Human Milk Oligosaccharides in the Prevention, Treatment of Nervous System Diseases
In this video, Alex Martinez discusses research on the use of human milk oligosaccharides (HMOs) in the prevention and treatment of nervous system diseases, such as Alzheimer disease, including the mechanism of action and the relationship between diet and the nervous system.
Additional Resources:
- Fan Y, McMath AL, Donovan SM. Review on the impact of milk oligosaccharides on the brain and neurocognitive development in early life. Nutrients. 2023;15(17):3743. doi:10.3390/nu15173743
- Ronchi G, Ryu V, Fornaro M, Czaja K. Hippocampal plasticity after a vagus nerve injury in the rat. Neural Regen Res. 2012;7(14):1055-63. doi:10.3969/j.issn.1673-5374.2012.14.003
- Yu QJ, Yu SY, Zuo LJ, et al. Parkinson disease with constipation: clinical features and relevant factors. Sci Rep. 2018;8(1):567. doi:10.1038/s41598-017-16790-8
- Braak H, Del Tredici K, Rüb U, de Vos RA, Jansen Steur EN, Braak E. Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol Aging. 2003;24(2):197-211. doi:10.1016/s0197-4580(02)00065-9
- Liu B, Sjölander A, Pedersen NL, Ludvigsson JF, Chen H, Fang F, Wirdefeldt K. Irritable bowel syndrome and Parkinson's disease risk: register-based studies. NPJ Parkinsons Dis. 2021;7(1):5. doi:10.1038/s41531-020-00145-8
- Konings B, Villatoro L, Van den Eynde J, Barahona G, Burns R, McKnight M, Hui K, Yenokyan G, Tack J, Pasricha PJ. Gastrointestinal syndromes preceding a diagnosis of Parkinson's disease: testing Braak's hypothesis using a nationwide database for comparison with Alzheimer's disease and cerebrovascular diseases. Gut. 2023;72(11):2103-2111. doi:10.1136/gutjnl-2023-329685
- Liu S, Gao J, Zhu M, Liu K, Zhang HL. Gut microbiota and dysbiosis in Alzheimer's disease: implications for pathogenesis and treatment. Mol Neurobiol. 2020;57(12):5026-5043. doi:10.1007/s12035-020-02073-3
- Constipation associated with cognitive and decline. Paper presented at: Alzheimer’s Association International Conference 2023; July 16-20, 2023. https://aaic.alz.org/releases_2023/constipation-gut-health-alzheimers-dementia-risk.asp#:~:text=Bowel%20movement%20frequency%20of%20every,more%20than%20twice%20a%20day
- Quagliani D, Felt-Gunderson P. Closing America's fiber intake gap: communication strategies from a food and fiber summit. Am J Lifestyle Med. 2016;11(1):80-85. doi:10.1177/1559827615588079
TRANSCRIPTION:
Alex Martinez: I'm Alex Martinez, I'm the CEO and co-founder of Intrinsic Medicine, a company devoted to using human milk biology to advance new solutions for gut-immune-brain-axis disorders.
Consultant360: What is the relationship between diet and the nervous system?
Alex Martinez: To understand the complex interaction, the complex system that is the gut-immune-brain-axis, it is important to think about the evolutionary context. And one of the ways I've been starting to help people conceptualize this is what is the gastrointestinal system. What is the marriage of our own system and these outside organisms, this outside community?
If you extracted the gastrointestinal system from a human being, what is it? It's a worm. So, if we think about it, if we go all the way back, and hopefully for your audience, they've spent a lot of time looking at a microscope probably very early on in their career. If you look at pond water, you look at it and it is absolute chaos for those little unicellular organisms.
And at some point, some of them said, “Hey, let's work together here, right? Let's form a colony. Let's form a complex structure.” And as part of that, that first structure was a tube. And it was an open system in the primordial, aqueous environment.
And at some point, some other microbes said, "Hey, we don't want to join on your colony full-time, but we'd appreciate using this as a refuge. And we think there's a way that we can work together, so let's form an early alliance. And so, there we have the first worm, right? And that is actually the first gastrointestinal tract, and it is a free living one. And so, the way I like to orient people is that the alliance decided that it needs an exoskeleton. And that exoskeleton needs a command center, the brain. And so, that system, that relationship may have allowed us to evolve into a much more complex superorganism. And that's the way I think, if we want to talk about the relationship between the diet and the nervous system, we have to think about it in that superorganism perspective.
C360: Please explain the basic structures of HMOs and the gut immune system.
