Abstract
Necrotizing enterocolitis (NEC) is a devastating condition affecting up to 5% of neonatal intensive care unit (NICU) admissions. Risk factors include preterm delivery, low birth weight, and antibiotic use. The pathogenesis is characterized by a combination of intestinal ischemia, necrosis of the bowel, reperfusion injury, and sepsis typically resulting in surgical resection of afflicted bowel. Targeted medical therapy remains elusive. Chondroitin sulfate (CS) holds the potential to prevent the onset of NEC through its anti-inflammatory properties and protective effect on the gut microbiome. The purpose of this review is to outline the many properties of CS to highlight its potential use in high-risk infants and attenuate the severity of NEC. The purpose of this review is to (1) discuss the interaction of CS with the infant microbiome, (2) review the anti-inflammatory properties of CS, and (3) postulate on the potential role of CS in preventing NEC.
Impact
-
NEC is a costly medical burden in the United States.
-
Breast milk is the best preventative measure for NEC, but not all infants in the NICU have access to breast milk.
-
Novel therapies and diagnostic tools are needed for NEC.
-
CS may be a potential therapy for NEC due to its potent anti-inflammatory properties.
-
CS could be added to the formula in an attempt to mitigate breast milk disparities.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Gupta, A. & Paria, A. Etiology and medical management of NEC. Early Hum. Dev. 97, 17–23 (2016).
Hull, M. A. et al. Mortality and management of surgical necrotizing enterocolitis in very low birth weight neonates: a prospective cohort study. J. Am. Coll. Surg. 218, 1148–1155 (2014).
Knell, J., Han, S. M., Jaksic, T. & Modi, B. P. Current status of necrotizing enterocolitis. Curr. Probl. Surg. 56, 11–38 (2019).
Li, Q. Y. et al. Differences in the clinical characteristics of early- and late-onset necrotizing enterocolitis in full-term infants: a retrospective case–control study. Sci. Rep. 7, 43042 (2017).
Boundy, E. O., Perrine, C. G., Nelson, J. M. & Hamner, H. C. Disparities in hospital-reported breast milk use in neonatal intensive care units—United States, 2015. Morb. Mortal. Wkly Rep. 66, 1313–1317 (2017).
Nanthakumar, N. et al. The mechanism of excessive intestinal inflammation in necrotizing enterocolitis: an immature innate immune response. PLoS ONE 6, e17776 (2011).
Ma, B. et al. Microbial biomarkers of intestinal barrier maturation in preterm infants. Front. Microbiol. 9, 2755 (2018).
Choi, Y. Y. Necrotizing enterocolitis in newborns: update in pathophysiology and newly emerging therapeutic strategies. Korean J. Pediatr. 57, 505–513 (2014).
Miller, J. et al. A systematic review and meta-analysis of human milk feeding and morbidity in very low birth weight infants. Nutrients 10, 707 (2018).
Meinzen-Derr, J. et al. Role of human milk in extremely low birth weight infants’ risk of necrotizing enterocolitis or death. J. Perinatol. 29, 57–62 (2009).
Herrmann, K. & Carroll, K. An exclusively human milk diet reduces necrotizing enterocolitis. Breastfeed. Med. 9, 184–190 (2014).
Hair, A. B. et al. Beyond necrotizing enterocolitis prevention: improving outcomes with an exclusive human milk-based diet. Breastfeed. Med. 11, 70–74 (2016).
Lucas, A. & Cole, T. J. Breast milk and neonatal necrotising enterocolitis. Lancet 336, 1519–1523 (1990).
Sitarik, A. R. et al. Breast milk transforming growth factor beta is associated with neonatal gut microbial composition. J. Pediatr. Gastroenterol. Nutr. 65, e60–e67 (2017).
Guner, Y. S. et al. P-glycoprotein induction by breast milk attenuates intestinal inflammation in experimental necrotizing enterocolitis. Lab. Invest. 91, 1668–1679 (2011).
Institute of Medicine of the National Academies. Infant Formula: Evaluating the Safety of New Ingredients (The National Academies Press, Washington, 2004).
Profit, J. et al. Racial/ethnic disparity in NICU quality of care delivery. Pediatrics 140, e20170918 (2017).
