Role of bovine IgG in human immunity

A review by Ulfman et al 2018 (1) shows that studies involving infants and adults have found that bovine immunoglobulin G (IgG) and colostrum that is very rich in bovine IgG may have a role in the prevention of gastrointestinal tract (GIT) infections (2-7) and upper respiratory tract (URT) infections (8-17). However, these studies vary with regard to target group, design, source of bovine IgG, dosage, and endpoints measured; making it difficult to draw firm conclusions. With that in mind, the review focuses on the effects of orally ingested bovine IgG and their potential mechanisms of action on the immune system of children and adults.

Summary | The review analysed studies on bovine IgG and colostrum, and showed that they have a prophylactic and therapeutic effect on GIT and URT infections (2-28). Bovine IgG may also reduce the risk of otitis media (29,30) and allergy (31,32). Bovine IgG confer their effect on the immune system by binding to pathogens and allergens, enhancing their clearance, limiting gastrointestinal inflammation, and in some cases even neutralizing infections. In in vitro models, bovine IgG also enhances phagocytosis by targeting the pathogens to phagocytes that express receptors for IgG; killing of bacteria; and antigen presentation (33, 34), and supports gastrointestinal barrier function (35-41).

Researchers have discovered that orally ingested bovine immunoglobulin G (IgG) can be recovered in faeces, indicating that it can be functionally active throughout the gastrointestinal tract. The levels recovered are higher in infants than in adults and this is most likely due to differences in gastrointestinal conditions such as pH. Studies involving both infants and adults have shown that bovine IgG can prevent gastrointestinal (GIT) infections (2-7) and upper respiratory tract (URT) infections (8-17).

Study characteristics

This is a state-of-the-art review on mechanisms and nutritional studies performed with products containing bovine IgG. The review explains that most human studies used serum-derived IgG, colostrum, colostrum- and milk-derived IgG, but also serum-derived immunoglobulins as the source of bovine IgG. IgG from vaccinated cows and nonimmunized animals were both used, depending on the study aim and setup.

Results

Effects of bovine IgG on the immune system

Gastrointestinal tract (GIT) infections

Role of bovine IgG in human immunity

Four studies on on-going GIT infections in infants and children suggest bovine IgG—which is isolated from cows that were vaccinated with the specific organism—plays a role in reducing the duration of GIT infections (18,20). Besides its therapeutic effect (18-24), the prophylactic effect (2-7) of bovine IgG has also been examined. The concept of preventing GIT infections in infants using pathogen-specific bovine immunoglobulins has been tested for several enteropathogens such as Escherichia coli and Helicobacter pylori (44-47). The most extensively researched enteropathogen in this area is rotavirus, and there are both animal and human studies that support the ingestion of rotavirus-specific bovine immunoglobulins for the prevention of rotavirus diarrhoea (7, 18-21, 42, 43). Bovine IgG has also been shown to confer a prophylactic effect against GIT infections in immune compromised individuals (48-54). Studies involving HIV-infected individuals with recurrent diarrhoea found that ingestion of bovine IgG led to reduction in stool frequency, lower fatigue scores and increased body weight and CD4+ T-cell counts.

Respiratory tract infections

Breastfed infants are less likely to develop respiratory tract infections and otitis media compared to formula fed infants. However, more research is needed to determine the optimal duration and amount of breastfeeding to confer protection against respiratory tract infections and otitis media.

There are 11 studies that showed bovine IgG and colostrum can prevent URT infections in children, adults, elderly people and athletes (8-17,55, 56). These studies mostly used normal IgG from non-vaccinated cows as vaccination was only done for gastrointestinal pathogens. Interestingly, an epidemiological study on the consumption of unprocessed cow milk as weaning food in the first year of life found a reduced risk for respiratory infections and otitis media, compared to ultra heat-treated (UHT) milk. A possible explanation is that intact milk protein, which is present in unprocessed cow milk, is responsible for the protective effect (57-59).

