Review

1. 1 Research and EBP Unit, Health Professions Department, Azienda USL-IRCCS di Reggio Emilia, Via Amendola, 2-42122 Reggio Emilia, Italy; [email protected] (M.G.); [email protected] (A.F.)
2. 2 Department of Biomedicine and Prevention, University of Rome Tor Vergata, Via di Montpellier, 1-00133 Rome, Italy; [email protected] (M.T.C.); [email protected] (S.N.)
3. 3 Hematology Unit, Azienda USL-IRCCS di Reggio Emilia, Via Amendola, 2-42122 Reggio Emilia, Italy
4. 4 ASST-Azienda Socio-Sanitaria Territoriale di Mantova, Strada Lago Paiolo, 10-46100 Mantova, Italy; [email protected]
5. 5 Unit of Food Science and Nutrition, Department of Science and Technology for Humans and the Environment, University Campus Bio-Medico of Rome, Via Alvaro del Portillo, 21-00128 Rome, Italy; [email protected]
6. 6 Research Unit Nursing Science, University Campus Bio-Medico of Rome, Via Alvaro del Portillo, 21-00128 Rome, Italy; [email protected] (M.P.); [email protected] (M.G.D.M.)

* Correspondence: [email protected]; Tel.: +39-05-2229-6661; Fax: +39-05-2229-5655

Citation: Guberti, M.; Botti, S.; Capuzzo, M.T.; Nardozi, S.; Fusco, A.; Cera, A.; Dugo, L.; Piredda, M.; De Marinis, M.G. Bovine Colostrum Applications in Sick and Healthy People: A Systematic Review. Nutrients 2021, 13, 2194. https:// doi.org/10.3390/nu13072194

Academic Editor: Raymond Playford

Received: 26 May 2021 Accepted: 22 June 2021 Published: 25 June 2021

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

Abstract: Colostrum is the first secretion of mammalian glands during the early period after birth giving. Its components are biologically active and have beneficial effects on new-born growth and well-being. Bovine colostrum has the highest concentration of these substances and its supplementation or application may provide health benefits. This systematic review was conducted to update current knowledge on bovine colostrum effects including all administration routes on healthy and sick subjects. Full texts or abstracts of twenty-eight papers as reports of systematic reviews, randomized controlled trials, observational studies and case series were included after searches in Medline, Embase, Cochrane Library and Cinahl databases. The full texts of selected studies were assessed for quality using validated tools and their results were summarized in different categories. Studies were highly heterogeneous as regards to population, intervention, outcome and risk of bias. Bovine colostrum topical application was shown effective on vaginal dryness related symptoms limitation. Its use as food supplement showed interesting effects preventing upper respiratory illness in sportsmen, modulating immune system response and reducing intestinal permeability in healthy and sick subjects. Conflicting results were provided in pediatric population and little evidence is available on its use with older adults. Further studies are mandatory to better understand all factors influencing its activity.

Keywords: bovine colostrum; whey; milk; food supplementation; health improvement; physical performance; immune system; systematic review

Colostrum is the secretion produced by the mammary gland immediately following parturition; it provides to infants sustenance, enhances their protection against pathogens, ensures immune system development, and provides to growth, maturation, and repair of several tissues [1]. The composition and physical properties of colostrum are highly variable due to a number of factors, including individuality, breed, parity, pre-partum nutrition, length of the dry period of cows and time post-partum [2–6]. It differs from milk as it contains less lactose and more fat, protein, peptides, non-protein nitrogen, ash, vitamins and minerals, hormones, growth factors, cytokines and nucleotides. The composition of both human and Bovine Colostrum (BC) have been largely studied highlighting higher concentrations than mature milk of a wide variety of biologically active substances [7].

Nutrients 2021, 13, 2194. https://doi.org/10.3390/nu13072194 https://www.mdpi.com/journal/nutrients

These retain their activity while passing the gastrointestinal tract, carrying out beneficial effect on the intestinal functions [8–10] mainly attributable to immune-modulatory [11,12], antimicrobial [8,13] and anti-inflammatory [12] activities. Immunoglobulin antibodies are the main immune components of the acquired immune system present in colostrum and milk. Colostrum is characterized by its very high concentration of immunoglobulin G (IgG), which is of particular importance as it confers passive immunity to the neonate immediately following parturition [6,8,14,15]. The most abundant immunoglobulin class in bovine milk and colostrum is IgG1 [16]. In contrast, IgA and IgM are present at much reduced concentrations in bovine colostrum and milk [17]. Lactoferrin and lactoperoxidase have significant antimicrobial effects [18] and other components such as cytokines and interleukins are involved in inflammatory regulation processes and contribute to infection control also [12]. The highly glycosylated polypeptide secretory component [19] is another immune factor present in colostrum and milk that interacts with the adaptive immune system. Secretory component derived from a portion of the IgA receptor not only enhances IgA functionality when it is attached to IgA [20] but may have direct protective properties itself. Lysozyme is a lytic enzyme that plays a role in the innate immune system by attacking peptidoglycan cell constituents found primarily in gram-positive bacteria, leading to bacterial lysis [18,21]. Bovine colostrum has shown an emerging role as a food supplement due to its healing properties targeted to boost the immune systems in both healthy and chronically ill patients [1,18,22]. Colostrum has been known for centuries for its health benefits [23]. Literature also showed that the active components in BC were 100 to 1000-fold more concentrated than in human one. This means that even human infants can rely on cow or buffalo colostrum to gain health benefits [22,24]. Topical application of the colostrum constituents has proven promising for open wound healing [25]. It has been suggested that nucleotides, epidermal growth factor (EGF), transforming growth factor (TGF) and insulin like growth factor-1 (IGF-1) promote cellular and skin growth and also help in repairing DNA and RNA damage [6]. A patent has also been granted for the use of a colostrum fraction to accelerate wound healing [26]. For all these reasons, BC has found its application in the prevention and treatment of several inflammatory diseases, such as those affecting the gastrointestinal and respiratory systems of adults and children [27]. In addition, bovine colostrum derivatives have been used for the treatment of rheumatoid arthritis. Studies have shown benefits of BC supplementation in healthy populations such as children, adolescents [13] and sporting individuals, more precisely because it can boost their immune, digestive, and hormonal systems, as well as it may improve their physical performances [11]. The aim of this literature review is to assess the evidence supporting the bovine colostrum administration in clinical and not clinical settings in order to provide additional knowledge on its use and updating results of the last review on this topic [21].

1. 2.1. Search Strategy

This review updated the last one published in 2014 [21]. The PICO method (P = Population, I = Intervention, C = Control, O = Outcome) was used to make the research question. Healthy and not-healthy subjects were included in the Population frame; Interventions were administration of BC (any formulation) with the aim to improve physical performances or health; all Control formulae including placebo and no-treatment were considered while the Outcomes were undefined. A literature search was conducted within the following databases: Medline, Embase, Cochrane Library and Cinahl. The following search strategy was used in Medline and adapted to the other databases: (“Colostrum” [Mesh] OR colostrum OR colostrums) AND (bovine OR cow OR cows OR cattle), records were filtered by time frame (from 1 January 2013 to 31 December 2020), language (English) and involved subjects (Human). Reference lists of included papers were manually checked in order to find further records. Full texts papers were considered in the analysis while abstracts were discussed separately.

