Human breast milk and its impact on inflammatory bowel disease

Abstract

Inflammatory bowel disease (IBD) is a term that describes disorders involving long-standing inflammation of tissues in the digestive tract. The onset and exacerbation of IBD is linked to multiple factors, including genetic and immunological influences, diet, and gut bacteria. Additionally, it is associated with a high risk of cancer. Research shows that the longer a person is breastfed, the lower their risk of developing IBD, highlighting the impact of human breast milk components on intestinal bacteria. Human breast milk contains many bioactive components, such as lactoferrin and milk oligosaccharides, are known to be effective in preventing and treating IBD. Probiotics are defined as live microorganisms that provide beneficial effects on the host by altering the balance of indigenous intestinal bacteria. While probiotics, such as lactic acid bacteria and bifidobacteria, have been clinically applied in IBD treatment, there are currently no reports on the application of human breast milk-derived probiotics for this purpose. We clarified the preventive and therapeutic effects of human breast milk-derived probiotics on IBD, as well as the underlying mechanisms. This review highlights the importance of breastfeeding to prevent IBD, and focuses on the therapeutic effects of human breast milk-derived probiotics in IBD. These bioactive compounds in human breast milk are instrumental in establishing a beneficial gut microbiota and promoting proper immune system maturation during early life.

Human Breast Milk and Inflammatory Bowel Disease (IBD)

Human breast milk is the primary source of nutrition for growing infants. The longer the duration of breastfeeding, the lower the risk of gastrointestinal inflammation (1, 2). Breastfeeding during infancy regulates gut microbiota over the long term and protects against the development of Crohn’s disease and ulcerative colitis (3, 4). This association has been observed across all ethnic groups, with the protective effect against Crohn’s disease being significantly higher in Asians than in Caucasians. The duration of breastfeeding shows a dose-dependent relationship, with those breastfeeding for at least 12 months experiencing the greatest reduction in risk for Crohn’s disease and ulcerative colitis compared to those breastfeeding for 3 or 6 months (3). Although the composition and function of the gut microbiota can be easily disrupted throughout life, the microbiota in early infancy is particularly unstable and sensitive to external environmental factors. Elements that influence the microbiota during early childhood may significantly affect the development of diseases like IBD. According to a global survey conducted in 2017, the prevalence of certain conditions is 22% in Caucasians and 69% in Asians (3). A study involving 46 infants demonstrated that breastfed infants had a higher abundance of gastrointestinal-protective bifidobacteria and fewer opportunistic pathogens (such as Staphylococcus aureus and Klebsiella pneumoniae) compared to formula-fed infants (5). In IBD patients, dysregulation of bacterial phyla involved in the production of short-chain fatty acids has been observed. The administration of probiotics to restore the balance of microbiota communities is considered effective for patients with IBD and CAC (6,7,8).

The relationship between human breast milk and IBD has been suggested by numerous studies. Here are the main points summarized: 1. Nutritional provision and diversity of gut microbiota: Human breast milk not only provides essential nutrients for infant growth but also plays a critical role in the development of gut microbiota. Oligosaccharides such as fucosyllactose and galacto-oligosaccharides found in human breast milk promote the growth of beneficial bacteria (such as bifidobacteria) in the intestines, and contribute to increasing the diversity of gut microbiota (9). A diverse gut microbiota is thought to protect gut health and help suppress inflammation. 2. Enhanced Immune Function: Human breast milk contains lactoferrin, immunoglobulins (particularly IgA) and anti-inflammatory cytokines (such as IL-10) that support the immune system (10). This enhances resistance to infections and inflammatory diseases, promoting long-term intestinal health. 3. Vitamins, Minerals and Fatty Acids: Human breast milk contains antioxidants like vitamins C and E, as well as minerals like zinc, which contribute to the suppression of inflammatory responses. Particularly unsaturated fatty acids, such as omega-3 fatty acids, are known for their anti-inflammatory properties (11). 4. Epigenetics: Components in human breast milk may influence the expression of the infant’s DNA, potentially impacting future health (12, 13). This includes epigenetic changes that may affect the risk of intestinal disease. Due to these factors, breastfeeding is considered to play an important role in the prevention and risk reduction of IBD. However, it should be noted that individual health conditions and environments can also influence outcomes, meaning that breastfeeding may not yield the same effects for every child (14).

Bioactive Components of Human Breast Milk

The composition of human breast milk varies depending on factors such as way of feeding, time of day, and stage of lactation (colostrum, transitional, and mature). Environmental factors, geographical differences, and gestational age also affect the composition of human breast milk. Below, we discuss some of the most abundant and well-studied bioactive components of human breast milk (Table 1).

Table 1. Bioactive components of human brest milk and IBD.

Bioactive components of human breast milk		Relationship with IBD (Ref)
Lactoferrin	Human Lactoferrin	Anti-inflammation, modulate intestinal flora, protect intestinal mucosa (15,16,17)
Fatty acids	Linoleic acid (C18:2n-6)Alpha-linolenic acid (C18:3n-3)	Precursors to the highly bioactive long-chain polyunsaturated fatty acids, including arachidonic acid, eicosapentaenoic acid, and docosahexaenoic acid (18, 19)
Cytokines	IL-1β, IL-6, IL-10, IFN, TNFα, TGFβ	Establish healthy immune system (20, 21)
Oligosaccharides	Human breast milk oligosaccharides	Metabolized by bacteria that produce SCFAs (22,23,24)
Immunoglobulins	IgM, IgG, IgA	Neutralization of pathogens, maternal immunity (25, 26)
Growth factors	IGF, TGF, EGF, PDGF, NGF, hEGF	Development, supporting the immune system, cell repair and regeneration (27)
Exosomes	Human breast milk exosome	Enhance intestinal barrier function, improvement in inflammation and mucosal injury (28, 29)
Microbes	820 bacterial species (Bifidobacteria, Lactobacillus, E. Coli, Butyrate-producing Bacteria etc.)	Supporting the immune system, formation of gut microbiota, preventing allergies (30)

IBD: inflammatory bowel disease.