Allergy

There is a complex link between early respiratory tract infection and the development of allergy. The hygiene hypothesis states that early infection is linked to reduced allergy and allergy disease (60). The proposed immunological mechanism is interferon gamma (IFN-g) generated during infection down-regulates T-helper 2 (Th2) activity associated with the production of interleukin-4 (IL-4) which promotes IgE production. In addition, infection also upregulates T-regulatory cell (T-reg) activity, which has additional controlling effects on Th2 and Th1 responses. The latter may explain why allergy, which correlates with Th2 response, and autoimmune diseases, which are associated with Th1 cells, are increasingly more common and co-exist in relatively affluent communities. In some communities where active infection such as measles has been linked to less allergy, it is possible that the commensal human microbiome plays a major role in promoting normal immune regulation. As such, a more accurate term has been coined: “the microbial exposure hypothesis.”

In line with the microbial exposure hypothesis, the findings of epidemiological cohort studies showing an increased frequency of respiratory infections in children who subsequently develop allergic sensitization and disease need to be interpreted with care. The underlying defects in immune response that increases the risk of infection may be responsible for allergy as well; this suggests that the relationship between infection and allergy may not be cause and effect.

Nevertheless, some viral infections in infants have been specifically linked to the later development of asthma. For instance, rhinovirus induced wheezing in infancy predicts a high probability of later asthma. To a lesser extent, asthma has also been linked to infant bronchiolitis caused by respiratory syncitial virus (RSV) infections. Of special interest is the fact that bovine IgG binds strongly to human RSV and can in in vitro assays prevent the infection of human cells with human RSV, thus speculatively linking bovine IgG to reducing RSV infections and subsequently asthma (61).

Generally, acute gastroenteritis in infancy increases the risk of allergic sensitization to food proteins, especially if the exposure to allergenic proteins occurs while there is intense gut inflammation. The latter provides co-stimulatory signals to trigger a sensitizing response. Thus, breastfeeding with its protective effects against gastrointestinal and RSV infections will reduce such events.

Mechanism of action

Bovine IgG binds to many human pathogens and prevent their adhesion to the intestinal epithelium. Moreover, bovine IgG can neutralize experimental infection of human cells and limits gastrointestinal inflammation. It exerts anti-inflammatory effects directly on the intestinal epithelium and blocks the translocation of bacterial components across the epithelial layer. Bovine IgG also binds to human Fc receptors, which leads to enhanced phagocytosis, killing of bacteria and antigen presentation. In in vitro models, bovine IgG was shown to support gastrointestinal barrier function. (33-41)

Conclusion

The review suggests that bovine IgG, when taken orally, may play a role in supporting the immune function in vulnerable groups such as infants, children, the elderly and immunocompromised persons.

