The Influence of The Protein Source in Clinical Outcomes of Patients on Enteral Nutrition Therapy

necessity the of the nutrients the formula. Abstract The nutritional therapy aims to maintain or recover the nutritional status, and the enteral nutrition therapy is used when oral feeding is not indicated or when the individual’s nutritional needs are not met. During hospitalization, nutritional status impairment may be fast, and malnutrition increases the risk of complications and mortality. Enteral formulas can be composed of plant or animal proteins, but it is not clear whether different sources influence in clinical outcomes. Considering the lack of studies addressing this topic, evidence related to the type of protein source in enteral nutritional therapy was compiled in order to identify differences in clinical outcomes of patients using nutritional therapy. Studies that were included in the review show that the use of enteral formulas based on vegetable protein appear to be as efficient as animal protein based formulas, regarding maintenance of nutritional status, improvement of glycemic control and minimizing gastrointestinal complications when compared to animal protein. The limited number of studies and differences in study design and characteristics make it difficult to draw evidence-based conclusions. Thus, further studies are needed to elucidate the role of vegetable protein in clinical outcomes when compared to animal protein.

difference between plant or animal protein absorption in the body, and vegetable protein is enough to provide the necessary amino acids for metabolic processes [9,10]. However, studies evaluating the difference between protein sources in enteral formulas are still scarce. Several dietary supplements of plant-based protein have appeared, aimed mainly at the sports public, and studies show good results when they relate their use to physical exercise and sports performance compared to animal protein supplements. However, these products are designed to complement the diet in terms of proteins and amino acids, not meeting the need for a complete enteral nutrition formula that is composed of all macronutrients and macronutrients in the recommended intake amounts [11,12].
There are few formulas with a purely vegetable protein source available on the market. Currently commercialized enteral formulas are composed of casein, whey protein or mixtures of these with soy protein. On the other hand, the number of patients with food intolerance or allergies who need specific formulas has increased.
Another fact to be considered is the cultural aspects and beliefs, in which individuals choose not to use animal protein sources. Strict vegetarians are a good example [13] because of issues related to health, ethics and animal rights, environment, economy and religion [14,15] they choose for the absolute restriction of animal sources.
Therefore, this study aims to promote a better understanding about EN with plant protein sources and to provide greater security for health professionals when prescribing ENT, so as to respect the bioethics principles of autonomy, nonmaleficence, beneficence and justice [16].Thus, this study aims to identify in the literature whether there are differences in clinical outcomes of individuals undergoing enteral nutrition therapy with different protein sources.

Methods
This study is an integrative review developed according to the following steps: 1 st Elaboration of a guiding question -A review was developed to answer the following question: "Is there any difference between the use of formulas with vegetable protein source and animal protein source in clinical outcomes of adult and elderly patients on enteral nutrition therapy?; 2nd Definition of search terms -The search was performed using combinations of terms to identify original studies that evaluated outcomes according to the protein source of enteral formulas. The descriptors used in the search were: "enteral nutrition", "food, formulated", "vegetable proteins" and "soybean protein". The search terms were combined using Boolean operators (OR to match the same group search terms and AND to match search terms from different groups) and quotation markers were used to search for exact terms or expressions and parentheses to indicate a group of search terms or to combine two groups of search terms, allowing all possible sentence combinations. The search description was as follows: ("Enteral Nutrition" OR "Food, Formulated") AND ("Vegetable Proteins" OR "Soybean Proteins"). were excluded, and the titles' articles were read. Subsequently, the abstracts of the found studies were read in order to refine the articles only potentially relevant to the study, disregarding all those that were not related to the theme and did not meet the inclusion criteria. All studies that met the inclusion criteria were reviewed. After the complete reading of the studies, they were analyzed according to the established criteria. The flowchart of the selection and eligibility process of the articles is shown in Figure 1.

Results
Comparison between the use of animal protein and vegetable

Nutritional Status
The intervention group which, received soy protein in the García-Talavera Espín et al. [17] study, presented lower rates of malnutrition at hospital discharge (either mild, moderate or severe). Also, higher nutritional recovery rates, even without statistical difference, were observed. The soy protein group showed improvement in nutritional status in 8 cases and worsened in 2, while in the casein group there was improvement in 4 cases and worsening in 4 cases. The group that received soy protein had higher number of patients who returned to oral feeding at hospital discharge and a lower proportion of infections and antibiotic use.
In the Viall et al. [18] and Vaisman et al. [20] studies, in which parameters of nutritional status were evaluated in a secondary way, no significant changes were observed in groups regarding weight, triceps skinfold and arm circumference19, and there was no significant difference in body mass index (BMI) values19 between groups.