1. 2.2. Inclusion and Exclusion Criteria
2. 2.3. Study Selection and Quality Assessment

Study selection was performed by removing duplicates and non-relevant records, or protocols, first, on title and abstract basis and, second, after full-text reading (Figure 1). The quality assessment of the studies included was conducted with the aid of validated tools. The Effective Public Health Practice Project (EPHPP) [30] was used for clinical trials, randomized clinical trials (RCTs) and observational studies, while A Measurement Tool to Assess Systematic Reviews—2 (AMSTAR-2) [31] was used in order to assess reviews. The EPHPP is widely used in evaluating RCTs and clinical trials, with an excellent degree of inter-rating reliability [30]. This tool consists of six domains (selection bias, study design, confounders, blinding, data collection methods, withdrawals and drop-outs), whose sum of scores constitutes the overall quality rating, where (1) “strong” includes papers without weak subscale grading, (2) “moderate” includes those with at least one weak grading, and (3) “weak” includes two or more weak rating of the sub-scales. The AMSTAR-2 tool consists of 16 items with an overall rating based on weaknesses in critical domains. The overall rating is classified as “high” (No or one non-critical weakness), “moderate” (More than one non-critical weakness) “low” (One critical flaw with or without non-critical weaknesses) and “critically low” (More than one critical flaw with or without non-critical weaknesses). Quality assessment of the included papers with EPHPP and AMSTAR-2 was performed by two independent reviewers, who met to discuss and solve any discrepancies in the study evaluation or results interpretation. With the aim to intercept minimal differences in studies quality and to better define level of evidence, two additional tools were applied. The risk of bias of the included RCTs was assessed by two different independent reviewers using the Cochrane Collaboration Risk of Bias Tool (CCRBT) including the following seven domains: random sequence generation; allocation concealment; blinding of participants and personnel; blinding of outcome assessment; incomplete outcome data; selective reporting and other biases. The CCRBT is different from EPHPP as, for example, outcome reporting is evaluated more in detail than in the EPHPP, which gives no specific evaluation on absence from reporting bias [30]. Then, the level of evidence was assessed by two independent reviewers using the 2011 Oxford Centre for Evidence Based Medicine level of evidence method (OCEBM), which was developed by an international group and took into account feedback from clinicians, patients, and researchers. It allows to rapidly find the likely best evidence encouraging clinicians, researchers and patients to autonomously assess evidence [32] (Table 1).

3 of

Level 1 * Systematic review of randomized trials or n-of-1 trials

Evidence Level (Treatment Benefits)

Randomized trial or observational study with dramatic effect

Non-randomized controlled cohort/follow-up study **

Case-series, case control studies, or historically controlled studies **

Mechanism-based reasoning

* Level may be graded down on the basis of study quality, imprecision, indirectness (study PICO does not match questions PICO), because of inconsistency between studies, or because the absolute effect size is very small; Level may be graded up if there is a large or very large effect size. ** As always, a systematic review is generally better than an individual study.

1. 3.1. Paper Selection and Categorization
2. 3.2. Studies Heterogeneity

Three studies (1 RCT, 2 OS) were on topical applications of BC-based creams on various vaginal conditions and recruiting only female participants with a mean age ranged from 27 to 61 years [33–35]. Twenty-four papers (23 RCTs, 1 OS) assessed the efficacy of BC as dietary supplement in various populations [36–59], including diseased ones [47–53,55–59] and healthy people [36–46,54]. Of these papers, 1 included 3 RCTs (please, note that it is considered as one study in this review) [39], 11 recruited only sporting males with a mean age ranged from 21 to 51 years [36–46], 11 involved pediatric subjects affected by various clinical conditions [47–53,56–59], 1 was on critically ill patients and 1 on healthy elderlies. The participants involved in the 23 full texts of primary studies included received 11 different commercially available BC formulas, while one study experimented the effects of “fresh” BC [47]. In addition, BC was administered at different dosages ranging from 1 to 60 g/day in adult setting (13 RCTs) [36–46,54,55] and from 0.014 g/day to 4.5 g/kg/day in the 7 pediatric ones (7 studies) [47–53]. Colostum and placebos were administered majorly as beverages supplementing meals in clinical settings (12 studies) [47–53,55–59] and supporting physical performances or specific training programs in healthy people (12 RCTs). Refs. [36–46,54] The control groups of the 19 included full texts RCTs received 9 different placebos including isoenergetic/isomacronutrient formulas, whey or mixed milk matrix, whey protein concentrated formulas, corn flour, maltodextrin. Limited information on BC and placebo products were available by the 4 RCTs (all involving pediatric subjects) available as abstracts [56–59]. Surrogate outcomes were used in 15 studies [37–47,50,51,54,55] while 8 [33–36,48,49,52,53] assessed morbidity outcomes. The 4 abstracts measured primary outcomes. Refs. [56–59] As explained above, the included papers were very heterogeneous precluding any meta-analysis in this review.

Table 2. BC topical applications in uro-gynecology setting.

Population Number Groups Gender Mean Age

TG Size Dosage Frequency Duration

CG Size Dosage Frequency Duration

Endpoints Data Collection Tools

Adverse Events

Intervention Matrix

Control Matrix

Results OCEBM EPHPP

Authors Study Design

PE: Vaginal discomfort (VRS) SE: (1) Symptoms (VRS);

↓ Vaginal discomfort ↓ Vaginal symptoms ↑ Vaginal health Sexual function improved ↓ Sexual distress

No severe or serious AEs Mild AEs in 16.7% CG: AEs in 8.5%

TG (n = 48) 5 mL, 1–2 time per day during intermenstrual period (23 days)

No-treatment, nonactive lubricants on demand were allowed

Women with vaginal dryness. n = 95; >18 ys

1. (2) Vaginal health (VHI mean sum score);
2. (3) Sexual function (FSFI);
3. (4) Sexual distress (FSDS-R).

Nappi, R. E., et al. (2016) [33]

Monurelle Biogel®

Level 1 1

CG (n = 47)

RCT

PE: Vaginal health (VHI); SE: (1) Sexual function (FSFI); (2) Sexual distress (FSDS); (3) Urinary symptoms

↑ Vaginal health Sexual function improved ↓ Sexual distress ↓ Urinary symptoms ↓ Urogenital distress ↓ OAB symptoms ↑ QoL

Postmenopausal

Schiavi, M. C., et al. (2019) [34]

women with VVA. n = 172 mean age 60.8 ys

5 mL once daily for 12 weeks

Monurelle Biogel®

No significant AEs

Level 3 3

Retrospective

No CG No CG

1. (4) Urogenital
2. (5) Overactive
3. (6) QoL (HRQL)

Women diagnosed as CIN1. n = 256; mean age 37.7 ys

Stefani, C., et al. (2014) [35]

twice/week at bedtime for 6 months.

ORR to negative histology (Cervical cytology)

Ginedie® vaginal tablets

Retrospective

NR 75.5% ORR Level 4 3

No CG No CG

OCEBM = Oxford Centre for Evidence Based Medicine; EPHPP = Effective Public Health Practice Project; RCT = Randomized Controlled Trial; ys = years; TG = Treatment Group; CG = Control Group; PE = Primary Endpoint; SE = Secondary Endpoint; VRS = Verbal Rating Scale; VHI = Vaginal Health Index; FSFI = Female Sexual Function Index; FSDS-R = Female Sexual Distress Scale-Revised; AEs = Adverse Events; VVA = Vulvovaginal Atrophy; UDI-6 = Urogenital Distress Index-6 questionnaire; OAB-Q = Overactive Bladder Questionnaire; HRQL = Health Related Quality of Life questionnaire; QoL = Quality of Life; CIN1 = Atypical squamous intraepithelial lesions; NR = Not Reported; ORR = Overall Reduction Rate. Symbols: ↑ = increased; ↓ = decreased.

Table 3. BC as dietary supplement in the sporting population.

Population Number Groups Gender Mean Age

TG size Dosage Frequency Duration

CG Size Dosage Frequency Duration

Intervention Matrix

Control Matrix

Endpoints/Data Collection Tools

Adverse Events

Results OCEBM EPHPP

Authors Study Design

PE: (1) Incidence of URI; SE: (1) URI days;

↓ URI incidence; ↓ URI days; ↓ salivary bacterial load; No significant effects on: severity and duration of URI episodes, immune-system parameters, salivary sIgA/AMPs

Regularly exercising males n = 53; mean age 50.5 ys Colostrum (n = 25) vs. Placebo (n = 28)

1. (2) URI duration (episodes)
2. (3) Immune-
3. (4) Salivary

TG (n = 25) 20 g/day 12 weeks.

Isoenergetic/ Isomacronutrient placebo

Jones, A. W.,

CG (n = 28) 20 g/day 12 weeks.

