Human Milk Oligosaccharides
- closed gaps between gut cells
- decreased inflammation
Newborn infants have leaky guts. That is, the normal gaps between the cells in their
intestinal epithelia–known as tight junctions–are poorly developed. In a
recent paper, Maciej Chichlowski and colleagues in David Mills’ lab at the
University of California, Davis, find that certain bacteria, whose
establishment in the infant gut is favoured by human milk oligosaccharides
(HMO), promote the expression and proper positioning of tight junctions
proteins. Crucially, the bacteria only do this when grown on HMO. In other
words, HMO aid in the physical development of a baby’s intestine through the
actions of gut bacteria.
How did the Mills lab show this? They took two types of gut cells (Caco-2 and HT-29 cells), two types of bifidobacteria, or “Bifs”, (B. infantis and B. bifidum), and two things the Bifs eat (HMO and lactose). They then incubated the gut cells with either of the two Bifs. Next, the researchers measured the expression of various proteins made in the gut cells that form part of tight junction complexes. The two types of gut cells yielded different results, and different sorts of proteins underwent different changes in their rate of production.
But, importantly, there were some obvious hikes in the expression of key tight
junction proteins when the gut cells had been incubated with HMO-fed bacteria
compared to when they were incubated with lactose-fed bacteria of the same
species. For example, Caco-2 cells made 5.7 times more of the protein JAM-A
(junction adhesion molecule) when these cells were incubated with B. bifidum grown
on HMO compared to when the B. bifidum was grown on lactose. HT-29 cells made
twice as much of the protein ZO-1 when grown with HMO-fed B. infantis than when
grown with lactose-fed B. infantis. Immunofluorescent microscopy provided further
insight into these changes in protein levels. Occludin, another tight junction
protein, was left flailing in the cytoplasm of gut cells grown alongside lactose-fed Bifs. Meanwhile, in gut cells incubated with HMO-fed Bifs, it was neatly shepherded towards the area around the tight junction.
The authors offer some other intriguing examples of intestinal cell stimulation by
HMO-fed Bifs. They report that an HMO diet somehow enables B. infantis to stick
to gut skin cells better. This, they suggest, happens probably because of
changes in the expression of genes in the gut cells, induced by the bacterium,
that cause the gut cells to bind and signal to the bacterium more successfully.
In their test, 8.5% of lactose-fed B. infantis cells stuck to a monolayer of
HT-29 cells, while 26.5% of HMO-fed B. infantis cells clung on.
Lastly, Chichlowski et al. considered how feeding Bifs with HMO might have an indirect
influence on the immune system in the gut. As with the proteins that compose
the tight junctions, the authors measured the expression of several proteins in
the two types of gut cells, but this time the proteins they chose were known to
have a role in immunomodulation. The authors report that B. infantis grown on
HMO causes Caco-2 cells incubated alongside to make more of the anti-inflammatory cytokine, IL-10, and hikes by a multiple of seven the expression of a factor called SELPLG (compared to B. infantis grown on lactose).
What does this mean? The latter experiment points towards HMO having a kind of
prophylactic influence on the human body, Chichlowski writes that HMO could
possibly lower the odds that a breast fed infant will develop chronic
inflammatory disease later in life. Intriguingly, the changes in the levels of
cytokines might explain the changes in the distribution of tight junction
proteins that were illuminated by fluorescent microscopy. This is because
cytokines are known to influence the association of tight junction proteins
with the cytoskeleton.
All in all, these new findings add weight to the re-characterization of HMO as more
active players than was previously imagined in the interplay of infant gut,
bacteria, and milk. The results prompt as many questions as answers. More work
is needed to understand how HMO-grown Bifs influence the development of the
intestine’s structure and immunological function. The achievement of
Chichlowski’s paper is to make clear that they do.
1. Chichlowski M, De Lartigue G, German JB, Raybould HE, Mills DA. (2012) Bifidobacteria Isolated From Infants And Cultured On Human Milk Oligosaccharides Affect Intestinal Epithelial Function. J Pediatr Gastroenterol Nutr.
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