Metabolic Outcomes
Biochemical parameters such as serum albumin, total lymphocyte count and total cholesterol were used in the García-Talavera Espín et al. [17] study to assess nutritional status, demonstrating improvement in the parameters of the group that used soy protein source. In a study evaluating glycemic control in type 2 diabetic patients (T2D)20, patients receiving soy protein formula, characterized as diabetes-specific formula in the study group, had reduction in the glycated hemoglobin (HbA1c) levels and there were no significant differences in fasting blood glucose, fasting insulin, lipid parameters (triglycerides, total cholesterol, LDL and VLDL), albumin, prealbumin, C-reactive protein (CRP) and diastolic blood pressure when compared to the group receiving nutrition from animal protein source. However, the systolic blood pressure increased in the group that used casein as a protein source, while it decreased in the group that used soy. There were no differences among renal function biomarkers, creatinine and urea. In the Viall et al. [18] study, in which secondary biochemical parameters were evaluated, the same result was found: no significant change between groups in serum albumin, hemoglobin, creatinine, total lymphocyte count, alkaline phosphatase, gamma glutamyl transferase, or bilirubin values was observed during the study. The study that compared protein sources in post stroke patients [19], showed that the use of soy protein formula improved postprandial glycemic control, and postprandial capillary glucose, mean glucose and peak glucose levels after treatment were significantly lower compared to their baselines, and no significant postprandial glucose changes were observed in the patients of the group that used the casein formula after treatment [20].
Also, the fasting glucose was significantly lower with soy formula and showed no difference with the casein formula. The HOMAIR index (Homeostasis Model Assessment of Insulin Resistance) did not differ significantly between the two groups. However, the soy protein resulted in a decrease in HOMAIR, whereas no significant changes were found within the casein group. The HOMAIR index estimates the insulin resistance based on the relationship between fasting glucose and insulin levels, with higher HOMA-IR values representing a more severe insulin resistance (IR). It is an efficient method to assess insulin resistance, widely used for primary prevention and diagnosis of diabetes [21]. No significant difference was found in the incidence of hypoglycemic episodes.

Discussion
Based on the database searches, this is the first review to is then adjusted for the true protein digestibility, which represents the difference between the amount of nitrogen ingested and the excreted fecal nitrogen, which is responsible for metabolic losses [24].
However, this method does not count the excreted fecal nitrogen that is produced from the fermentation of gut bacteria, and the true fecal digestibility that is being used to calculate the PDCAAS score does not cover the whole table in terms of total digestibility [25].
This way, FAO recommended replacing the PDCAAS protein quality assessment method by DIASS [26]. The DIASS has been proposed to address the limitations of PDCAAS, the main one is that DIASS uses ileal digestibility coefficients for each amino acid instead of using true fecal nitrogen digestibility [27]. The DIAAS can provide comprehensive information on protein quality in foods [28]. Studies show that quality, rather than total protein quantity, may be more important from the point of view of human health and well-being [23][24][25][26][27]. In this review it was demonstrated that formulas with vegetable protein source, being soy the protein source used in all studies, presented similar or superior effects when compared with formulas with animal protein source, which could be demonstrated by García-Talavera Espín et al. [17] in their study, in which patients who received formula with vegetable protein source had higher prevalence of nutritional recovery. Also, to understand the relationship between muscle mass and food intake, in the study conducted with 168 elderly people with T2D was evaluated the relationship between muscle mass, through the skeletal muscle index, and the type of protein ingested and it was found that the vegetable protein intake was positively associated with increased muscle mass in elderly [28], corroborating with the study mentioned previously. The adequate intake of a variety of plant-based protein sources and necessary calories is easily achieved [29,30], and the protein requirements can be easily met even in elderly, pregnant women / infants and children31.
The soy protein has a good amino acid profile and can be considered as the main source of protein due to its protein quality, covering the nutritional needs [32,33]. The soy protein aminogram is very similar to casein, a protein source commonly used in enteral formulas [34] , which corroborates the findings of this review, where soy protein showed similar or superior results. The whey protein has higher amounts of some essential amino acids, however, there have been no reported differences in muscle protein synthesis and other outcomes for its use when compared to soy protein12.
In general, vegetable protein sources contain limited amounts of one or more essential amino acids. However, it is now recognized that, when consumed a varied of vegetable foods daily, the strict combination of proteins in the same meal is not required [30][31][32][33][34][35].
This way, in an enteral formula, all essential amino acids would be contemplated once they aim to meet the total needs of individuals.
According to a meta-analysis review study, vegetable protein incorporation is no different from animal protein in the human organism [36] and, when combined to supply all essential amino acids, vegetable proteins provide an excellent source of proteins10.
when analyzing the metabolic outcomes, it was observed that soy protein formulas provided better glycemic control. The soy protein was an important factor that contributed to reduce insulin resistance and fasting glucose demonstrating to be more effective in improving insulin sensitivity and fasting glucose concentrations in patients with T2D and metabolic syndrome than another protein source [37,38]. A possible hypothesis would be that soy protein presented better stimulation of β-cell proliferation and stimulation, and insulin secretion [39].  [45].
One of the limitations of this study is that it analyzed only the protein source of the formulas and not the total nutrient content.
Regardless the method to be used for protein quality assessment, protein quality methods that consider only the content and distribution of essential amino acids can be misleading because they represent the biological value of a single nutrient alone, not the total effects of consumption the source of this nutrient as a whole27. This review focused on proteins, as they are the subject of great debate due to their protein quality. The source of the nutrients that are part of the formula is an important aspect to be taken into consideration due to the number of individuals with restrictions, such as food allergies and intolerances, or the increased number of vegetarians, especially strict vegetarians/vegans. Interest and adherence to vegetarianism has been growing [46,47]. According to a 2016 survey, approximately 3.3% of American adults are vegetarians and about 46% of these are vegans [48]. There are many reasons that lead individuals to adopt a vegetarian diet, and, in this case, vegan patients on enteral nutrition therapy would need a formula made up of an exclusively vegetarian protein source.
Despite the limited number of studies that served as the basis for this review, this study stands out for its originality and scarcity of the subject in the literature, in addition to provide support for health professionals to prescribe safely.

Conclusion
The use of soy protein enteral formulas seems to be efficient