BC (Neovite® UK, London)

Level 2 1

NR

1. et al. (2014) [36]

RCT, DB, PC

antimicrobial proprieties (sIgA/AMPs) (5) Salivary microbiome composition

Recreationally active males n = 16; mean age 25.0 ys CO after a week

Isoenergetic/ Isomacronutrient

BC (Neovite® UK, London) during 4.5 h long moderate exercise

No significant effects on IGF-1 blood levels

NR

RCT, DB, PC, CB, CO

TG (n = 16): 40 g

placebo during 4.5 h long moderate exercise

CG (n = 16) 40 g

Level 2

IGF-1 blood levels

Isoenergetic/ Isomacronutrient

BC (Neovite® UK, London) + training program

Recreationally active males n = 20; mean age 28.0 ys

TG (n = 10) 20 g/day 4 weeks

CG (n = 10) 20 g/day 4 weeks

No significant effects on IGF-1 blood levels

RCT, DB, PC

Placebo + training program

IGF-1 blood levels NR

Level 3

Davison G., et al. (2019) [39]

1

Recreationally active males n = 57; mean age NR Colostrum (n = NR) vs. Placebo (n = NR) n = 4 excluded from the analysis

Isoenergetic/ Isomacronutrient

BC (Neovite® UK, London) + training program

TG (n = 25): BC 20 g/day 12 weeks

CG (n = 28) 20 g/day 12 weeks

No significant effects on IGF-1 blood levels

RCT, DB, PC

Placebo + training program

IGF-1 blood levels NR

Level 3

Freeze-dried whole BC

Identical pouches (500 mg of dehydrated whey and 500 mg of desiccated banana) were used as the placebo.

obtained within 2 h of calf delivery (Genactiv®, Poznan, Poland) was packaged in pouches BC 500 mg and desiccated banana 500 mg.

↓ sugar absorption ↓ zonulin concentration

Gut permeability: sugar absorption test, zonulin concentration

Competitive athletic males n = 16; mean age 27.5 ys

No AEs in the TG. Mild AEs in 50% of CG

CG (n = 8) 1 g/day 20 days

TG (n = 8) 1 g/day 20 days

Halasa, M., et al. (2017) [40]

Level 3 1

RCT, DB, PC

isoenergetic/ isomacronutrient

↓immune sensitivity decreasing after prolonged exercise No significant effects on in-vivo immune responsiveness, IGF-1 blood levels, Immune cell counts and other biochemical parameters

BC + water + training program Day 28: 2 h of 60% maximal aerobic capacity and immune system sensitisation Day 56: elicitation of immunity

Recreationally active males n = 34; mean age NR Colostum (n = 17) vs. Placebo (n = 17) n = 3 excluded from the analysis

Placebo + training program Day 28: 2 h of 60% maximal aerobic capacity and immune system sensitisation Day 56: elicitation of immunity

PE: Cell mediated response following prolonged exercise (skinfold reactivity) SE: (1) IGF-1 blood levels

TG (n = 15) 20 g/day 58 days.

Jones, A. W., et al. (2019) [38]

CG (n = 16) 20 g/day 58 days

RCT, DB, PC

NR

Level 2 1

1. (2) Immune cell counts
2. (3) Biochemical parameters

Beneficial in vitro effects on receptordependent (fMLPstimulated) oxidative burst responses. No in vitro effect on PMAstimulated oxidative burst, sIgA and AMP. No effects on leukocyte trafficking and other biochemical parameters

PE: (1) In-vitro blood neutrophil function: fMLP and PMA (2) Mucosal responses: sIgA and AMP SE: (1) Circulating cells count (2) Biochemical parameters

Recreationally active males n = 20, mean age 28.0 ys

TG (n = 10) 20 g/day 4 weeks

isoenergetic/ isomacronutrient Placebo

Jones, A. W.,

CG (n = 10) 20 g/day 4 weeks

BC (Neovite® UK, London)

Level 2 1

NR

1. et al. (2015) [37]

RCT, DB, PC

Commercial BC 378 Kcal, 67 g protein, 17 g carbohydrates and 4.7 g fat per 100 g Pre and post supplementation LIST exercise program

Commercial whey protein 369 Kcal, 90 g protein, 1 g carbohydrates and 0.5 g fat per 100 g Pre and post supplementation LIST exercise program

↓ RTD decline in both groups without significant difference

Soccer players n = 22; mean age 21.1 ys

TG (n = 11) 3.2 g/day 6 weeks.

CG (n = 11) 3.2 g/day 6 weeks.

Kotsis, Y., et al. (2019) [42]

Post-LIST RTD reduction

RCT, DB, PC

NR

Level 3 1

Commercial whey protein 369 Kcal, 90 g protein, 1 g carbohydrates and 0.5 g fat per 100 g Pre and post supplementation LIST exercise program

Commercial BC 378 Kcal, 67 g protein, 17 g carbohydrates and 4.7 g fat per 100 g Pre and post supplementation LIST exercise program

↑ SQJ, CRP, CK, IL-6 recovery. No significant differences on MIVC, CMJ, PMS and other outcome

Soccer players n = 22; mean age NR n = 4 excluded from the analysis

CG (n = 8) 3.2 g/day 6 weeks + 4 days

EIMD: MIVC, SQJ, CMJ, PMS, biochemical parameters

TG (n = 10) 3.2 g/day 6 weeks + 4 days

Kotsis, Y., et al. (2018) [41]

Level 2 1

NR

RCT, DB, PC

Regularly exercising males n = 12; mean age 26 ys Colostrum (n = 12) vs. Placebo (n = 12) CO after 2 weeks of washout

CG (n = 12): Isoener-

↓ I-FABP plasma concentration after exercise No effects Bacterial DNA plasmatic concentration No significant differences on other outcome

PE: Exercise-induced intestinal cell damage (I-FABP) SE: (1) Bacterial translocation (plasmatic bacterial DNA) (2) Other physical parameters

TG (n = 12):

BC 20 g/day for 14 days Exercise program 70% aerobic capacity for 1 h

getic/Isomacronutrient

placebo for 14 days Exercise program 70% aerobic capacity for 1 h

March, D. S., et al. (2018) [43]

BC (Neovite® UK, London)

RCT, DB, PC, CO

Level 2 1

NR

Trained and Untrained males n = 28

BC (Hokitika, New Zealand) protein, 58.2% m/m; fat, 1.4% m/m; lactose, 29.3% m/m; and IgG, 15.3%. Before 90 min multi-mode exercise session

PE: GI permeability (Double sugar model, I-FABP) SE: (1) cytokine level and other blood parameters (2) thermal and cardiovascular measures (3) Other parameters

CG (n = 7 trained, n = 8 untrained): corn flour placebo for 7 days before 90 min multi-mode exercise session

(14 trained, 14 untrained) Colostrum (n = 14) vs. Placebo (n = 14) n = 13 (6 untrained, 7 trained) lost and excluded from the analysis CO time NR

↑ I-FABP in trained group No significant differences on other outcome

TG (n = 7 trained, n = 8 untrained): BC 1.7 g/kg/day for 7 days

Morrison, S. A., et al. (2014) [45]

RCT, DB, PC, CO

Corn flour placebo

No AEs

Level 3 1

PE: (1) BBB permeability (S100ß protein, cerebral oxygenation) (2) Cognitive function (Stroop test and perceptions) SE: (1) thermal and cardiovascular measures (2) Other parameters

BC (Hokitika, New Zealand) protein, 58.2% m/m; fat, 1.4% m/m; lactose, 29.3% m/m; and IgG, 15.3%. Before 90 min multi-mode exercise session

Healthy males n = 15 (7 highly-fit, 8 moderatelyfit); mean age 22 ys

TG (n = 7 highly fit, n = 8 moderatelyfit) 1.7 g/kg/day 7 days

CG (n = 7 highly fit, n = 8 moderately fit) 1.77 g/kg/day 7 days

No effects on BBB, cognitive and physical performance

Morrison, S.

