- Previous research has shown that the body releases specialized chemical signals that help resolve infections.
- A new study identifies previously undescribed chemical signals present in human breast milk that accelerate tissue repair and regeneration in addition to resolving infections.
- The discovery of these molecules may improve our understanding of the beneficial properties of breast milk and could lead to new approaches to treating infections and several human diseases.
What do breast milk, regenerating flatworms, and infected mice have in common? That might sound like a particularly cryptic riddle, but the answer may improve our understanding of the beneficial properties of breast milk and could potentially lead to new therapies for many diseases.
In a new study, Charles Serhan and his team from Brigham and Women’s Hospital identified new chemical signals that help resolve bacterial infections and speed up tissue repair and regeneration . They isolated these molecules from human breast milk, mice with self-limiting bacterial infections, and regenerating flatworms called planaria.
“The primary response in an infection and in an inflammatory response is to recruit cells to the site of injury or bacterial invasion,” explains Serhan, a biochemist and experimental pathologist. Serhan studies how the human body stops this cell recruitment and shuts down the inflammatory response before it can become harmful. Uncontrolled inflammation has been implicated in a number of diseases, including cardiovascular disease, asthma, Alzheimer’s disease, and arthritis. Finding new ways to stop the inflammatory response could potentially help treat many of these ailments.
Serhan’s previous work has helped show that the resolution of inflammation is an active process, mediated by molecules dubbed ‘specialized pro-resolving mediators’ or SPMs [2,3,4,5]. “This is a pretty novel concept,” says Serhan. SPMs are small molecules made at the site of an infection that promote the clearance of bacteria and cellular debris from the infection site and stimulate the resolution of the inflammatory response.
But that may not be all they do. In a recent study, Serhan and his team showed that in pigs with periodontitis—a gum infection that destroys the bone supporting teeth—using pro-resolving molecules to control inflammation actually allowed the tissue to regenerate . Serhan recounts that the team “started to think hard about how all these specific signals in the resolution response can actually stimulate tissue regeneration.”
In the new PNAS study, Serhan and his team isolated chemical signals from self-limited bacterial infections in mice, and then examined whether these could promote tissue regeneration. They looked at the effects of these signals on flatworms called planaria, which have an amazing ability to regrow body parts that have been injured or cut off . According to Serhan, “They’re an ideal model for looking at tissue regeneration. You can cut those planaria in half, and then they’ll regenerate on their own, and we looked at whether these specific signals would regulate this.”
Serhan and his team cut off the heads of planaria and found that the heads grew back faster in the presence of these chemical signals. They characterized the molecules responsible for this regenerative effect as lipid-protein conjugates, and called them sulfido-conjugated product I (SCI) and sulfido-conjugated product II (SCII) based on their structures.
Next, they decided to look for similar chemical signals in human milk. Serhan says that “anything important is present in human breast milk.” The team was able to isolate chemical signals from human milk that also promoted regeneration in planaria. This discovery, he remarks, “really clinched it for us that this could be important in human biology.”
Jesmond Dalli, a biochemical pharmacologist at Brigham and Women’s Hospital and the first author on the PNAS study, estimates that “if these signals are as important as we think they are, then they have to be conserved in evolution.”
“So, we started with a mouse, and then we went to planaria, to see whether these processes were active there,” says Dalli. Looking at human milk, “gave us a way to look at regeneration in humans,” he says. “We can’t really chop someone’s fingers off and look at what’s happening, so these regenerative processes that are happening in infants that are developing, that was our validation.”
The team had good reason to think that these signals might be present in milk. Human breast milk has been previously shown to contain chemicals and nutrients that play a role in infant development and immunity . A recent study also found high concentrations of certain types of SPMs in human breast milk . Moreover, many SPMs, including SCI and SCII, are synthesized from fatty acid precursors such as docosahexaenoic acid, or DHA. Serhan says that “Another reason we were interested in milk was because we know that in mother’s milk, there’s a high concentration of DHA.” DHA from breast milk is thought to play a role in early neural development, and is added to some infant formulas, although, according to the FDA, it is still unclear whether DHA in infant formula is beneficial .
Serhan is currently working on determining therapeutic uses for SPMs. The compounds found in the PNAS paper and in another more recent study by Serhan’s team enhance the killing and clearance of E. coli . He explains, “They’re actually enhancing the anti-microbial action of the innate immune system.” The ability of SPMs to control inflammation could prove useful against the many diseases where unresolved inflammation may play a role. In fact, he says, “There are a couple of these molecules and their analogs that are already in clinical trials for things like periodontal disease, and eye inflammation.” What makes SPMs particularly handy is that unlike many common anti-inflammatory molecules, they do not suppress the overall immune system, so they wouldn’t disrupt the body’s ability to respond to other infections.
There’s also the question of what natural role these molecules might be playing in human breast milk. We don’t have specific answers yet, but Serhan thinks we can speculate. From his work, “what becomes even more exciting is the possibility that these agents are present in milk to enable growth and tissue development,” he says. Given that breast milk carries many immune mediators, these molecules could also be important for the infant’s immune development. Serhan says, “Those are really exciting possibilities, and I guess more reason why breast milk is very important.”
1. Dalli, J, Chiang N, Serhan, CN. Identification of 14-series sulfido-conjugated mediators that promote resolution of infection and organ protection. Proc Natl Acad Sci USA. 2014 Nov 4;111(44):E4753-61.
2. Serhan CN et al. (2011) Novel anti-inflammatory–pro-resolving mediators and their receptors. Curr Top Med Chem. 11(6):629-47
3. Chiang N, et al. (2012) Infection regulates pro-resolving mediators that lower antibiotic requirements. Nature 484(7395):524–528.
4. Serhan CN (2014) Pro-resolving lipid mediators are leads for resolution physiology. Nature 510(7503):92–101.
5. Serhan CN et al. (2014) Lipid mediators in the resolution of inflammation. Cold Spring Harb Perspect Biol. 7(2):a016311.
6. Van Dyke TE et al. (2015) Proresolving nanomedicines activate bone regeneration in periodontitis. J Dent Res 94(1):148-56.
7. Sánchez Alvarado A (2006) Planarian regeneration: Its end is its beginning. Cell 124(2):241–245.
8. Calder PC, et al. (2006) Early nutrition and immunity — progress and perspectives. Br J Nutr 96(4):774–790.
9. Weiss GA et al. (2013) High levels of anti-inflammatory and pro-resolving lipid mediators lipoxins and resolvins and declining docosahexaenoic acid levels in human milk during the first month of lactation. Lipids Health Dis. 12:89
10. “Questions & Answers for Consumers Concerning Infant Formula.” FDA.gov. Web. 26 Nov. 2014. http://www.fda.gov/Food/FoodborneIllnessContaminants/PeopleAtRisk/ucm108079.htm
11. Dalli J et al. (2015) Novel proresolving and tissue-regenerative resolvin and protectin sulfido-conjugated pathways. FASEB J. pii: fj.14-268441. [Epub ahead of print]
Freelance Science Writer