Sigurdson, K., Morton, C., Mitchell, B. & Profit, J. Correction: disparities in NICU quality of care: a qualitative study of family and clinician accounts. J. Perinatol. 38, 1123 (2018).
Simental-Mendia, M. et al. Effect of glucosamine and chondroitin sulfate in symptomatic knee osteoarthritis: a systematic review and meta-analysis of randomized placebo-controlled trials. Rheumatol. Int. 38, 1413–1428 (2018).
Hori, Y. et al. Effects of chondroitin sulfate on colitis induced by dextran sulfate sodium in rats. Jpn J. Pharmacol. 85, 155–160 (2001).
Shmagel, A. et al. The effects of glucosamine and chondroitin sulfate on gut microbial composition: a systematic review of evidence from animal and human studies. Nutrients 11, 294 (2019).
Franzosa, E. A. et al. Identifying personal microbiomes using metagenomic codes. Proc. Natl Acad. Sci. USA 112, E2930–E2938 (2015).
Staude, B. et al. The microbiome and preterm birth: a change in paradigm with profound implications for pathophysiologic concepts and novel therapeutic strategies. Biomed. Res. Int. 2018, 7218187 (2018).
Gonzalez-Rivera, R., Culverhouse, R. C., Hamvas, A., Tarr, P. I. & Warner, B. B. The age of necrotizing enterocolitis onset: an application of Sartwell’s incubation period model. J. Perinatol. 31, 519–523 (2011).
La Rosa, P. S. et al. Patterned progression of bacterial populations in the premature infant gut. Proc. Natl Acad. Sci. USA 111, 12522–12527 (2014).
Yang, I. et al. The infant microbiome: implications for infant health and neurocognitive development. Nurs. Res. 65, 76–88 (2016).
Willis, A. D. Rarefaction, alpha diversity, and statistics. Front. Microbiol. 10, 2407 (2019).
Mosca, A., Leclerc, M. & Hugot, J. P. Gut microbiota diversity and human diseases: should we reintroduce key predators in our ecosystem? Front. Microbiol. 7, 455 (2016).
Minter, M. R. et al. Antibiotic-induced perturbations in gut microbial diversity influences neuro-inflammation and amyloidosis in a murine model of Alzheimer’s disease. Sci. Rep. 6, 30028 (2016).
Human Microbiome Project C. Structure, function and diversity of the healthy human microbiome. Nature 486, 207–214 (2012).
McMurtry, V. E. et al. Bacterial diversity and Clostridia abundance decrease with increasing severity of necrotizing enterocolitis. Microbiome 3, 11 (2015).
Stewart, C. J. et al. The preterm gut microbiota: changes associated with necrotizing enterocolitis and infection. Acta Paediatr. 101, 1121–1127 (2012).
Sanchez, E. et al. Reduced diversity and increased virulence—gene carriage in intestinal enterobacteria of coeliac children. BMC Gastroenterol. 8, 50 (2008).
Neu, J. & Pammi, M. Pathogenesis of NEC: impact of an altered intestinal microbiome. Semin. Perinatol. 41, 29–35 (2017).
Brower-Sinning, R. et al. Mucosa-associated bacterial diversity in necrotizing enterocolitis. PLoS ONE 9, e105046 (2014).
Ford, S. L. et al. Improved feeding tolerance and growth are linked to increased gut microbial community diversity in very-low-birth-weight infants fed mother’s own milk compared with donor breast milk. Am. J. Clin. Nutr. 109, 1088–1097 (2019).
Dobbler, P. T. et al. Low microbial diversity and abnormal microbial succession is associated with necrotizing enterocolitis in preterm infants. Front. Microbiol. 8, 2243 (2017).
Houghteling, P. D. & Walker, W. A. Why is initial bacterial colonization of the intestine important to infants’ and children’s health? J. Pediatr. Gastroenterol. Nutr. 60, 294–307 (2015).
Gareau, M. G., Sherman, P. M. & Walker, W. A. Probiotics and the gut microbiota in intestinal health and disease. Nat. Rev. Gastroenterol. Hepatol. 7, 503–514 (2010).