RCT, DB, PC, CO

Corn flour placebo

Level 3 1

1. A., et al. (2013) [44]

NR

↑ testosterone concentration maintenance ↑ cortisol concentration before the race

Whey protein concentrate (Alacen® 80” Fonterra Co-op Group Limited, Auckland, New Zealand) before and during a 5 days cycling race

Intact® bovine CPC (Numico Research Australia Pty Ltd., South Australia) before and during a 5 days cycling race

PE: hormonal (salivary hormones level), immune (salivary IgA) and autonomic (parasympathetic indices of HRV) response SE: Mood profile (POMS)

Highlytrained males n = 10; mean age NR CPC (n = 4) vs. WPC placebo (n = 6)

↑ parasympathetic indices of HRV No significant differences on cortisol concentration during race, POMS and salivary IgA concentration

TG (n = 4) 10 g/day for 8 weeks + 5 days

CG (n = 6) 10 g/day for 8 weeks + 5 days

Shing, C. M., et al. (2013) [46]

RCT, DB, PC Pilot study

NR

Level 3 1

OCEBM = Oxford Centre for Evidence Based Medicine; EPHPP = Effective Public Health Practice Project, RCT = Randomized Controlled Trial; DB = Double Blind; PC = Placebo Controlled; CB = Conterbalanced; CO = Crossover; ys = years; TG = Treatment Group; BC = Bovine Colostrum; CG = Control Group; PE = Primary Endpoint; URI = Upper Respiratory Illness; IGF-1 = Insulin like Growth Factor 1; sIgA = salivary Immunoglobulin A; AMP = Anti-Microbial Peptides; SE = Secondary Endpoint; NR = Not Reported; AEs = Adverse Events; fMLP = formylmethionyl-leucyl phenylalanine; PMA = phorbol-12-myristate-13-acetate; LIST = Loughborough Intermittent Shuttle Test; RTD = Rate of Torque; EIMD = Exercise Induced Muscle Damage; MIVC = Maximum Isometric Voluntary Contraction; SQJ = Squat Jump; CMJ = Countermovement Jump; PMS = Perceived Muscle Soreness; CRP = C-Reactive Protein; CK = Creatin Kinase; IL-6 = Interleukin-6; I-FABP = Intestinal Fatty Acid Binding Protein; BBB = Blood Brain Barrier; CPC = Colostrum Protein Concentrate; WPC = Whey Protein Concentrate; HRV = Hearth Rate Variability; POMS = Profile Of Mood States questionnaire. Symbols: ↑ = increased; ↓ = decreased.

Table 4. BC as dietary supplement in the pediatric and preterm infants.

Population Number Groups Gender Mean Age

TG size Dosage Frequency Duration

CG Size Dosage Frequency Duration

Intervention Matrix

Control Matrix

Endpoints/Data Collection Tools

Adverse Events

Results OCEBM EPHPP

Authors Study Design

No significant differences in intestinal energy and wet weight absorption, knemometry, IGF-1, IGF-BP3 levels

“Fresh” BC from 15 different cows (Danish Holstein) within the first 24 h after calving

PE: Nutrients and Fluid balances SE: Anthropometric, knemometry, biological parameters

Children with SBS n = 9 (4 females,

Mixed milk, cream, and whey protein

Aunsholt, L., et al. (2014) [47]

CG (n = 9) 20% of BFR

TG (n = 9) 20% of BFR

RCT, DB, PC, CO, PS

Level 2 1

NR

5 males); median age 39 months CO after 4 weeks washout

No significant differences in NEC, sepsis and mortality. ↑IL-6 and radiological features of NEC in TG

VLBW Neonates n = 86; chronological age < 96 h Colostrum (n = 43) vs. Placebo (n = 43)

CG (n = 43) 1.2–2.0 g/die + feeding 4 times a day 21 days

TG (n = 43) 1.2–2.0 g/dose + feeding 4 times a day 21 days

PE: NECSE: sepsis, mortality and stool interleukin-6 (IL-6) levels

BC Pedimmune® (Mumbai, India)

Equal dose placebo (not specified)

Balachandran,

RCT, DB, PC, PS

Level 2 1

1. B., et al. (2016) [48]

No AEs

PE: Diarrhea frequency and duration, vomiting duration SE: fever duration and Vesikari scoring

↓ Diarrhea and vomit frequency and duration ↓ Vesikari Scoring after 48 h

ImmuGuard®, sachets (London, England)

Pediatrics with acute diarrhea n = 160; aged 6 months to 2 ys

TG (n = 80) 3 g/sachet + standard therapy

Equal dose pla-cebo (not speci-fied)

CG (n = 80)

Barakat et al. (2019) [49]

RCT, DB, PC

+ standard therapy

NR

Level 2 1

1 death for NEC not related to BC intake Late onset sepsis (2 TG, 1 CG), pulmonary dysplasia (1 TG), ROP (2 TG), metabolic acidosis (2 TG) No significant differences

↑ protein intake in TG (China group) ↑ in TG Temporary elevation in plasmatic tyrosine levels on day 7 No significant differences on dietary intolerances and other outcomes

NPI n = 40; gestational age 27–32 weeks Country stratification (ChinaDenmark)

Unmodified intact BC powder (ColoDan®; Gesten, Denmark) as supplement of MM, DM or IF

TG (n = 21) max 4.5 g/kg/day 10–14 days

PE: Tolerability and safety SE: nutritional outcomes

Meinich Juhl,

Standard feeding with MM, DM or IF

CG (n = 19) 10–14 days

Level 3 2

S., et al. (2018) [50]

RCT, OL, PS

Population Number Groups Gender Mean Age

TG size Dosage Frequency Duration

CG Size Dosage Frequency Duration

Intervention Matrix

Control Matrix

Endpoints/Data Collection Tools

Adverse Events

Results OCEBM EPHPP

Authors Study Design

IgA deficient paediatrics with viral URI n = 31; median age 8.5 ys; n = 18 males and 13 females Colostrum (n = 16) vs. Placebo (n = 15)

BC sucking tablet that contains 14 mg of colostrum and 2.2 mg of lysozyme (Igazym®; Vejle, Denmark)

No AEs

No significant differences in sIgA secretion ↓infection severity score in BC after 1 week

1. 1 patient included
2. 2 times and 1 included 3

Patırog˘lu, T. and M. Kondolot

TG (n = 16) 3 times a day 1 week

CG (n = 15) 3 times a day for 1 week

PE: sIgA SE: Infection severity

placebo sucking tablets

Level 2 1

RCT, DB, PC

time for different infections

(2013) [51]

PE: fever level and duration.SE: CRP levels, neutrophil count, bacteraemia or fungaemia episodes, treatment delay, mucositis severity, PROs on chemotherapy toxicity, compliance

Pediatrics with ALL n = 62, aged 1–18 ys n = 32 males and 30 females Colostrum (n = 30) vs. Placebo (n = 32)

↓ Peak severity of oral mucositis No significant differences on PE and other SE, low compliance reported

Isocaloric placebo. whole-milk powder enriched with whey protein isolate powder

Intact, spray-dried BC powder (Gesten, Denmark®).

TG (n = 30) 0.5–1 g/kg/day 4 weeks

RCT, DB, PC Multicentre study

Rathe, M., et al. (2020) [52]

CG (n = 32) 4 weeks

Level 2 1

No AEs

Mild transient AEs reported in 12 patients: Skin rush (9), itching (1), and diarrhea (2). 6 patients discontinued the BC treatment.

Children with recurrent acute URI or diarrhea due to infection n = 160; aged 1–6 ys. n = 81 males and 79 females

URI or diarrhea episodes and frequency of hospitalizations Follow up period 24 weeks

↓ Infection episodes at 2 and 6 months ↓ Hospitalizations

ImmuGuard®, sachets (London, England)

Cohort Prospective Multicentric

TG n = 160

Saad, K., et al. (2016) [53]

Level 3 3

1. 3 g/sachet
2. 4 weeks.