References

  1. Ulfman LH et al. (2018) Effects of Bovine Immunoglobulins on Immune Function, Allergy, and Infection. Front Nutr2018; 5: 52.
  2. Tacket CO, Losonsky G, Link H, Hoang Y, Guesry P, Hilpert H, et al. Protection by milk immunoglobulin concentrate against oral challenge with enterotoxigenic Escherichia coli. N Engl J Med. (1988) 318:1240–3. doi: 10.1056/NEJM198805123181904.
  3. Freedman DJ, Tacket CO, Delehanty A, Maneval DR, Nataro J, Crabb JH. Milk immunoglobulin with specific activity against purified colonization factor antigens can protect against oral challenge with enterotoxigenic Escherichia coli. J Infect Dis. (1998) 177:662–7.
  4. Savarino SJ, Tribble DR, Porter CK, O’Dowd A, Cantrell JA, Sincock SA, et al. Prophylactic efficacy of hyperimmune bovine colostral antiadhesin antibodies against enterotoxigenic Escherichia coli diarrhea: a randomized, double-blind, placebo-controlled, phase 1 trial. J Infect Dis. (2017) 216:7–13. doi: 10.1093/infdis/jix144
  5. OttoW, Najnigier B, Stelmasiak T, Robins-Browne RM. Randomized control trials using a tablet formulation of hyperimmune bovine colostrum to prevent diarrhea caused by enterotoxigenic Escherichia coli in volunteers. ScandJ Gastroenterol. (2011) 46:862–8. doi: 10.3109/00365521.2011.574726
  6. Hammarstrom L, Weiner C. Targeted antibodies in dairy-based products. Adv Exp Med Biol. (2008) 606:321–43. doi: 10.1007/978-0-387-74087-4_13
  7. Ebina T, Sato A, Umezu K, Ishida N, Ohyama S, Ohizumi A, et al. Prevention of rotavirus infection by cow colostrum antibody against human rotaviruses. Lancet (1983) 2:1029–30
  8. Saad K, Abo-Elela MGM, El-Baseer KAA, Ahmed AE, Ahmad F-A, Tawfeek MSK, et al. Effects of bovine colostrum on recurrent respiratory tract infections and diarrhea in children. Medicine (Baltimore) (2016) 95:e4560. doi: 10.1097/MD.0000000000004560
  9. Patel K, Rana R. Pedimune in recurrent respiratory infection and diarrhoea–the Indian experience–the pride study. Indian J Pediatr. (2006) 73:585–91. doi: 10.1007/BF02759923
  10. Patiroglu T, Kondolot M. The effect of bovine colostrum on viral upper respiratory tract infections in children with immunoglobulin A deficiency. Clin Respir J. (2013) 7:21–26. doi: 10.1111/j.1752-699X.2011.00268.x
  11. Nigro A, Nicastro A, Trodella R. Retrospective observational study to investigate Sinerga, a multifactorial nutritional product, and bacterial extracts in the prevention of recurrent respiratory infections in children. Int J Immunopathol Pharmacol. (2014) 27:455–60. doi: 10.1177/039463201402700318
  12. Vitetta L, Coulson S, Beck SL, Gramotnev H, Du S, Lewis S. The clinical efficacy of a bovine lactoferrin/whey protein Ig-rich fraction (Lf/IgF) for the common cold: a double blind randomized study. Compl Ther Med. (2013) 21:164–71. doi: 10.1016/j.ctim.2012.12.006
  13. Crooks C, Cross M, Wall C, Ali A. Effect of bovine colostrum supplementation on respiratory tract mucosal defenses in swimmers. Int J Sport Nutr Exerc Metab. (2010) 20:224–35. doi: 10.1123/ijsnem.20.3.224
  14. Uchida K, Yamagucki H, Kawasaki M, Yamashita K, Kaji N. Bovine late colostrum (colostrum 6 or 7 days after parturition) supplement reduces symptoms of Upper Respiratory Tract Infection in Infant. Jap J Clin Nutr. (2010) 31:122–7.
  15. Brinkworth G, Buckley J. Concentrated bovine colostrum protein supplementation reduces the incidence of self-reported symptoms of upper respiratory tract infection in adult males. Eur J Nutr. (2003) 42:228–32. doi: 10.1007/s00394-003-0410-x