Alex Martinez: This is really an extension of the framing that I gave you. When we think about what's coming into the gut, the gut microbiome is an environmental sensing organ. Because imagine we need caloric energy, but this is the first time we're essentially taking the outside environment and bringing it inside of ourselves. So, when we think about what the gut immune system is, that's the thin line between the outside environment that we've now internalized and our internal environment, which is extremely privileged. When something enters into circulation, guess what? It's going to all the cells of our body and then it's even crossing that inner barrier, the blood-brain barrier going directly to the crown jewels of self, the central nervous system.
And so, when we think about the gut immune system, it is really that barricade, that line where we have our somatic cells and about 70 % of the immune cells are right there in the gut. It's why after you eat, there's always postprandial inflammation. There's always a postprandial inflammatory response, essentially as the borders are open and the guards are making sure the right things get in and the pathogens are outside organisms or toxins stay out.
HMOs are human milk oligosaccharides, so these are complex sugars. They're based on a galactose backbone, and then the bonds really determine their structure.
There are really three. There are fucosylated ones that have fucose moiety, there are neutral ones, and then there are acidic ones that typically have sialic acid with very different bonds. And there are about 200 distinct structures of these HMOs found in the repertoire of human milk.
And what's pretty neat about them is that even ones that you would consider an isomer have a completely different function. So, each one exists for a specific purpose, and those purposes are multifaceted. So, this is almost like the Swiss army knife of glycobiology. So, they select ones directly… are preferential substrates for certain microbiota, including up-regulating things like adhesion genes. So, for example, one of these up-regulates adhesion genes in bifidobacteria, which then enables them to form a biofilm over our gut, and that forms the basis of what we would call a healthy microbiome.
And then one of the things we're discovering about the microbiome is who they are may matter less than what they do. And so, each one of these distinct structures, then with precision, has downstream metabolites after it's metabolized by that good microbe that we wanted to invite to stay a long time in our GI tract.
And then the other very special thing about an HMO, which you can understand from the adaptive context, it's like, this is human milk after all. This is when a baby's immune system is maturing. It's fresh into boot camp. If it doesn't know anything. So, these HMOs are also educating the somatic cells and the immune cells, both innate and adaptive immune cells, macrophages, and T cells, making sure they recognize themselves, the baby's intestinal epithelial cells: “Hey, these are friendly forces. Do not attack them. Friendly bacteria. Hey, these are also the good guys. Don't attack them.”
And saying, “Hey, these are E. coli. It's part of the community but watch it. We don't want it to outgrow.”
And so, they're capable of really balancing the TH1 and TH2 response to make sure that we have an appropriate immune response, not one that leads to collateral damage.
C360: What are the beneficial effects of HMOs shown in cell and animal studies? What is the mechanism of action?
Alex Martinez: It’s hard to talk about the structures without talking about the functions, but I think it's really three buckets: It's promoting eubiosis–the healthy ecosystem in the microbiome–making sure that those drug-like metabolites are ones that are beneficially bioactive.
This is important because these are extremely small molecules and they are active at picomolar concentrations, which for your clinicians, it's a completely different pharmacology and these things can penetrate the blood-brain barrier as well. And then I think on the other side, as I had already kind of previewed, for example, some of these directly bind to TLR4, to Siglecs, so CD receptors on immune cells, can change the phenotype of the immune cells.
So, we've even seen direct effects working through epigenetic-type mechanisms by which you can shift macrophage polarization, for example, from an M1 to an M2, or to increase and enhance t-regs, as I mentioned, to balance that TH1, TH2 response. And so, one of the very fascinating things is that I think we're going to be able to do that. think will be interesting to clinicians is these compounds in multiple settings of inflammation, both sterile inflammation but also pathogen-induced inflammation.
HMOs have been shown through this multifaceted mechanism to reduce systemic inflammation, you know, TNF-alpha, IL -1 -beta, IL -6, but they're not doing it through immune suppression. They're doing it via a pro-resolution, and that's the exciting thing.
It's why I started the company around these compounds because what are our chronic diseases driven by? A maladaptive inflammatory response. You know, all clinicians know inflammation is great. We're all here because of it. But it's not supposed to last more than three weeks. It's supposed to be an acute phase to resolution. And so to see these compounds essentially be the bumper plates for the baby's very primed, very aggressive early immune system… if we can recapitulate that biological mechanism and bring people that have a dysregulating immune system and say “hey, it's okay. It’s resolved. The threats are gone." You can focus more on regenerative aspects. That's the application that we're looking for here.
C360: What research is being done on the HMOs’ impact on the prevention and treatment of nervous system disease, such as Alzheimer disease?
Alex Martinez: Early on, and this stacks onto your previous question, early on it's been shown in human epidemiology, because we can look at the levels of HMOs in different mothers' milk, and we can actually see that high levels of some are actually associated with neurodevelopment in infants, including executive function.