Lin, H. C. et al. Oral probiotics prevent necrotizing enterocolitis in very low birth weight preterm infants: a multicenter, randomized, controlled trial. Pediatrics 122, 693–700 (2008).
Hoyos, A. B. Reduced incidence of necrotizing enterocolitis associated with enteral administration of Lactobacillus acidophilus and Bifidobacterium infantis to neonates in an intensive care unit. Int. J. Infect. Dis. 3, 197–202 (1999).
Dieterich, C. M., Felice, J. P., O’Sullivan, E. & Rasmussen, K. M. Breastfeeding and health outcomes for the mother-infant dyad. Pediatr. Clin. N. Am. 60, 31–48 (2013).
Thompson, A. L., Monteagudo-Mera, A., Cadenas, M. B., Lampl, M. L. & Azcarate-Peril, M. A. Milk- and solid-feeding practices and daycare attendance are associated with differences in bacterial diversity, predominant communities, and metabolic and immune function of the infant gut microbiome. Front. Cell Infect. Microbiol. 5, 3 (2015).
Ho, N. T. et al. Meta-analysis of effects of exclusive breastfeeding on infant gut microbiota across populations. Nat. Commun. 9, 4169 (2018).
Steele, J. R., Meskell, R. J., Foy, J. & Garner, A. E. Determining the osmolality of over-concentrated and supplemented infant formulas. J. Hum. Nutr. Diet. 26, 32–37 (2013).
Kriss, M., Hazleton, K. Z., Nusbacher, N. M., Martin, C. G. & Lozupone, C. A. Low diversity gut microbiota dysbiosis: drivers, functional implications and recovery. Curr. Opin. Microbiol. 44, 34–40 (2018).
Wang, Z. et al. Characteristic dysbiosis of gut microbiota of Chinese patients with diarrhea-predominant irritable bowel syndrome by an insight into the pan-microbiome. Chin. Med. J. 132, 889–904 (2019).
Tanaka, S. et al. Influence of antibiotic exposure in the early postnatal period on the development of intestinal microbiota. FEMS Immunol. Med. Microbiol. 56, 80–87 (2009).
Mai, V. et al. Fecal microbiota in premature infants prior to necrotizing enterocolitis. PLoS ONE 6, e20647 (2011).
Underwood, M. A. & Sohn, K. The microbiota of the extremely preterm infant. Clin. Perinatol. 44, 407–427 (2017).
Coggins, S. A., Wynn, J. L. & Weitkamp, J. H. Infectious causes of necrotizing enterocolitis. Clin. Perinatol. 42, 133–154, ix (2015).
Warner, B. B. et al. Gut bacteria dysbiosis and necrotising enterocolitis in very low birthweight infants: a prospective case-control study. Lancet 387, 1928–1936 (2016).
de la Cochetiere, M. F. et al. Early intestinal bacterial colonization and necrotizing enterocolitis in premature infants: the putative role of Clostridium. Pediatr. Res. 56, 366–70. (2004).
Aujoulat, F. et al. Temporal dynamics of the very premature infant gut dominant microbiota. BMC Microbiol. 14, 325 (2014).
Romano-Keeler, J. et al. Distinct mucosal microbial communities in infants with surgical necrotizing enterocolitis correlate with age and antibiotic exposure. PLoS ONE 13, e0206366 (2018).
Arboleya, S. et al. Intestinal microbiota development in preterm neonates and effect of perinatal antibiotics. J. Pediatr. 166, 538–544 (2015).
Kuppala, V. S., Meinzen-Derr, J., Morrow, A. L. & Schibler, K. R. Prolonged initial empirical antibiotic treatment is associated with adverse outcomes in premature infants. J. Pediatr. 159, 720–725 (2011).
Greenwood, C. et al. Early empiric antibiotic use in preterm infants is associated with lower bacterial diversity and higher relative abundance of Enterobacter. J. Pediatr. 165, 23–29 (2014).
Volpi, N. Chondroitin sulfate safety and quality. Molecules 24, 1447 (2019).
Kastana, P. et al. Insight into the role of chondroitin sulfate E in angiogenesis. FEBS J. 286, 2921–2936 (2019).
