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A paper fresh off-the-press in the journal Cell Host & Microbe entitled “Dosing a synbiotic of human milk oligosaccharides and B. infantis leads to reversible engraftment in healthy adult microbiomes without antibiotics” provides the framework for a simple and affordable a proof-of-concept strategy to modulate the microbiome and improve markers of health in adult volunteers. Before we unpack the methods, results, and conclusions of the research, let’s begin by establishing some background information.
A synbiotic is combination therapy which includes a prebiotic and a live biotherapeutic product (LBP).
Prebiotics are molecules that cannot be broken down by our digestive processes and, as a result, arrive intact in the colon where they can directly feed the microbiome. These molecules are found in both foods and dietary supplements. Some of the most important prebiotics becoming increasingly available in the nutraceutical space are human milk oligosaccharides (HMOs).
First isolated from human breast milk, the function of HMOs is to provide a food source for the nascent microbiome of the infant gut. One bacterium that is particularly adept at breaking down HMOs is Bifidobacterium longum subspecies infantis (B. infantis). In fact, B. infantisis the most abundant bacteria in the infant gut for this very reason. This bacterium breaks down HMOs into the metabolites acetate and lactate, which feed the bacteria in the microbiome that produce butyrate: a molecule that plays important roles in host satiety, immune function, metabolic health, and more. Following cessation of breast feeding, B. infantis levels decline as exposure to HMOs is restricted.
LBPs, or probiotics, are live bacteria that are considered to be beneficial to human health. In this paper, B. infantisserved as the LBP and was administered orally in conjunction with an HMO prebiotic. In the infant gut, B. infantislevels are associated with decreased levels of pathogenic bacteria within the microbiome, increased butyrate production, and enhancements in gastrointestinal health.
The goal of this study was to determine whether the administration of a synbiotic consisting of B. infantisand HMOs could facilitate B. infantiscolonization of the adult gut and if this colonization could improve both the quality of the microbiome and levels of key metabolites like butyrate and lactate.
This study contained six experimental cohorts that can be broadly categorized into three groups.
Group 1 received B. infantis alone on days 1-7, Group 2 received 18g of HMOs alone on days 1-14, and Group 3 received both B. infantis on days 1-7 and either 4.5g, 9g, or 18g of HMOs daily on days 1-14. The HMOs used in this study were isolated from donor breast milk. Prior to beginning treatment, all subjects were screened for the presence of B. infantisin the microbiome, and all results came back below the limit of detection, which is consistent with the notion that this bacterium is absent from the adult gut.
Although some researchers in the field believe that antibiotic pre-treatment is required for the engraftment (i.e. colonization) of probiotics like B. infantisinto the adult gut, subjects in this study were not administered antibiotics. The research team hypothesized that the co-administration of HMOs with the LBP would be sufficient to facilitate engraftment without the use of antibiotics, which often come with unwanted effects such as dysbiosis, diarrhea, and gut distress.
Stool samples were collected on day 0 and again on days 5, 8, 15, 22, and 29 to assess 1) B. infantislevels in the microbiome before, during, and after treatment 2) changes to microbiome composition more broadly and 3) levels of key metabolites including short chain fatty acids (i.e. acetate and butyrate) and lactate.
Stool from Group 1, the group administered B. infantis alone for days 1-7, contained measurable levels of B. infantisduring and immediately after (day 8) the dosing period. However, B. infantis levels dropped precipitously after day 8, returning to levels below the limit of detection by day 15. There was no increase in the abundance of B. infantis in the stool samples from Group 2, the HMO-only group. Strikingly, stool samples from Group 3, the group administered the synbiotic, showed that B. infantislevels remained elevated until day 15.
In other words, the administration of HMO alone from day 8 to day 14 was sufficient to sustain levels of B. infantisin the stool. This indicates that the B. infantisprovided days 1 through 7 as part of the synbiotic regimen effectively colonized the gut and was sustained via the consumption of HMOs in the subsequent days. Importantly, the dose of HMO provided played a role in the success of B. infantisengraftment. Specifically, the sub-group administered 18g of HMO daily showed the highest levels of engraftment relative to the sub-groups given 9g and 4.5g.
