The Human Milk Oligosaccharide, 2’-FL, and its Effects on Stress-Induced Gut Motility

Most of us are aware of the term stress, but the relationship between stress and disease hasn’t always been well recognised. Known as the father of stress research, it was scientist Hans Selye, who first introduced the term stress into the medical world to describe the “nonspecific response by the body to any demand”[i], in 1936.

According to the Cambridge dictionary, stress, is “great worry caused by a difficult situation, or something that causes this condition”. In other words, stress is synonymous with many scenarios we find ourselves in. Only, it’s what happens to us physiologically when we fall victim to this little six letter word, that we will be focusing on in this article.

Stress and gut dysmotility

Stress is a reaction to so many areas of our lives, and as a result, in many cases this leads to a condition called dysmotility. It occurs because of a neurological reaction that causes the muscles or nerves within the digestive tract to become affected to the point of disruption. So, the digestive process no longer works as it should. Dysmotility leads to interruption of the absorption of nutrients and has a direct impact on how you will perform on a social and professional level[ii].

The focal point of this article will be a study by Farhin et al (2018) entitled "Restraint stress induced gut dysmotility is diminished by a milk oligosaccharide 2’-fucosyllactose (2’FL) in vitro’’[iii]. The purpose of the study was to test to see if human milk oligosaccharides (HMOs) can benefit dysmotility after being subjected to stress. The study was conducted in mice, so was an animal study rather than a human study.  

What changed that made this study viable?

Past research has been conducted with the main outcome being the prevention of the effects of stress which has gathered a lot of attention. Research into stress and its effects on the human body is an area of interest because it is associated with a long list of symptoms. These can affect you in many ways, not only physically, but also psychologically. Stress also impacts the way you behave, both in the short and long term. The following are short and long-term symptoms of stress.

Short Term Symptoms of Stress

Long Term Symptoms of Stress

Source:NHS (2022).[iv]

What is evident from the above list is that IBS is a long-term physical effect of stress. For this reason, it is possible that many people may be unaware that they are experiencing the early stages of stress and that it could lead them to being at a greater susceptibility of higher stress levels later in life[v]. So, the need for prevention is key to beating stress and reducing its cost to health. Therefore, many studies incorporating wellness or mindful-based stress reduction programs have been conducted to help find stress preventing solutions[vi].

But what about the individuals who were already experiencing the debilitating effects of stress?

Up until the study by Farhin et al (2018), research into treatment for those affected by stress-related symptoms, particularly in relation to the gut, was little in comparison. A common treatment is the μ-opioid receptor agonist, Loperamide, an opioid drug. It works by inhibiting peristalsis, the series of muscle contractions that move food through the digestive tract. But although this relaxed the muscles, it did not restore normal function.

Another study by West et al (2016), demonstrated for the first time that beneficial microbes could help to treat stress-induced gut dysmotility and restores normal function[vii] but further treatments are lacking. Hence the need for further research.

Milk oligosaccharides are found in the milk of mammals, but higher concentrations are found in humans, these are known as human milk oligosaccharides (HMOs). HMOs, in the past had only been considered prebiotics, molecules that encourage the growth of beneficial bacteria. However, there is mounting evidence to suggest that HMOs could be used in specific types of treatments targeted to the human gut.  

Previous lab findings conducted on colonic segments of mice, showed the human milk oligosaccharide, 2’FL, could moderate propulsive motility (peristalsis)[viii] through the modulation of the enteric nervous system dependent motility.

This raised the question of whether 2’FL could reverse the effects of previous restraint stress, in vivo or in whole, living organisms or cells. So, the study by Farhin et al (2018) aimed to test the effects of 2’FL in stressed mice.  

How was the study conducted?

Two tests were performed as part of the study. One to test the effect of restraint stress on faecal pellet production and the second on another cohort of stressed mice. These mice were fed 2’-FL immediately after being exposed to stress to determine the effects of this HMO on pellet production.

Segments of the colon and jejunum were taken from untreated Swiss Webster mice that had been subjected to severe restraint stress, either by being placed in a wire mesh restraint device or kept in their cage for one hour.

The segments were then perfused with a solution used as a buffer that can be used to take readings called Krebs, along with propagating contractile clusters (inducing contractions to record the results).

A 1 mg/ml of either 2’FL or β-lactose was then added. Spatiotemporal maps were created to show how the segments from the two specified regions of the gut reacted to the treatment using propagating contractile clusters[ix]. The parameters tested were velocity (rate of change), frequency (number of times the event occurs within one timeframe), and amplitude (size of change) These were in frames of 20-minute durations.

Results

The results of the study showed that 2’FL can reverse stress related effects on intestinal motility to almost normality for mouse jejunum or colon segments, in vitro.