  16. Cesarone MR, Belcaro G, Di Renzo A, Dugall M, Cacchio M, Ruffini I, et al. Prevention of influenza episodes with colostrum compared with vaccination in healthy and high-risk cardiovascular subjects: the epidemiologic study in San Valentino. Clin Appl Thromb Hemost (2007)13:130–6. doi: 10.1177/1076029606295957
  17. Jones AW,March DS, Curtis F, Bridle C. Bovine colostrum supplementation and upper respiratory symptoms during exercise training: a systematic review and meta-analysis of randomised controlled trials. BMC Sports Sci Med Rehabil. (2016) 8:21. doi: 10.1186/s13102-016-0047-8
  18. Mitra AK, Mahalanabis D, Ashraf H, Unicomb L, Eeckels R, Tzipori S, et al. Hyperimmune cow colostrum reduces diarrhoea due to rotavirus: a double-blind, controlled clinical trial. Acta Paediatr. (1995) 84:996–1001. doi: 10.1111/j.1651-2227.1995.tb13814.x
  19. Sarker S, Casswall T, Mahalanabis D, Alam N, Albert M, Brussow H, et al. Successful treatment of rotavirus diarrhea in children with immunoglobulin from immunized bovine colostrum. Pediatr Infect Dis J. (1998) 17:1149–54. doi: 10.1097/00006454-199812000-00010
  20. Ylitalo S, Uhari M, Rasi S, Pudas J, Leppaluoto J. Rotaviral antibodies in the treatment of acute rotaviral gastroenteritis. Acta Paediatr (1998) 87:264–7.
  21. Hilpert H, Brüssow H, Mietens C, Sidoti J, Lerner L, Werchau H. Use of bovine milk concentrate containing antibody to rotavirus to treat rotavirus gastroenteritis in infants. J Infect Dis. (1987) 156:158–66.
  22. Dissel JT Van, Groot N De, Hensgens CMH, Numan S, Kuijper EJ, Veldkamp P, et al. Bovine antibody-enriched whey to aid in the prevention of a relapse of Clostridium difficile- associated diarrhoea: preclinical and preliminary clinical data. JMedMicrobiol. (2005) 54:197–205. doi: 10.1099/jmm.0.45773-0
  23. Mattila E, Anttila VJ, Broas M, Marttila H, Poukka P, Kuusisto K, et al. A randomized, double-blind study comparing Clostridium difficile immune whey and metronidazole for recurrent Clostridium difficile-associated diarrhoea: efficacy and safety data of a prematurely interrupted trial. ScandJ Infect Dis. (2008) 40:702–8. doi: 10.1080/00365540801964960
  24. Hu D, Zhang F, Zhou J, Xu B, Zhang H, Qiang H, et al. The clearance effect of bovine anti-Helicobacter pylori antibody-containing milk in O blood group Helicobacter pylori-infected patients: a randomized double-blind clinical trial. J Transl Med. (2015) 13:205. doi: 10.1186/s12967-015-0558-1
  25. Xu ML, Kim HJ, Wi GR, Kim H-J. The effect of dietary bovine colostrum on respiratory syncytial virus infection and immune responses following the infection in the mouse. J Microbiol. (2015) 53:661. doi: 10.1007/s12275-015-5353-4
  26. Ng WC, Wong V, Muller B, Rawlin G, Brown LE. Prevention and treatment of influenza with hyperimmune bovine colostrum antibody. PLoS ONE (2010) 5:e13622. doi: 10.1371/journal.pone.0013622
  27. Wong EB, Mallet J-F, Duarte J, Matar C, Ritz BW. Bovine colostrum enhances natural killer cell activity and immune response in a mouse model of influenza infection and mediates intestinal immunity through toll-like receptors 2 and 4. Nutr Res. (2014) 34:318–25. doi: 10.1016/j.nutres.2014.02.007
  28. Meyer G, Deplanche M, Schelcher F. Human and bovine respiratory syncytial virus vaccine research and development. Comp Immunol Microbiol Infect Dis. (2008) 31:191–225. doi: 10.1016/j.cimid.2007.07.008