No CG No CG

OCEBM = Oxford Centre for Evidence Based Medicine; EPHPP = Effective Public Health Practice Project, RCT = Randomized Controlled Trial; DB = Double Blind; PC = Placebo Controlled; CO = Crossover; PS = Pilot Study; SBS = Short bowel syndrome; ys = years; TG = Treatment Group; BC = Bovine Colostrum; BFR = Basal Fluid Requirement; CG = Control Group; PE = Primary Endpoint; IGF-1 = Insulin like Growth Factor 1; IGF-BP3 = Insulin like Growth Factor Binding Protein 3; VLBW = Very Low Birth Weight; NEC = Necrotizing Enterocolitis; OL = Open Label; NPI = Newborn Preterm Infants; MM = Mother Milk; DM = Donor Milk, IF = Infant Formulae; ROP = Retinopathy of Prematurity; URI = Upper Respiratory Illness; sIgA = salivary Immunoglobulin A; ALL = Acute Limphoblastic Leukemia; CRP = C-Reactive Protein. Symbols: ↑ = increased; ↓ = decreased.

Table 5. BC as dietary supplement in healthy older adults.

Population Number Groups Gender Mean Age

TG Size Dosage Frequency Duration

CG Size Dosage Frequency Duration

Intervention Matrix

Control Matrix

Endpoints/Data Collection Tools

Adverse Events

Results OCEBM EPHPP

Authors Study Design

↑ leg press strength ↓ bone resorption No differences in body composition, muscle thickness and other outcomes

PE: Body composition and strength SE: Muscle thickness, serum assessment, bone resorption, cognitive function

spray-dried BC (Eterna Gold®, Saskatoon, Canada) + resistance training program

Mildmoderate GI AEs was reported by 5 participants (2 in TG, 3 in CG)

whey placebo (Cereal®, Illinois, US) + resistance training program

CG (n = 21): 38 g/day WP complex (60 g total) for 8 weeks

Older adults n = 40; mean age 59 ys n = 15 males and 25 females

TG (n = 19) 60 g/day of BC 8 weeks

Duff, W. R., et al. (2014) [54]

Level 2 1

RCT, DB, PC

OCEBM = Oxford Centre for Evidence Based Medicine; EPHPP = Effective Public Health Practice Project, RCT = Randomized Controlled Trial; DB = Double Blind; PC = Placebo Controlled; ys = years; TG = Treatment Group; BC = Bovine Colostrum; CG = Control Group; WP = Whey Protein; PE = Primary Endpoint; SE = Secondary Endpoint; GI = Gastrointestinal; AEs = Adverse Events. Symbols: ↑ = increased; ↓ = decreased.

Table 6. BC administration in critically ill patients.

Population Number Groups Gender Mean Age

TG Size Dosage Frequency Duration

CG Size Dosage Frequency Duration

Intervention Matrix

Control Matrix

Endpoints/Data Collection Tools

Adverse Events

Authors Study Design

Results OCEBM EPHPP

↓ Plasmatic endotoxin and zonulin concentrations at day 10. ↓ Diarrhea No significant differences in other comparisons

ICU patients n = 70; mean age 62 ys Colostrum (n = 35) vs. Placebo (n = 35) n = 8 not included in the analysis

PE: Intestinal permeability (plasmatic endotoxin and zonulin) SE: mortality, LOS, GI complications

CG (n = 30): Isocaloric maltodextrin + enteral feeding for 10 days

TG (n = 32): BC 20 g/day + enteral feeding for 10 days

Eslamian, G., et al. (2019) [55]

ENTERA Meal®; (Tehran, Iran)

Neovite ® (London, UK).

RCT, DB, PC

No AEs

Level 2 1

OCEBM = Oxford Centre for Evidence Based Medicine; EPHPP = Effective Public Health Practice Project, RCT = Randomized Controlled Trial; DB = Double Blind; PC = Placebo Controlled; ICU = Intensive Care Unit; ys = years; TG = Treatment Group; BC = Bovine Colostrum; CG = Control Group; WP = Whey Protein; PE = Primary Endpoint; SE = Secondary Endpoint; LOS = Length of Stay; GI = Gastrointestinal; AEs = Adverse Events. Symbol: ↓ = decreased.

Table 7. Abstracts on BC clinical applications.

Population Number Groups Gender Mean Age

Interventions Dosage Frequency Duration

Control Dosage Frequency Duration

Endpoints Data Collection Tools

Authors Study Design

Adverse Events Results OCEBM

Pediatrics undergoing chemotherapy for ALL n = 21; aged 6 months to 18 ys

TG (n = NR): BC twice a day for a week from the first day of chemotherapy

CG (n = NR) Placebo twice a day for a week from the first day of chemotherapy

Caysido et al. (2017) [56]

PE: neutropenia (CBC, ANC)

No AEs ↑ ANC, WBC and

RCT, DB, PC

Level 5

PLT blood levels

Pediatrics with acute diarrhea n = 160; aged 6 months to 2 ys

Diarrhea stopped

PE: n◦ of patients with diarrhea after 72 h

TG (n = 80) BC 3 g/day for 1 week

Barakat, S., et al. (2019)b [57]

CG (n = 80) placebo for 1 week

in 65% of TG vs. 95% of CG after 72 h

RCT, DB, PC

NR

Level 5

CG (n = NR) micronutrient sprinkles twice a day 30 days

↓ fecal MPO and reg1B No significant differences in other parameters

TG (n = NR) 7 g of PTM202 twice a day 30 days

PE: EED (fecal MPO, fecal Reg 1B, serum CRP, serum sCD14, and L:M

Infants (income country) n = NR; 6 to 9 months

Donowitz, J., et al. (2019) [58]

RCT, PC

NR

Level 5

↓ nasal congestion (TNSS) and lung function in monosensitized subjects ↑ ACT and CASI scores in polysensitized subjects

PE: Symptoms improvement (TNSS, ACT, CASI and pulmonary function test)

Pediatrics with respiratory allergies n = 38; aged 7 to 18 ys

CG (n = 19) Placebo 1000 mg day 3 months

Oloroso-Chavez, K., et al. (2017) [59]

TG (n = 19) BC 1000 mg day 3 months.

RCT Subgroup analysis

NR

Level 5

OCEBM = Oxford Center for Evidence Based Medicine; RCT = Randomized Controlled trial; DB = Double Blind, PC = Placebo Controlled, ALL = Acute Lymphoblastic Leukemia; ys = years; TG = Treatment Group; NR = Not Reported; BC = Bovine Colostrum; CG = Control Group; PE = Primary Endpoint; CBC = Complete Blood Count; ANC = Absolute Neutrophil Count; AEs = Adverse Events; WBC = White Blood Cells; PLT = Platelets; PTM202 = Nutritional Supplement with Bovine Colostrum; EED = Environmental Enteric Dysfunction; MPO = Myeloperoxidase; Reg 1B = Regenerating Gene 1B; sCD14 = plasma soluble CD14; CRP = C-Reactive Protein; L:M = Lactulose Mannitol ratio; TNSS = Total Nasal Symptoms Score; ACT = Asthma Control Test; CASI = Composite Asthma Severity Index. Symbols: ↑ = increased; ↓ = decreased.

Table 8. Systematic reviews on BC clinical applications.

n of Paper Included Heterogeneity n of Participants

Bovine Colostrum Effects Measured

Authors Study Design

Evidence Adverse Events OCEBM AMSTAR 2

1. - Evidence suggests that BC protect GI tract from NSAID (short period) induced injuries
2. - Evidence suggests that BC may reduce microbial translocation across the gut mucosa in patients undergoing abdominal surgery
3. - Evidence suggests that BC can effectively ameliorate HIV-associated diarrhea
4. - Contradictory evidence are shown on the effects of bovine colostrum on sports performance, body composition, and nutrient absorption
5. - Not conclusive evidence are available on the effects of colostrum on immunity
6. - Evidence suggests that BC triggers immunological events followed by systemic ones
7. - No evidence of a marked effect on intestinal function has been documented in SBS patient
8. - Inconclusive evidence of benefit of BC on thrive failures and on metabolic control of type II diabetes
9. - Evidence of no effect of BC supplementation on clinical outcomes
10. - Evidence of no significant effect of BC on irritable bowel syndrome

1. - NSAID and surgery induced GI toxicity (2 RCT—n = 122 participants)
2. - HIV associated diarrhea and immunosuppression (1 CSS, 3 OBS, 1 RTn = 182 participants)
3. - Sports nutrition and exercise (12 RCT, 1 NRT, 1 OBS—n = 370 participants)
4. - Immune functions in sport and exercise (9 RCT; 1 NRT—n = 244 participants)
5. - Infection and immune responses (10 RCT, 1 OBS—n = 1090 participants)
6. - SBS (2 RCT—n = 21 participants)
7. - Growth and metabolic
8. - Disorders (1 RCT, 1 OBSn = 138 participants)
9. - Juvenile idiopathic arthritis (1 RCTn = 30 participants)
10. - Chronic pain syndrome and irritable bowel syndrome (1 RCT, 1 CSS—n = 114 participants)

49 record covering 51 studies High heterogeneity: settings, methodologies, treatment/placebos preparations and dosages, population, diseases, endpoints and outcomes 2326 participants

No serious AEs Mild/moderate AEs were reported: unpleasant taste, nausea, flatulence, diarrhea, skin rash, and unspecified abdominal discomfort. Nine studies reported an absence of side effects.