De-engraftment of B. infantis in the gut occurred in most Group 3 subjects by day 22—one week following cessation of HMO consumption. In other words, B. infantisengraftment is dependent upon the co-administration of HMO, and removal of HMO will result in depletion of the B. infantis population back to baseline levels below the limit of detection. There were no serious adverse events within any of the study groups, indicating that the synbiotic can be safely used in healthy adults.
With regards to broad changes in the microbiome, none of the groups displayed changes in alpha diversity. Alpha diversity is a measure of the number of different bacterial species present in one sample. In other words, when assessed in isolation, each sample in Group 1, 2, and 3 possessed a number of bacterial species that is considered normal for healthy adults.
However, the group that received both B. infantis and 18g of HMO exhibited a significant increase in beta diversity. Beta diversity is the difference in the bacterial composition between two samples or groups of samples. Put simply, when comparing samples from Group 3 to samples from Groups 1 and 2, Group 3 samples possessed the greatest variety of bacterial species. Moreover, in addition to having elevated levels of B. infantis, engrafted individuals also possessed higher levels of other species of Bifidobacteria including B. kashiwanohense, B. breve, B. catenulatum, and B. bifidum.
Given the important roles of Bifidobacteria in gut and immune function, the enhancements in the populations of these species is associated with tangible health improvements. Many of the benefits are associated with enhanced production of acetate and lactate by Bifidobacteria, and the resulting boost in butyrate production by other species that are fueled by acetate and lactate. To this end, the researchers measured short chain fatty acids (SCFAs) and lactate in the stool samples to determine whether augmentation of the various Bifidobacteria species resulted in elevated levels of these important metabolites.
They observed significantly higher levels of lactate in engrafted individuals, which they attributed to the fermentation of HMOs to lactate by B. infantis. No differences in the levels of SCFAs were observed across groups. The production of lactate and SCFAs is crucial for the maintenance of a lower pH environment in the colon, where a lower pH is positively associated with a healthy microbiome and optimal gut function.
In addition to testing the synbiotic in healthy humans, the researchers also performed a study in mice grafted with microbiomes from unhealthy, dysbiotic human patients. When the mice were administered the B. infantis, HMO synbiotic, fecal butyrate levels increased markedly. Given the importance of butyrate in establishing, or re-establishing, a healthy microbiome, these findings suggest that the synbiotic may facilitate important clinical improvements in individuals with dysbiosis.
Finally, in vitroculture experiments were performed to assess the effects of the synbiotic on the growth of various bacteria present in the human gut. Encouragingly, the synbiotic was shown to inhibit the growth of pathogenic species of gut bacteria.
A synbiotic consisting of a combination of B. infantisand HMOs led to the successful engraftment of B. infantis into the microbiome of healthy adults. In addition to facilitating meaningful colonization of the gut by B. infantis, the engraftment also increased the levels of other species of Bifidobacteria, bolstered lactate production, and enhanced gut beta diversity. Finally, the in vivo mouse experiments and in vitroexperiments suggest that the synbiotic not only enhances the growth and colonization of beneficial bacteria, but also actively inhibits the growth of harmful microbes characteristic of dysbiosis. Thus, the B. infantis-HMO synbiotic appears to be a safe, affordable, and effective tool for both gut health remediation and optimization.
Written By:
Dr. Alexis Cowan, a Princeton-trained PhD specializing in the metabolic physiology of nutritional and exercise interventions. Follow Dr. Cowan on Instagram: @dralexisjazmyn
Reference
Julie E. Button et al. “Dosing a synbiotic of human milk oligosaccharides and B. infantis leads to reversible engraftment in healthy adult microbiomes without antibiotics” Cell Host & Microbe, Volume 30, Issue 5. 11 May 2022. 712-725. https://doi.org/10.1016/j.chom.2022.04.001.