  • 132 Timby N, Hernell O, Vaarala O, Melin M, Lönnerdal B, Domellöf M. Infections in infants fed formula supplemented with bovine milk fat globule membranes. J Pediatr Gastroenterol Nutr. (2015): 60:384–9. doi: 10.1097/MPG.0000000000000624
  1. Loss G, Depner M, Ulfman LH, van Neerven RJJ, Hose AJ, Genuneit J, et al. Consumption of unprocessed cow’s milk protects infants from common respiratory infections. J Allergy Clin Immunol. (2015) 135:56–62. doi: 10.1016/j.jaci.2014.08.044
  2. Riedler J, Braun-Fahrländer C, Eder W, Schreuer M, Waser M, Maisch S, et al. Exposure to farming in early life and development of asthma and allergy: a cross-sectional survey. Lancet (2001) 358:1129–33. doi: 10.1016/S0140-6736(01)06252-3
  3. von Mutius E, Vercelli D. Farm living: effects on childhood asthma and allergy. Nat Rev Immunol. (2010) 10:861–8. doi: 10.1038/nri2871
  4. den Hartog G, Jacobino S, Bont L, Cox L, Ulfman LH, Leusen JHW, et al. Specificity and effector functions of human RSV-Specific IgG from bovine milk. PLoS ONE (2014) 9:e112047. doi: 10.1371/journal.pone.0112047
  5. Loimaranta V, Nuutila J, Marnila P, Tenovuo J, Korhonen H, Lilius EM. Colostral proteins from cows immunised with Streptococcus mutans/S. sobrinus support the phagocytosis and killing of mutans streptococci by human leucocytes. J Med Microbiol. (1999) 48:917–26.
  6. Kubinak JL, Round JL. Do antibodies select a healthy microbiota? Nat Rev Immunol. (2016) 16:767–4. doi: 10.1038/nri.2016.114
  7. Dollé L, Tran HQ, Etienne-Mesmin L, Chassaing B. Policing of gut microbiota by the adaptive immune system. BMC Med (2016) 14:4–7. doi: 10.1186/s12916-016-0573-y
  8. Stephens WZ, Round JL. Previews IgA targets the troublemakers. Cell Host Microbe (2014) 16:265–7. doi: 10.1016/j.chom.2014.08.012
  9. Jung K, Miyagawa M, Matsuda A, Amagai Y, Oida K, Okamoto Y, et al. Antifungal effects of palmitic acid salt and ultrapure soft water on Scedosporium apiospermum. J ApplMicrobiol. (2013) 115:711–7. doi: 10.1111/jam.12298
  10. Palm NW, de Zoete MR, Cullen TW, Barry NA, Stefanowski J, Hao L, et al. Immunoglobulin A coating identifies colitogenic bacteria in inflammatory bowel disease. Cell (2014) 158:1000–10. doi: 10.1016/j.cell.2014.08.006
  11. Macpherson AJ, McCoy KD. Independence day for IgA. Immunity (2015) 43:416–8. doi: 10.1016/j.immuni.2015.08.024
  12. Fransen F, Zagato E, Mazzini E, Fosso B, Manzari C, El Aidy S, et al. BALB/c and C57BL/6 Mice Differ in Polyreactive IgA Abundance, which Impacts the Generation of Antigen-Specific IgA and Microbiota Diversity. Immunity (2015) 43:527–540. doi: 10.1016/j.immuni.2015.08.011
  13. Davidson G, Tam J, Kirubakaran C. Passive protection against hospital acquired symptompatic rota virus gasteroenteritis in India and Hong Kong. J Pediatr Gastroenterol Nutr. (1994) 19:351. doi: 10.1097/00005176-199410000-00102
  14. Turner RB, Kelsey DK. Passive immunization for prevention of rotavirus illness in healthy infants. Pediatr Infect Dis J. (1993) 12:718–22.
  15. Tawfeek HI, Najim NH, Al-Mashikhi S. Efficacy of an infant formula containing anti-Escherichia coli colostral antibodies from hyperimmunized cows in preventing diarrhea in infants and children: a field trial. Int J Infect Dis. (2003) 7:120–8. doi: 10.1016/S1201-9712(03)90007-5
  16. Funatogawa K, Ide T, Kirikae F, Saruta K, Nakano M, Kirikae T. Use of immunoglobulin enriched bovine colostrum against oral challenge with enterohaemorrhagic Escherichia coli O157:H7 in mice. Microbiol Immunol. (2002) 46:761–6. doi: 10.1111/j.1348-0421.2002.tb02761.x
