stay and complications in these patients [102].

Another study with high vitamin C doses, involving 84 AP patients and 40 healthy subjects in China, demonstrated therapeutic efficacy on the disease, and they proposed that promoting anti-oxidizing capability in these patients, may block lipid peroxidation and improve cellular immune function [103]. This hypothesis cannot yet be proven, as another group studied multiple vitamin-based antioxidant therapy

(vitamin A, vitamin C, and vitamin E) in a randomized study involving 39 patients, in which there was no proven benefit [104].

### **4.2 Curcumin**

Curcumin (CUR) has been described as an important antioxidant, anti-apoptotic, anti-cancer, and anti-inflammatory supplement, [105–109], acting as a free radical scavenger [42, 110], and increases the expression of anti-oxidant enzymes like superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), hemo oxygenase-1 (HO-1), and others [111]. Also, CUR exerts an anti-inflammatory effect through its ability to diminish the activation of nuclear factor κ B (NFκB, p65/p50), [112], which reduces the expression of inflammatory cytokines like IL-1β, IL-6, TNFα, cyclo-oxygenase 2, lipoxygenase 5, and inducible nitric oxide synthase [113].

In experimental models of AP, CUR decreased the level of serum amylase, the number of myeloperoxidase, NFκB, and apoptotic cells. Furthermore, pancreatic inflammation, edema, and necrosis of fat cells also decreased after inducing pancreatitis with L-arginine. Histopathological features in experimental pancreatitis were normalized by effect of CUR [114]. Similar findings were reported by Yu [115] in an AP induced with caerulein. Finally, a clinical study in tropical pancreatitis suggested the beneficial effect of CUR by decreasing the level of lipid peroxidation and reinforcing the activation of the endogenous antioxidant enzymes [116]. Thus, the potential benefits of CUR alone or combined with other antioxidants contained in micro or nano-formulations [116] continue to be evaluated and applied in AP.

### **4.3 Gut microbiome impact in AP**

The human gastrointestinal tract has a rich microbiota, consisting of a vast number of microorganisms and >5000 genes. About 80–90% of the gut microbiome are Firmicutes and Bacteroidetes, being the most prevalent bacteria [55]. The gut microbiome influences the immune system through its effect on systemic metabolism.

In acute pancreatitis, the microbiome is altered by the increased intestinal permeability [117], resulting in important dysbiosis [118]. Changes in the intestinal microbiota during AP depend on the course of the disease, with a decrease in the diversity of microorganisms in acute necrotic pancreatitis [119]. Also, the need for aggressive medical therapy with acid suppression and reduced oral feeding creates a microbial imbalance [117, 118].

Increased intestinal permeability has been demonstrated in a significant percentage of patients with AP [120], with circulating bacterial DNA representative of gut bacteria in 68.8% of patients with AP. Zhang and colleagues showed that patients with AP had more Proteobacteria and Bacteroidetes and fewer Actinobacteria and Firmicutes in their feces, compared with normal controls [121]. The clinical significance of gut dysbiosis is poorly understood, but these patients have been found to have worse outcomes .

Mechanisms of microbiome alteration include 1. poor intestinal mobility: resulting in the growth of Gram negative and anaerobic microflora, in addition to the accumulation of substances that will inhibit the growth of probiotics, [122]. 2. Gut mucosal ischemia: Inflammation in the environment generated by AP can cause ischemia injury due to the release of proinflammatory cytokines, which together, with the increased migration of cells of the immune system, alters the microbiota destroying the bacterial glycocalyx [123]. 3. Oxidative stress: The subsequent inflammation in the tissue leads to the release of reactive oxygen species, and the oxidative state present in the tissue allows the presence of oxygen-tolerant bacteria [124].

Different strategies are recommended to recover the intestinal microbiome in the treatment of AP, mainly with the use of probiotics. These are live microorganisms that confer a health benefit through the inhibition of pathogenic microorganisms, the induction of growth of the mucous layer, and inhibiting apoptosis of epithelial cells. The most used probiotics are Lactobacillus, Bifidobacterium, Streptococcus, and Lactococcus lactis among others [125, 126]. Other strategies as antibiotics are not widely used in patients with AP since their prophylactic use does not reduce mortality, and in spite of this, Ahuja et al. [127] reported that the pancreatic acini were able to regulate the intestinal microbiota through the secretion of antimicrobials and different pro-inflammatory cytokines, which still must be proven.

### **4.4 Glutamine**

For unfed sterocytes, glutamine represents an important substrate [30]. Longterm parenteral nutrition can cause glutamine deficiency, which in turn leads to intestinal dysfunction [47]. Supplementing PN with glutamine is recommended for patients with critical illnesses associated with a catabolic response, as it helps preserve the cell mass of the stomach-associated lymphatic tissue and antibacterial defenses [30, 51].

It has been shown that glutamine can be associated with a decrease in infectious complications, as a result of a meta-analysis of 12 RCTs (RR = 0.58; 95% CI: 0.39–0.87) and mortality (RR = 0 .30, 95% CI: 0.15–0.60). In this study, statistically significant benefits were shown among patients who received total PN but not EN [128]. The above findings were confirmed in another study that determined the advantages of intravenous glutamine [129]. Among the most recent studies was found that enteral glutamine showed an improvement in the organ failure score, it did not obtain significant benefits in infected necrosis and mortality [130]. One study showed that giving PN with glutamine supplementation reduced overall complications by 25% compared to the PN-only group by 47% [131]. Overall, giving intravenous glutamine appears to be beneficial in patients with total PN, however, the beneficial effects of enteral glutamine should be investigated in the future. Glutamine is recommended as a supplement in the following doses 0.3 to 0.5 g/kg/d [130, 132, 133].

### **4.5 Omega-3 fatty acids**

Remarkable immunomodulatory benefits are described from dietary polyunsaturated fatty acids, especially lipoxins, resolvins, and protectins, [134, 135]

A randomized study found that enteral formula enriched with ω-3 FA in the treatment of AP reduced the total time of jejunal feeding and hospital length [136]. Also, more studies evaluated the effects of ω-3 FA supplemented in the PN during SAP. Wang et al. performed a randomized, double-blind trial of 40 SAP patients receiving PN with the same amount of nutrients but different lipid contents, including soybean oil-/fish oil-based fat solutions. It was observed that patients with ω-3 FAs-supplemented PN had higher levels of eicosapentaenoic acid and decreased pro-inflammatory cytokines, together with improved respiratory function and a minor renal replacement therapy time, suggesting an attenuated systemic response to pancreatic and organ injury [137]. Another study by the same authors who included 56 patients receiving an isocaloric and isonitrogenous PN with fats of all ω-6 FAs or

*Advances in Nutritional Therapy of Acute Pancreatitis DOI: http://dx.doi.org/10.5772/intechopen.106765*

4:1 ω-6:ω-3 FAs demonstrated that ω-3 FAs-supplemented PN augmented the expression of IL-10, and human leukocyte antigen-DR in SAP patients [137]. In the same way, during the first hours of SAP, supplementation with ω-3 fish oil emulsion in PN decreased SIRS, and improved the balance of pro-/anti-inflammatory cytokines and thus improved AP-associated severe [138]. Moreover, a meta-analysis of eight small RCTs showed that omega-3 fatty acids supplementation was beneficial in the total mortality, infectious complications, and length of hospital stay, especially when received parenterally. Nonetheless, large and well-designed RCTs are required to elucidate the efficacy of omega-3 FA supplementation during SAP.