Lactoferrin

Glycoprotein belongs to the transferrin family and has a high binding affinity for iron, as well as antioxidant and bacteriostatic properties. Its iron-binding activity provides a competitive advantage to potentially beneficial bacteria, such as Lactobacillus and Bifidobacterium, which have low iron requirements. In addition to modulating bacterial growth, lactoferrin has protective effects, including promoting intestinal cell proliferation, differentiation, and maturation, as well as modulating the host immune response. Animal studies have demonstrated that lactoferrin suppresses inflammation, increases immunoglobulin levels, and promotes intestinal cell proliferation (15,16,17).

Fatty acid and lipases

Lipids account for about 4% of human breast milk in the form of fat globules and provide 50% of the energy supply. Human breast milk also contains lipases, which aid in the digestion of these lipids. The lipids in human breast milk play vital roles in numerous biological processes, including cell membrane synthesis, intracellular signaling, organ development, and the regulation of inflammation. Key components of the lipid composition of human breast milk are the essential fatty acids linoleic acid and alpha-linolenic acid (31). These fatty acids are precursors to bioactive long-chain polyunsaturated fatty acids (LC-PUFAs), such as arachidonic acid, eicosapentaenoic acid, and docosahexaenoic acid (32). LC-PUFAs are particularly important for brain, retina, and immune function and IBD (33).

Human breast milk oligosaccharides

Human milk oligosaccharides (HMOs) are a large family of structurally diverse glycans consisting of over 100 different members. HMOs act as prebiotics that are not digested by human intestinal enzymes; instead, they are metabolized by intestinal bacteria, especially bifidobacteria (23). HMOs can be metabolized by bacteria to produce short-chain fatty acids (SCFAs), help establish the neonatal microbiota by serving as a nutrient source for these bacteria and protecting them from potential pathogen invasion (34). The activity of the maternal “secretor” gene fucosyltransferase 2 (FUT2) can influence the levels of 2’-fucosylated (2-FL) HMOs, significantly impacting the abundance of bifidobacterial (23, 24).

Lactulose, a galactose-fructose disaccharide, is made from the milk sugar lactose by heating or isomerization processes. We examined the therapeutic effects of Lactulose in experimental colitis associated cancer model mice, Lactulose reduced pathogen abundance and increased the abundance of Muribaculum and Lachnospiraceae (35).

Exosomes

Exosomes, measuring 30–150 nm in size, are membrane-enclosed vesicles derived from endosomes. They contain complex cellular components such as proteins, microRNA, and lipids and are found in human breast milk, including colostrum, transitional milk, and mature milk. Exosomes act directly on intestinal epithelial cells to promote cell growth and prevent apoptosis. They also reduce epithelial damage caused by gram-negative bacterial lipopolysaccharide (LPS) in organoids (28, 29).

Microbes

The bacterial species present in human breast milk play a vital role in the establishment of a healthy gut microbiota in infants. Given the abundance of nutrient substrates and fuel sources for bacteria, such as HMOs, human breast milk contains its unique microbiota. A comprehensive review of studies analyzing the microbial composition of human breast milk has found that 820 species of bacteria have been detected in human breast milk to date, with Proteobacteria and Firmicutes being the dominant groups (30).

Inner Mongolia Agricultural University isolated and identified lactic acid bacteria from human colostrum and screened potential probiotic strains (36). Lacticaseibacillus rhamnosus Probio-M9 proven to be safe, reach the intestine alive, and exert beneficial effects in the digestive tract. Probio-M9 improving the colitis associated cancer in mice model by increasing the diversity of the gut microbiota and restored fecal microbial function (37). Furthermore, we found that Probio-M9 suppresses the decreased expression of tight junction proteins and mitochondrial dysfunction induced by lipopolysaccharide (LPS) in the co-cultured colon cancer Caco-2 cell line (38). Additionally, we confirmed that the Probio-M9 strain contains beneficial enzymes. The Probio-M9 possesses a gene sequence for L-rhamnose isomerase, which can also be utilized for the production of rare sugars (39). Using recombinant L-rhamnose isomerase, we have demonstrated that the enzyme retains its activity even under acidic conditions, and have also succeeded in performing X-ray crystallography of the complex with a rare sugar (39). Additionally, Gao et al. showed that the administration of Probio-M9 enhances the efficacy of anti-PD-1 antitumor therapy by restoring the gut microbiota disrupted by antibiotics (40,41,42). Furthermore, Probio-M9 has been shown to improve the quality of life in stressed adults and extend the lifespan of C. elegans (43, 44). All these data suggest that human breast milk-derived Probio-M9 may be highly effective against IBD and carcinogenesis.

Summary

This review emphasized the importance of breastfeeding in terms of the intestinal immune system formation, and reaffirmed the ameliorative effects of the beneficial bacteria Probio-M9 derived from human breast milk on gastrointestinal inflammation and carcinogenesis. Bioactive compounds in human breast milk, along with the microbiota, may help establish a beneficial intestinal flora during early childhood and promote proper immune system maturation. Future research into human breast milk components will provide important information for the prevention of IBD.

Funding

This research was funded by KAKENHI (grant number 21K11699) and Inner Mongolia Science and Technology Major Projects (grant number 2021ZD0014). Takeda Science Foundation, Suzuken Memorial Foundation, NORTHERNWEST INC and NWI HOLDINGS INC.

Conflicts of Interest

The authors declare no conflict of interest in association with the present study.