The oligosaccharide 2’-FL increased propulsive motility of the stressed jejunal segments after 10 to 15 minutes whereas the β-lactose had little or no effect.

The effect of 2’-FL changed the sample means for the stressed jejunal segments by +50% for velocity, +42% for frequency and -3% for amplitude. The results for the same parameters for the ß-lactose were -6%, +7% and -6%.

The Krebs + 2’FL effects on the unstressed jejunal segments showed increases of +8% velocity, +39% frequency and +11% for peak amplitude compared to Krebs alone. The results for the same test using the β-lactose were considerably less. The result for the stressed colon segments were also decreased with the 2’FL solution and again the β-lactose had little effect.

What do these results mean?

Ultimately, the HMO, 2’FL, displayed for the first time, that a single oligosaccharide rather than a live microbe can have stress reversing abilities in intestinal motility.

There are over 200 oligosaccharides in human milk, most of which are a fucosylated or sialylated. 2’FL is the most abundant. In this study, 2’FL showed a greater response to the treatment of gut dysmotility than using β-lactose.

One drawback of the study was that it did not allow any possible side effects of the treatment to be highlighted concerning the central, sympathetic, or parasympathetic nervous systems. However, the results in mice are promising and show that HMOs, particularly 2’ FL could offer potential benefits for the treatment of stress-induced gut dysmotility.

Summary

Stress has been around for a long time but only emerged in scientific literature in the 1930s. It causes many symptoms ranging from mild signs like, sweating through to painful and debilitating conditions such as IBS.

Studies into previous treatments have been largely looking at ways to treat or stop the symptoms of stress. This study shows a whole new approach to dealing with the condition, namely actually reversing the process stress can activate.

This is the first study into this type of treatment. Although there still needs to be further research into the effect 2’-FL, and other HMOs, can have on stress related gut symptoms, this is another study showing how HMOs can be used throughout life to help maintain and sustain the human gut.

Written by: Leanne Edermaniger, M.Sc. Leanne is a professional science writer who specializes in human health and enjoys writing about all things related to the gut microbiome. 

References:

[i] Fink G. Stress: Definition and History. Encyclopedia of Neuroscience. 2009;:549-555.

[ii] Kamperidis N, Nightingale J. Neurological disorders and small bowel dysmotility. Curr Opin Gastroenterol. 2022 May 1;38(3):299-306. doi: 10.1097/MOG.0000000000000836. PMID: 35645022.

[iii] Farhin S, Wong A, Delungahawatta T, Amin J, Bienenstock J, Buck R, Kunze W. Restraint stress induced gut dysmotility is diminished by a milk oligosaccharide (2′-fucosyllactose) in vitro. PLOS ONE. 2019;14(4):e0215151.

[iv] Short and Long term effects of stress [Internet]. Peoplefirst.nhsbt.nhs.uk. 2022 [cited 2022 Sep 2]. Available from: https://peoplefirst.nhsbt.nhs.uk/Wellbeing/short-and-long-term-effects-of-stress.htm

[v] Kalmakis, K, A. Chiodo, L, M. Kent, N. & Meyer, J, S. (2020) Adverse childhood experiences, post-traumatic stress disorder symptoms, and self-reported stress among traditional and nontraditional college students, Journal of American College Health, 68:4, 411-418, DOI: 10.1080/07448481.2019.1577860

[vi] Khoury B, Sharma M, Rush SE, Fournier C. Mindfulness-based stress reduction for healthy individuals: A meta-analysis. J Psychosom Res. 2015 Jun;78(6):519-28. doi: 10.1016/j.jpsychores.2015.03.009. Epub 2015 Mar 20. PMID: 25818837.

[vii] West C, Wu R, Wong A, Stanisz A, Yan R, Min K, Pasyk M, McVey Neufeld K, Karamat M, Foster J, Bienenstock J, Forsythe P, Kunze W. Lactobacillus rhamnosusstrain JB-1 reverses restraint stress-induced gut dysmotility. Neurogastroenterology & Motility. 2016;29(1):e12903.

[viii] Sarna SK, Otterson MF. Gastrointestinal motility: some basic concepts. Pharmacology. 1988;36 Suppl 1:7-14. doi: 10.1159/000138415. PMID: 3285364.

[ix] Wu RY, Pasyk M, Wang B, Forsythe P, Bienenstock J, Mao YK, Sharma P, Stanisz AM, Kunze WA. Spatiotemporal maps reveal regional differences in the effects on gut motility for Lactobacillus reuteri and rhamnosus strains. Neurogastroenterol Motil. 2013 Mar;25(3):e205-14. doi: 10.1111/nmo.12072. Epub 2013 Jan 15. PMID: 23316914.