The normal development and maintenance of central neural functions are highly correlated with the
amount of docosahexaenoic acid (DHA; x-3 fatty acid) accumulated in the brain. DHA incorporated at
the sn-2 position of lipids is well absorbed by intestinal mucosa and utilized efficiently in vivo.
However, modern consumers have a reduced direct intake of DHA and increased intake of saturated fats
or x-6 fatty acid oils, resulting in behavioral and neurophysiological deficits. To provide an understanding
of the integrated beneficial effects of DHA on the human brain, this review introduces the positional
difference (sn-2 and sn-1,3 positions) of DHA on a glycerol skeleton in natural fats and oils, and further
discusses the possible functional mechanism regarding DHA supplementation and the gut-brain axis. The
multiple bidirectional routes in this axis offer a novel insight into the interaction between DHA supplementation,
the gut microbiota, and brain health. To achieve high sn-2 DHA in diets, it is suggested that sn-
2 DHA lipids be enzymatically produced in more efficient and economical ways by improving the specific
activities of lipases and optimizing the purification procedures. These types of diets will benefit individuals
with strong needs for sn-2 x-3 lipids such as infants, children, and pregnant and lactating women.