Rathe, M., et al. (2014) [21] Systematic review

Level 1 HIGH

OCEBM = Oxford Centre for Evidence Based Medicine; AMSTAR 2 = A Measurement Tool to Assess Systematic Reviews 2; NSAID = Nonsteroidal anti-inflammatory drug; GI = Gastrointestinal; RCT = Randomized Controlled Trial; HIV = Human Immunodeficiency Virus; CSS = Cross Sectional Study; OBS = Observational Study; RT = Randomized Trial; NRT = No Randomized Trial; SBS = Short Bowel Syndrome; BC = Bovine Colostrum; AEs = Adverse Events.

Table 9. CCRBT bias assessment.

icipants and Personnel (Performance Bias)

Outcome Assessment (Detection Bias)

equence Generation (Selection Bias)

lete Outcome Data (Attrition Bias)

ion Concealment (Selection Bias)

tive Reporting (Reporting Bias)

Other Bias

1. 3.3. BC Topical Applications in Uro-Gynecology Setting

BC was used as component of topical ointments in the treatment of different vaginal conditions (Table 2). Nappi et al. [33] studied the efficacy of a BC-based gel cream (Monurelle Biogel®) on Vaginal Dryness (VD) of 95 women randomized in two groups, patients in the Treatment Group (TG; n = 48) received BC gel during the intermenstrual period (23 days) versus no treatment in the Control Group (CG; n = 47). Clinical success was defined as the reduction of the vaginal discomfort of at least 1 point on a 5 points Verbal Rating Scale after the treatment period. Vaginal symptoms were significantly decreased in TG (92.7% vs. 63.6%; p = 0.002). Assessing vaginal health, significant improvements of the Vaginal Health Index (VHI) scores were obtained in TG than CG (4.4 ± 2.6 vs. 1.2 ± 1.9; p < 0.001), as well as the sexual function evaluated by the Female Sexual Function Index (FSFI) (p < 0.032). No differences were on Female Sexual Distress Scale-revised (FSDS-R) scores (p = 0.16). The same product was used daily for 12 weeks in a large retrospective cohort (n = 172) of women (mean age 61 years) with Vulvo-Vaginal Atrophy (VVA) [34]. In this study VHI mean scores were improved from 12.5 ± 3.67 at baseline to 19.3 ± 3.49 after treatment (p < 0.001), FSFI scores from 21.64 ± 2.99 to 28.16 ± 1.93 (p < 0.001) and FSDS scores decreased from 20.52 ± 5.90 to 8.15 ± 4.18 (p < 0.001). The effectiveness of BC-based

vaginal tablets (Ginedie®) on Cervical Intraepithelial Neoplasia low grade lesions (CIN1) caused by the Human Papilloma Virus (HPV) was retrospectively assessed in a large group (n = 256) of patients (mean age 38 years) [35]. After 6 months of treatment (twice a week night time) 71% of cases were histologically negative while in 27% CIN1 histology was confirmed and in 2% the evolution to CIN2 was observed.

1. 3.4. BC as Dietary Supplement in the Sporting Population

Eleven double blinded placebo controlled randomized trials reports were included in this category [36–46]. One of them included three RCTs [39] and 3 trials adopted a crossover design [39,43,45]. These trials recruited only male subjects (n = 289; range 10–57 participants; mean age range 22–51 years) at various level of training including regularly/recreationally trained people (7 RCTs) [36–39,43–45] and highly trained ones such as cyclists, soccer players and professional fighters (4 RCT) [40–42,46]. Desiccated BC and placebo formulations were administered to the participants within beverages. The dosages varied among studies from 1 to 60 g/day as well as the exposition duration was variable from 4.5 h to 12 weeks. The majority of control groups (n = 5) received isoenergetic and isomacronutrient placebo [36–39,43]; whey proteins (n = 4) [40–42,46] and corn flour (2) were also used. In 3 trials, BC and placebo were administered as dietary supplement [36,37,40] without other variables modification while in 8 studies were associated to various exercise programs. These programs differed between them for intensity and duration [38,39,41–46]. In one study BC was associated to desiccated banana [40] and in another one was administered as colostrum protein concentrate [46]. A wide heterogeneity was present regarding assessed outcomes. The efficacy of BC preventing Upper Respiratory Illnesses (URI) were evaluated by one trial [36] (53 participants; mean age 51 years) that reported significant difference between groups on URI incidence (0.4 ± 0.7 vs. 0.8 ± 0.7; p = 0.03) after 12 weeks of treatment and a significantly lower proportion of URI duration (days) (0.05 vs. 0.09; p < 0.001). One study including 3 RCTs reported findings on safety [39] measuring IGF-1 blood level variations after assumption of 40 g of BC during 4.5 h of moderate exercises (n = 16 participants), and then after 4 (n = 20) and 12 weeks (n = 57) of 20 g/day supplementation. No significant changes (per study group and per time) were reported. The gut permeability was assessed by 3 RCTs [40,43,45]. BC was more effective than placebo reducing sugar absorption (p = 0.01) and zonulin stool concentration (p = 0.03) after 20 days of supplementation in 16 athletic males during competitive period [40]. In a crossover trial (n = 20), Intestinal Fatty Acid Binding Protein (I-FABP) plasmatic level increasing were significantly less (p = 0.015 and p = 0.019 at the end and 1 h after exercises respectively) in treatment group of regularly exercised males undergoing study specific exercise program (heat condition) after 14 days of BC supplementation (20 g/day) [43]. The same outcome was evaluated in another RCT recruiting 57 trained and untrained subjects supported for 7 days with BC or placebo at 1.7 g/kg/day [45]. Immediately after the study exercise, I-FABP blood levels significantly increased than baseline in both groups (p < 0.001), but higher values were in trained group compared with untrained one (p = 0.006). Two RCTs by Jones et al. [37,38] (n = 34, n = 20, respectively) evaluated the effects of BC on immune response. BC supplementation (20 g/day) for 58 days blunted immune response attenuation due to physical activity and increasing immune sensitivity at 24 h (p < 0.001) and at 48 h (p = 0.023). No significant effects on in-vivo immune responsiveness, IGF-1 blood levels, immune cell counts [37]. Improved attenuation of the decline in formyl-Methionyl-Leucyl-Phenylalanine (fMLP) stimulated oxidative burst response in a model of exercise-induced immune dysfunction after 4 weeks of BC administration (20 g/day) was showed in a little placebo controlled trial (10 subjects per arm) (p < 0.05). No significant effects on other receptors or on mucosal barrier function were observed [38]. The effects of BC (3.2 g/day for 6 weeks) on muscular health and performance maintaining were studied in two trials [41,42] involving 44 soccer players (22 per RCT) undergone the Loughborough Intermittent Shuttle Test (LIST). The decline of rate of torque was reduced in both groups (intervention and placebo) without significant difference as well as no

difference resulted by maximum isometric voluntary contraction, countermovement jump and perceived muscle soreness comparisons. Some beneficial effects were showed on faster recovery of squat jump performance and of some biochemical parameters. The effects of BC on blood brain barrier (BBB) permeability and cognitive function (CF) were assessed by one trial [44] recruiting 15 trained and untrained men in a crossover design study. BC and placebo were administered for 7 days at 1.7 g/kg/day before a 90 min exercise program in heat conditions. No significant results were obtained. Significant differences were showed in a pilot study by Shing et al. [46] on hormonal and autonomic response of cyclists assigned to BC (n = 4) supplementation (10 g/day over 8 weeks of colostrum protein concentrate) than placebo (whey protein concentrate) (n = 6). Table 3 summarize further information on this category.

