It was already known that HMOs may prevent NEC in experimental models, but the mechanism had not been elucidated. New data published in Pediatric Research clearly showed that the HMOs 2’-fucosyllactose (2’-FL) and 6’-sialyllactose (6’-SL) may inhibit the toll-like receptor 4 (TLR4) in the intestine.
According to the World Health Organisation, more than 15 million babies are born prematurely each year and the number is increasing. More than 500,000 of these are in the United States. NEC is one of the major causes of morbidity and mortality in these infants, with a 30% mortality rate in infants that develop the disease.
NEC results in inflammation in the intestine, which can lead to holes forming in the lining of the gut allowing bacteria to invade the rest of the body. This can ultimately lead to infection and sepsis.
“Given the lack of specific treatments for NEC, the focus has shifted to prevention strategies, especially in those infants at the greatest risk for disease development,” explained the authors of the new paper in Pediatric Research.
Previous research has suggested a role for TLR4, which is activated by lipopolysaccharide (LPS) and “leads to a disruption of the intestinal mucosa, resulting in bacterial translocation into the blood stream, where the activation of TLR4 on the endothelium results in vasoconstriction and the intestinal ischemia that characterizes NEC.”
The Abbott and Johns Hopkins researchers focused on the potential of 2ʹ-FL and 6ʹ-SL to inhibit TLR4.
HMOs are unique carbohydrates that make up about 10% of the dry weight of mother’s milk. HMOs are not easily digested, so experts postulate that their purpose is to jump-start the infant’s microbiome.
There are more than 130 different HMOs, and they fall into two categories, Dr Rachael Buck, Research Fellow at Abbott and co-author on the paper, told NutraIngredients-USA: neutral and acidic (which carry a charge). 2’-FL is the most abundant neutral HMO, while 6’-SL is the most abundant acidic HMO.
To date, 2’-FL is the most studied, and the one that is already commercially available from a number of different suppliers.
Dr Buck added that the researchers also chose to look at 6’-SL (in addition to 2’-FL) because, “data from pre-clinical models showed it could reduce inflammation, and the immune effects were compelling.”
The new studies used newborn mice and premature piglets with induced NEC and then supplemented infant formula with 2’-FL, 6’-SL, or lactose.
The data indicated that the 2’-FL and/or 6’-SL infant formula, but not lactose, reduced NEC in both animal models.
Additional cell studies showed that both 2’-FL and 6’-SL, but not lactose, inhibited TLR4, with in silico modeling showing that the HMOs ‘docked’ in a specific binding pocket, which explained their ability to inhibit TLR4.
The majority of the science to date has focused on infants, with a study published in Gut (He et al., 2016, Vol. 65, pp. 33–46) by scientists from Harvard Medical School indicated that 2’-FL could reduce the inflammatory response to pathogenic bacteria.
Results of a study published in the Journal of Nutrition in 2016 by scientists at Abbott Nutrition found that infants fed a formula with 2’-FL had levels of inflammatory cytokines similar to those observed for breast feeding, and significantly lower than those observed for infants fed a control formula containing no 2’-FL.
“We showed in this breakthrough study that 6’-SL and 2’-FL reduced the severity of NEC,” Dr Buck told us. “And the most novel finding from the study was that both of these HMOs bind to a key immune receptor to dampen intestinal inflammation, and we did not previously know that.”
In terms of next steps, Dr Buck noted that Abbott is “committed to HMO research” and will continue to seek “insights for pre-term formula to help reduce NEC”.
From early life to old age
At the other end of the age spectrum, the bifidogenic effects of HMOs may also make these prebiotics interesting to aging populations, which are characterized by declining Bifidobacteria levels.
In the elderly, Dr Buck noted that Abbott has already published studies in this field, and the key in these people is immunosenescence, or immune decline.
The probiotic angle
In addition to the potential of these HMO prebiotics, researchers around the world have also examined if probiotics may help with NEC, and a review from the prestigious Cochrane Collaboration concluded that “probiotics reduces the occurrence of NEC and death in premature infants”.
Source: Pediatric Research
2020, Published online ahead of print, doi: 10.1038/s41390-020-0852-3
“The human milk oligosaccharides 2’-fucosyllactose and 6’-sialyllactose protect against the development of necrotizing enterocolitis by inhibiting toll-like receptor 4 signaling”
Authors: C.P. Sodhi, et al.