  17. Casswall TH, Sarker SA, Albert MJ, Fuchs GJ, Bergström M, Björck L, et al. Treatment of Helicobacter pylori infection in infants in rural Bangladesh with oral immunoglobulins from hyperimmune bovine colostrum. Aliment Pharmacol Ther. (1998) 12:563–8.
  18. Casswall T, Nilsson H, Bjorck L, Sjostedt S, Xu L, Nord C, et al. Bovine anti-Helicobacter pylori antibodies for oral immunotherapy. Scand J Gastroenterol. (2002) 37:1380–85. doi:10.1080/003655202762671242
  19. Rump JA, Arndt R, Arnold A, Bendick C, Dichtelmuller H, Franke M, et al. Treatment of diarrhoea in human immunodeficiency virus infected patients with immunoglobulins from bovine colostrum. Clin Investig. (1992) 70:588–94
  20. Shield J, Melville C, Novelli V, Anderson G, Scheimberg I, Gibb D, et al. Bovine colostrum immunoglobulin concentrate for cryptosporidiosis in AIDS. Arch Dis Child (1993) 69:451–3. doi: 10.1136/adc.69.4.451
  21. Plettenberg A, Stoehr A, Stellbrink HJ, Albrecht H,MeigelW. A preparation from bovine colostrum in the treatment of HIV-positive patients with chronic diarrhea. Clin Investig. (1993) 71:42–5. doi: 10.1007/BF00210962
  22. Florén C-H, Chinenye S, Elfstrand L, Hagman C, Ihse I. ColoPlus, a new product based on bovine colostrum, alleviates HIV-associated diarrhoea. Scand J Gastroenterol. (2006) 41:682–6. doi: 10.1080/00365520500380817
  23. Asmuth DM,Ma Z-M, Albanese A, Sandler NG, Devaraj S, Knight TH, et al. Oral serum-derived bovine immunoglobulin improves duodenal immune reconstitution and absorption function in patients with HIV enteropathy. Aids (2013) 27:2207–17. doi: 10.1097/QAD.0b013e328362e54c
  24. Odong PO, Angwech PJ, Obol J, Kuule J, Florén C. Management of HIV in Children Using a Bovine Colostrum-Based Food Product — An Observational Field Study. AIDS (2015) 5:100–4. doi: 10.4236/wja.2015.52012
  25. Kaducu FO, Okia SA, Upenytho G, Elfstrand L, Floron CH. Effect of bovine colostrum-based food supplement in the treatment of HIV-associated diarrhea in Northern Uganda: a randomized controlled trial. Indian JGastroenterol. (2011) 30:270–6. doi: 10.1007/s12664-011-0146-0
  26. Jones C, Heath P. Antenatal immunization. Hum Vaccin Immunother (2014) 10:2118–22. doi: 10.4161/hv.29610
  27. Shing CM, Peake J, Suzuki K, Okutsu M, Pereira R, Stevenson L, et al. Effects of bovine colostrum supplementation on immune variables in highly trained cyclists. J Appl Physiol. (2007) 102:1113–22. doi: 10.1152/japplphysiol.00553.2006
  28. Loss G, Apprich S, Waser M, Kneifel W, Genuneit J, Buchele G, et al. The protective effect of farm milk consumption on childhood asthma and atopy: the GABRIELA study. J Allergy Clin Immunol. (2011) 128:766–773.e4. doi: 10.1016/j.jaci.2011.07.048
  29. Mainer G, Sánchez L, Ena JM, Calvo M. Kinetic and thermodynamic parameters for heat denaturation of bovine milk IgG, IgA and IgM. J Food Sci. (1997) 62:1034–38.
  30. Van Neerven, RJJ. The effects of milk and colostrum on allergy and infection: mechanisms and implications. Front. Anim. (2014) 4:16–22. doi: 10.2527/af.2014-0010
  31. Warner J, Turner P. Allergy. In The Science of Paediatrics, Carroll W, editor London: Elsevier. (2017) p. 297–316. Available online at: https://www.elsevier.com/books/the-science-of-paediatrics-mrcpch-mastercourse/lissauer/978-0-7020-6313-8
  32. Brown EM, Arrieta M-C, Finlay BB. A fresh look at the hygiene hypothesis: how intestinal microbial exposure drives immune effector responses in atopic disease. Semin Immunol. (2013) 25:378–87. doi: 10.1016/j.smim.2013.09.003