Dyck, S. et al. Perturbing chondroitin sulfate proteoglycan signaling through LAR and PTPsigma receptors promotes a beneficial inflammatory response following spinal cord injury. J. Neuroinflamm. 15, 90 (2018).
Uhlin-Hansen, L., Eskeland, T. & Kolset, S. O. Modulation of the expression of chondroitin sulfate proteoglycan in stimulated human monocytes. J. Biol. Chem. 264, 14916–14922 (1989).
Pichette, J., Fynn-Sackey, N. & Gagnon, J. Hydrogen sulfide and sulfate prebiotic stimulates the secretion of GLP-1 and improves glycemia in male mice. Endocrinology 158, 3416–3425 (2017).
Liu, X. et al. Antithrombotic activities of fucosylated chondroitin sulfates and their depolymerized fragments from two sea cucumbers. Carbohydr. Polym. 152, 343–350 (2016).
Egea, J., Garcia, A. G., Verges, J., Montell, E. & Lopez, M. G. Antioxidant, antiinflammatory and neuroprotective actions of chondroitin sulfate and proteoglycans. Osteoarthr. Cartil. 18, S24–S27 (2010).
Pai, V. C. et al. The chondroitin sulfate moiety mediates thrombomodulin-enhanced adhesion and migration of vascular smooth muscle cells. J. Biomed. Sci. 25, 14 (2018).
Zancan, P. & Mourao, P. A. Venous and arterial thrombosis in rat models: dissociation of the antithrombotic effects of glycosaminoglycans. Blood Coagul. Fibrinolysis 15, 45–54 (2004).
Coppa, G. V. et al. Glycosaminoglycan content in term and preterm milk during the first month of lactation. Neonatology 101, 74–76 (2012).
Coppa, G. V. et al. Composition and structure elucidation of human milk glycosaminoglycans. Glycobiology 21, 295–303 (2011).
Henrotin, Y., Mathy, M., Sanchez, C. & Lambert, C. Chondroitin sulfate in the treatment of osteoarthritis: from in vitro studies to clinical recommendations. Ther. Adv. Musculoskelet. Dis. 2, 335–348 (2010).
Korotkyi, O. et al. Effect of chondroitin sulfate on blood serum cytokine profile during carrageenan-induced edema and monoiodoacetate-induced osteoarthritis in rats. Rev. Recent Clin. Trials 14, 50–55 (2019).
Barthe, L. et al. In vitro intestinal degradation and absorption of chondroitin sulfate, a glycosaminoglycan drug. Arzneimittelforschung 54, 286–292 (2004).
du Souich, P. Absorption, distribution and mechanism of action of SYSADOAS. Pharm. Ther. 142, 362–374 (2014).
Nutrition ECo, Arslanoglu, S. et al. Donor human milk for preterm infants: current evidence and research directions. J. Pediatr. Gastroenterol. Nutr. 57, 535–542 (2013).
Burge, K., Bergner, E., Gunasekaran, A., Eckert, J. & Chaaban, H. The role of glycosaminoglycans in protection from neonatal necrotizing enterocolitis: a narrative review. Nutrients 12, 546 (2020).
Liu, F. et al. Chondroitin sulfate disaccharides modified the structure and function of the murine gut microbiome under healthy and stressed conditions. Sci. Rep. 7, 6783 (2017).
Rotimi, V. O. & Duerden, B. I. The bacterial flora of neonates with congenital abnormalities of the gastro-intestinal tract. J. Hyg. 88, 69–81 (1982).
Burge, K. Y., Hannah, L., Eckert, J. V., Gunasekaran, A. & Chaaban, H. The protective influence of chondroitin sulfate, a component of human milk, on intestinal bacterial invasion and translocation. J. Hum. Lact. 35, 538–549 (2019).
Tuncil, Y. E. et al. Reciprocal prioritization to dietary glycans by gut bacteria in a competitive environment promotes stable coexistence. mBio 8 (2017).
Salyers, A. A., Vercellotti, J. R., West, S. E. & Wilkins, T. D. Fermentation of mucin and plant polysaccharides by strains of Bacteroides from the human colon. Appl. Environ. Microbiol. 33, 319–322 (1977).