1. 3.5. BC as Dietary Supplement in Pediatrics and Preterm Infants

Six RCTs and 1 OS were in this category, all of them exploring the effects of BC administration as dietary supplement (Table 4) [47–53]. Five RCTs were double blinded placebo controlled [47–49,51,52] while 1 was controlled versus standard practice without blinding [50]. The studies recruited 548 patients (RCTs n = 388, OS n = 160), 290 males and 258 females including toddlers [47,53], newborns [48], infants and toddlers [49], preterm newborns [50], any children [51,52]. Seven different diseased populations were involved in the 7 studies: Short Bowel Syndrome (SBS) [47], Very Low Birth Weight (VLBW) newborns [48], acute diarrhea and vomit [49], preterm newborns [50], IgA deficient children [51], Acute Lymphoblastic Leukemia (ALL) [52], recurrent acute URI or diarrhea [53]. BC was administered within beverage (various powder formulas) in 5 studies [48–50,52,53], sucking tablets in 1 [51] and as “fresh product” in the study by Aunsholt et al. [47] It was administered at various dosages ranging from 14 mg to 4.5 g/kg/day and following different protocols (from

1. 1 to 12 weeks, from 1 to 4 time per day) based on ageing, underlying diseases, nutritional needs and study protocols. Aunsholt et al. studied the supplementation with BC (versus milk mixed matrix) of 20% of the Basal Fluid Requirement (BFR) in children (n = 9) affected by SBS. A crossover designed RCT was performed. The lack of significant differences among groups on energy (p = 1) and wet weight absorption (p = 0.93) suggested that BC dietary supplementation did not improve intestinal function in these patients [47]. Balachandran et al. evaluated the efficacy of BC in a pilot study comparing BC (1.2–2.0 g/dose, 4 time/day for 21 days) and placebo in 86 VLBW neonates. No significant differences on incidence of Necrotizing Enterocolitis (NEC), sepsis and mortality were found between groups (p = 0.4, p = 0.4, p = 1 respectively). However, a trend toward a higher incidence of NEC in BC group was showed (9.3% vs. 2.1%, RR = 4.31, 95% CI = 0.42–105.82) [48]. An RCT recruited 160 children (6 months-2 years) with acute diarrhea [49] randomizing them to receive BC (3 g/day for 1 week) or placebo in addition to standard therapy. After 48 h, the BC group had a significantly lower frequency of vomiting, diarrhea, fever and Vesikari scoring compared with the placebo group (p < 0.001, p = 0.001, p < 0.001, p < 0.001, respectively). Significant results on number of children with diarrhea were reported after 72 h and 7 days (35% vs. 94%, p < 0.001; 0% vs. 12.5%, p = 0.001 respectively) suggesting beneficial effects of BC supplementation in this population. Tolerability and safety of BC (max 4.4 g/kg/day for 10–14 days) in addition to standard feeding (mother milk, donor milk or infant formula) versus standard feeding alone were studied on 40 preterm neonates [50]. A number of Adverse Events (AEs) without significant differences between groups were reported by this study, including 1 death (NEC not related to colostrum supplementation), 3 sepsis, 1 bronchopulmonary dysplasia, 2 retinopathies, 4 intraventricular hemorrhages. No significant differences in dietary intolerances were reported. No significant difference in salivary IgA secretion was reported in a RCT involving 31 IgA deficient patients who received BC 14 mg + lysozyme 2.2 mg sucking tablets 3 time per day for 1 week [51]. Rathe et al. in a multicenter RCT recruited 62 pediatric patients affected by ALL (age range 1–18 years) [52]. Patients were randomized to receive a BC or an isocaloric placebo (0.5–1 g/kg/day) during 4 weeks of chemotherapy treatment. Data on fever level

1. and duration, bacteriemia episodes, mucositis severity and biochemical parameters were collected. Severity of oral mucositis (peaks) resulted significantly reduced in BC group (p = 0.02); however, BC did not show any effects on fever, infections and other outcomes. A large cohort prospective multicenter study by Saad et al. enrolled 160 children (81 males, 79 females) between 1 and 6 years with recurrent infectious URI or diarrhea [53]. The cohort was supplemented for 4 weeks with 3 g/day of BC. Reduction of infection episodes were observed at 2 and 6 months follow up (mean 8.6 ± 5.1 baseline vs. 5.5 ± 1.2 after
2. 2 months; p < 0.001 vs. 5.7 ± 1.6 after 6 months; p < 0.001) and the reduction of hospitalization frequency was reported (p < 0.001). Further details on included study of this category were in Table 4.

1. 3.6. BC as Dietary Supplement in Healthy Older Adults
2. 3.7. BC Administration in Critically Ill Patients
3. 3.8. Abstracts on BC Clinical Applications
4. 3.9. Systematic Reviews on BC Clinical Applications

Table 8 summarize the results provided by the last systematic review on clinical applications of BC (enteral intake only).

Three included studies considered different BC topical applications in uro-gynecology setting [33–35]. VD was often associated with a genitourinary syndrome, leading to sexual dysfunction and poor quality of life of affected women; the vaginal gel formulation (Monurelle Bio-gel®) used in two studies included in this review [33,34] showed characteristics similar to the physiological vaginal secretions creating a conducive to natural lubrication environment. Considering the high patients’ compliance and the lack of AEs reported by these studies, very encouraging results were found on vaginal and sexual health as well as urinary symptoms. Despite these findings were available by one RCT

alone without blinding strategies, the reviewer considered robust its results attributing high level of evidence supporting the use of this formulae to reduce VD symptoms in young women (OCEBM and EPHPP level 1 evidence). In elderly women this approach seemed to be effective managing VD due to vaginal atrophic issues [34]. However, weak evidence (Table 2) may be provided in this population and these findings should be confirmed by well-designed RCTs. The immune-stimulatory and nutritive functions of topical application of BC could have a positive effect in the management of CIN1 lesions [35]. However, the level of evidence provided on this topic (OCEBM 4 and EPHPP 3) should be improved with randomized controlled studies. The humectant, moisturizing, re-epithelizing, antioxidant and immune-stimulant activities of BC were effective improving vaginal health and reducing sexual distress in women affected by VD conditions. Furthermore, the topical use of BC appeared safe and inexpensive. Further well-designed studies such as randomized controlled trials should be conducted to increase the level of evidence of the results on CIN1 and to explore the effects of BC topical applications in other conditions.