And so that lets some really fascinating research say, "How does this happen?" The dominant HMO being assessed in rat models of executive function and actually showing that if you severed the vagus nerve, guess what, we lost that improvement in executive function. And so that was kind of like the early dataset that made us look at this and say, “Hey, these are, this is being mediated by the vagus nerve?” And when we look in brains, we're actually seeing an increase in brain-derived neurotrophic factor. We're seeing the preservation of doublecortin-positive neurons, the ones responsible for brain plasticity. And so now, we say, “Wow, this is very hypothesis-generating that these may be useful in something like Parkinson's, something like Alzheimer's.”
And so, we originally set out to study this in irritable bowel syndrome, constipation dominant. We're getting ready to run a phase 2B study in that. And secondary to that, we had noticed a long-standing association with constipation and Parkinson's disease. Up to 80 % of people with Parkinson's, in fact, have constipation as a preceding symptom.
And so that set up Braak's hypothesis, which was also supported by the fact that patients with Parkinson's had very distinct oral pharyngeal microbiomes and gut microbiomes. And so, then there was a massive study in Gut BMJ, British Medical Journal that was published in August testing Braak's hypothesis and looking at exposure to those gut symptomologies. And saying, "Hey, what's the strength of this association?" And lo and behold, they showed that patients with a history of irritable bowel syndrome, constipation dominant had over four times the odds of developing Parkinson's with a p-value of .001, so verified association.
So, we looked at that and that was really a sufficient compiled dataset, including human epidemiology, to say “This is worth testing interventionally.” And so, that led to the development of the protocol. So, we were approved in Australia. to start dosing a phase two Parkinson's study. Also, recently, preclinical data has supported that same hypothesis for Alzheimer's, and there has been data showing that it looks like there's dysbiosis in the gut as a causal driver for Alzheimer's and a study in amyloid-beta and tau-producing mice orally dosed with the dominant HMO actually were able to reduce amyloid beta and tau aggregates in the central nervous system. So, that is very exciting stuff, and knowing that we can rapidly translate it into an interventional clinical context is I think the most exciting aspect of these compounds and our approach.
C360: What is next for research on HMOs and Alzheimer disease and other nervous system diseases?
It's to test them in clinic. And that's the beauty of what we've done because HMOs have been explored for several decades to be included in infant formula, and that includes supporting safety studies in both animals, as well as human beings. And so, what we've realized that we have the opportunity to do is go to local ethics committees and say “Here's the data, here's the protocol, we’re working with world-class clinician researchers.” And they're saying “Yes, run the study. It's very unlikely that these are going to harm anyone.”
They've not shown any toxicity. The LD-50 is unknown for these compounds, somewhere above 25 g/kg of body weight per day, so that's five times less toxic than baking soda.
And so, if you have an opportunity to benefit people based on epidemiology, just make sure it's safe and powered correctly. I think what's special here is that pioneers in the field of fecal-matter transplants have done early explorative, open-label studies showing the ability of gut-targeting, a microbiome-targeting intervention to improve clinical outcomes in patients.
And so, we're not going in blind with powering assumptions either. And because we have the ability to scale these up in the right format and now, we're informed on what powering looks like, we can go directly into a phase two program. So, when we say, “Hey, we have an announcement, we have something new,” it's not like, "Hey, let's wait for 5 years until we have a clinical candidate." Instead, it's "Let's get an early answer, see if there's a signal, and then think creatively about how we advance this to the people in need."
C360: What are the overall take-home messages from our conversation today?
Alex Martinez: Hippocrates has been telling us for a very long time, “Let food be thy medicine.”
And that all diseases start in the gut. And one of the low-hanging opportunities here is that all of this emerging evidence shouldn't just be designed to wait until there's an intervention, wait until there's a therapy for it. It means that the behavioral and lifestyle changes that always are the first line for a lot of these, should be reinterrogated.
And thoughst about doing nutritional audits for patients with some of these, I think, may be an early opportunity to deliver something meaningful. For example, constipation is associated with a 73 % reduction in cognition. We have that.
When I talk about human milk oligosaccharides, of course, we selected them because they are Mother Nature’s drugs, but what are they? They're prebiotics, they're dietary fiber, and 95 % of US adults are so far below the target dietary fiber ranges.
So, there really is a meaningful opportunity through nutritional intervention to explore helping to mitigate and slow down or even prevent some of these neurodegenerative disorders that previously we've been thinking of as only in the brain and that require brain intervention. And so, this is really an earlier opportunity.
I think that the science is really exciting and that folks on the ground level have an opportunity to experiment and improve their patients today, looking at nutrition truly as an interventional opportunity.