Claud, E. C. et al. Developmentally regulated IkappaB expression in intestinal epithelium and susceptibility to flagellin-induced inflammation. Proc. Natl Acad. Sci. USA 101, 7404–7408 (2004).
Nanthakumar, N. N., Fusunyan, R. D., Sanderson, I. & Walker, W. A. Inflammation in the developing human intestine: a possible pathophysiologic contribution to necrotizing enterocolitis. Proc. Natl Acad. Sci. USA 97, 6043–6048 (2000).
Zhang, Q., Lenardo, M. J. & Baltimore, D. 30 Years of NF-kappaB: a blossoming of relevance to human pathobiology. Cell 168, 37–57 (2017).
Stabler, T. V., Huang, Z., Montell, E., Verges, J. & Kraus, V. B. Chondroitin sulphate inhibits NF-kappaB activity induced by interaction of pathogenic and damage associated molecules. Osteoarthr. Cartil. 25, 166–174 (2017).
Navarro, S. L. et al. Randomized trial of glucosamine and chondroitin supplementation on inflammation and oxidative stress biomarkers and plasma proteomics profiles in healthy humans. PLoS ONE 10, e0117534 (2015).
Campo, G. M. et al. Glycosaminoglycans modulate inflammation and apoptosis in LPS-treated chondrocytes. J. Cell. Biochem. 106, 83–92 (2009).
Chan, P. S., Caron, J. P. & Orth, M. W. Short-term gene expression changes in cartilage explants stimulated with interleukin beta plus glucosamine and chondroitin sulfate. J. Rheumatol. 33, 1329–1340 (2006).
Namachivayam, K. et al. Transforming growth factor-beta2 is sequestered in preterm human milk by chondroitin sulfate proteoglycans. Am. J. Physiol. Gastrointest. Liver Physiol. 309, G171–G180 (2015).
Frey, H., Schroeder, N., Manon-Jensen, T., Iozzo, R. V. & Schaefer, L. Biological interplay between proteoglycans and their innate immune receptors in inflammation. FEBS J. 280, 2165–2179 (2013).
Tan, G. K. & Tabata, Y. Chondroitin-6-sulfate attenuates inflammatory responses in murine macrophages via suppression of NF-kappaB nuclear translocation. Acta Biomater. 10, 2684–2692 (2014).
Gross, A. R. & Theoharides, T. C. Chondroitin sulfate inhibits secretion of TNF and CXCL8 from human mast cells stimulated by IL-33. Biofactors 45, 49–61 (2019).
De Winter, B. Y., van den Wijngaard, R. M. & de Jonge, W. J. Intestinal mast cells in gut inflammation and motility disturbances. Biochim. Biophys. Acta 1822, 66–73 (2012).
Green Corkins, K. & Shurley, T. What’s in the bottle? A review of infant formulas. Nutr. Clin. Pract. 31, 723–729 (2016).
Vandenplas, Y., Zakharova, I. & Dmitrieva, Y. Oligosaccharides in infant formula: more evidence to validate the role of prebiotics. Br. J. Nutr. 113, 1339–1344 (2015).
Acknowledgements
This work was supported by K08DK113226 from the National Institutes of Health, the Koret Foundation, The George H. Clowe’s Memorial Research Career Development Award, and the Department of Surgery at the Indiana University School of Medicine.
Author information
Authors and Affiliations
Contributions
T.A.K. drafted the manuscript, made critical revisions, and approved the final submission. B.D.H., A.R.P., H.L., W.C.S., and T.A.M. all made critical revisions to the manuscript and approved its final submission.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests.
Patient consent
This was not a clinical trial and human research was not conducted. Thus, consent was not required
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Knowles, T.A., Hosfield, B.D., Pecoraro, A.R. et al. It’s all in the milk: chondroitin sulfate as potential preventative therapy for necrotizing enterocolitis. Pediatr Res 89, 1373–1379 (2021). https://doi.org/10.1038/s41390-020-01125-7
Received:
Revised:
Accepted:
Published:
Version of record:
Issue date:
DOI: https://doi.org/10.1038/s41390-020-01125-7
This article is cited by
-
Necrotizing enterocolitis: current understanding of the prevention and management
Pediatric Surgery International (2024)