Bovine colostrum was used as dietary supplement in the sporting population. The studies included explored the benefits of BC as natural sporting nutritional supplement on subjects’ well-being and physical performances [36–46]. Jones et al. [36], used BC as a nutritional supplement to boost immunity and reduce the risk of URI in athletes. The study showed that BC supplementation limited salivary bacterial load and reduced URI more significantly than placebo supplements. Some selection bias-related concerns (Table 9) and the characteristics of the sample (only males) limited the level of evidence provided by this study. As reported by Rathe et al. in the systematic review included here [21], the relationship among physical exercise intensiveness and URI development depends on many factors and is not well recognized, yet. In agreement with the previous findings, not conclusive evidence were provided by our review due to study shortage, heterogeneity and risk of bias. Further well designed RCTs are warranted in this population. The safety of BC use during physical activity was explored. IGF-1 plasmatic levels did not increase during the short and long periods after the administration of standard doses of BC associated to training programs [39]. Intestinal permeability may change due to various factors such as inflammation or heat stress produced by intensive physical activity [38]. The safety and effectiveness of BC supplementation intake on athletes’ health were demonstrated in another placebo-controlled comparison where the reduction of the intestinal permeability was highlighted measuring zonulin stool concentration and sugar absorption [40]. However, some doubts on reporting bias and the very little sample size did not allow to provide strong evidence on these findings. Intestinal fatty acid binding protein (I-FABP) was considered a marker of gut heat-related permeability changes in subjects undergone intensive physical exercises [60]. The effectiveness of BC supplementation reducing its plasmatic level increasing after intensive activity was detected in a placebo controlled RCT included in this review [43]. However, despite there was a main effect in the treatment arm, this trial reported no statistically significant effect on bacterial plasmatic DNA concentration. These results were in contrast with the study by Morrison et al. [45] that showed how prolonged exertion in hot environment enough to produce heat stress increased gastrointestinal permeability independently by subjects’ level of training. I-FABP was higher in colostrum group and more in trained people than untrained ones in this study. Further studies are mandatory in order to provide further knowledge on factors influencing intestinal damage and its permeability changes during exercise with or without colostrum supplementation. Weak evidence of no effects were provided evaluating the efficacy of BC on blood brain barrier permeability and cognitive function [44]. Despite evidence of effects were showed on some outcomes, inconclusive findings were available on BC effects on immune system responsiveness during intensive exercises (neutrophil response and innate immunity) [37,38] as well as on BC effects on physical performances and muscle damaging [41,42] due to the lack of response on other outcomes considered in these studies, the large use of surrogate endpoints and their very small sample sizes. Interesting results was showed examining the effects of BC on participants’ hormonal

profile that could have impact in recovery improvement and fatigue reduction; however, these results must be carefully considered due to very small sample size of the pilot study included [46]. An agreement would be needed in scientific community defining the endpoints to be included in well-designed randomized controlled trials to better explore the effects of BC in athlete populations.

The seven studies included in this review exploring the use of BC as dietary supplement in pediatric population and preterm infants were very heterogeneous in terms of the target population, outcomes, and study designs. Short Bowel Syndrome (SBS) causes nutrients and fluids malabsorption and may lead to severe consequences such as necrotizing enterocolitis, volvulus or gastroschisis [61]. The pilot RCT included in this review [47] hypothesized that the BC high concentration of peptide hormones, immunoglobulins, macro and micronutrients could implement intestinal absorption in SBS children. However, confirming Rathe and colleagues findings [21], evidence of no effects on intestinal absorption and metabolic balance of BC supplementation in this population was reported by our review. Although a protective effect of BC on gastrointestinal mucosa was suggested, there were evidence of no effects of BC supplementation on neutropenic fever, antibiotic drugs utilization and bacteriemia incidence in Acute Lymphoblastic Leukemia pediatric patients undergoing chemotherapy. A large cohort study by Saad et al. [53] showed that oral administered BC prophylaxis in children affected by recurrent Upper Respiratory Tract Infections (URTI) and diarrhea reduced both infection and hospitalization rates maintaining a protective effect in the long time period. The direction of these results was confirmed by two double-blind RCTs with placebo where BC was effective reducing severity of URTI affecting IgA deficient patients [51] and decreasing frequency and severity of both vomiting and diarrhea in infants with gastrointestinal infection diseases [49]. The authors hypothesized that the positive effect of BC may be traced to its high concentration of immunoglobulins (IgG, IgM, IgE, and IgD), lactoferrin and lysozyme. These findings should be still managed carefully in relation to patients’ clinical condition and ageing due to controversial results achieved on BC supplementation in frailest populations of this category (preterm and VLBW infants) [48,50]. In these two settings BC administration for mothers’ milk supplementation resulted a feasible option for protein intake enhancing without increasing feeding intolerance and without any side effects, apparently [50]. However, a number of AEs was reported in preterm infant population (equally distributed among groups) [50] and a trend of increased frequencies of necrotizing enterocolitis and sepsis were observed in treatment group [48]. These findings might due to the frailty of the studied populations (AEs) as well as to the production process of the colostrum-based product used [48]. It is known that industrial processed formula products may increase necrotizing enterocolitis and sepsis in this population [50]. Despite BC supplementation in pediatrics suggested protective effects on respiratory infectious diseases and other conditions related symptoms, its role preventing gastrointestinal issues or supporting preterm infants remain controversial. Further studies are needed in order to provide new evidence on BC administration as dietary supplement in pediatric populations (such as those with cancer) and to clarify the effects of its different preparations.

BC was used as dietary supplement in healthy older adults in a single double blind RCT, where BC intake outcomes were assessed during a specific resistance training and compared with those of whey proteins administered as placebo. BC was effective increasing legs strength (OCEBM level 2 and EPHPP level 1 evidence) and reducing bone resorption. No significant results were found on inflammation, upper body performances and body composition. These findings were interesting in order to promote further investigations on BC effects on bone health in this population [54].

The effects on gastrointestinal permeability of early enteral bovine colostrum supplementation versus placebo were investigated in intensive care unit (ICU) setting [55]. Significant reductions of plasmatic concentrations of both zonulin and endotoxin were found (high level of evidence), meaning safe effect reducing intestinal permeability in these

patients. In addition, positive results were found on length of ICU stay and diarrhea. No effects were found on mortality, sepsis and other gastrointestinal outcomes.

Two systematic reviews were published in the time period considered. The review by Blair et al. [62] was aimed to evaluate the benefits of both milk and BC as dietary supplements in the healthy adult population ≥35 years old. However, this review included only one study on BC already selected in our review, then the review was excluded as not pertinent. The review by Rathe et al. [21] included 51 reports including RCTs, observational and case series studies published until March 2013. The review assessed the effects of BC enteral supplementation. Evidence of BC’s benefits was reported on patients’ intestinal tract protection from non-steroidal anti-inflammatory drugs (NSAID) induced injuries, and on bacterial translocation through gut barrier in patients undergoing abdominal surgery as well as on immuno-compromised patients’ (Human Immunodeficiency Virus) diarrhea control. In addition, inconclusive evidence were showed on growth or metabolic issues and idiopathic arthritis. We could not update these findings in our review due to the lack of further studies. Despite was clear that BC’s activity may triggers bowel immunological events that provides systemic ones, and its biological effects on intestinal permeability and upper respiratory tract health were explored suggesting a role of BC supplementation in URI prevention and intestinal infections treatment in both adult and pediatric populations; the interaction mechanisms of BC components with the immune system are largely underexplored. This suggests the need of pre-clinical (in-vitro and in-vivo) studies to better understand the process that influences its effects.

This review highlighted multiple clinical applications of BC and confirmed some general benefits on intestinal and respiratory recovery in absence of adverse effects. BC seemed to promote immune system enhancing and modulating local and systemic responses in various clinical and not clinical conditions. However, the studies’ heterogeneity regarding included populations, sample sizes, intervention and control protocols, and outcomes did not allow to perform meta-analyses. Moreover, the risk of biases and the large use of surrogate endpoints in the studies included did not consent to provide strong evidence on its use in any situation. Further well-designed studies are needed to support the administration of BC in adult, pediatric, clinical and not clinical settings. Pre-clinical studies should be performed to improve knowledge on BC effects.

Author Contributions: Conceptualization, M.G. and M.P.; methodology, M.G.D.M.; software, A.F., M.T.C. and S.N.; validation, M.G.D.M. and S.B.; formal analysis, A.F. and S.B.; investigation, M.G. and A.C.; resources, L.D.; data curation, A.F.; writing—original draft preparation, L.D. and S.B.; writingreview and editing, S.B.; visualization, A.F.; supervision, M.G., M.P.; project administration, M.G., M.G.D.M. and M.P. All authors have read and agreed to the published version of the manuscript.

Funding: This research received no external funding. Institutional Review Board Statement: Not applicable. Informed Consent Statement: Not applicable. Data Availability Statement: No new data were created or analyzed in this study. Data sharing is not applicable to this article.

Acknowledgments: All authors thank to Lucia Mariani for the English language editing. Thanks to Massimo Costantini and to the AUSL-IRCCS of Reggio Emilia Health Professions Directorate for their support.

Conflicts of Interest: The authors declare no conflict of interest.