Past, Present, and Future of “Biological Aging” with Dr. Fitzgerald
Remember the first time you heard about FMT (Fecal Microbiota Transplantation)? Maybe it sounded promising yet kinda viscerally challenging? It’s come a long way from humble beginnings, and has since covered a lot of health territory. And FMT preparations are increasingly standardized, with some pretty cool research happening well beyond the limited C diff application. Including for allergy.
The gut microbiome is emerging as a key negotiator determining how—and whether—the body reacts to a substance (e.g., bacterial lipopolysaccharide) as an antigen. And at least in animal models of allergy, it can go either way: An adaptive gut microbiota can establish immune tolerance to the LPS, whereas an out-of-balance microbiota can inhibit tolerance. Likewise, our microbiota play a major role in establishing tolerance (or allowing reactivity) to food. Now more than ever, we are in need of powerful and effective interventions for food allergy, as the rise of allergy- and more alarming- anaphylaxis- continues with children AND adults.
Could FMT, which can be seen a complex probiotic with broadband intestinal communication capacity, be our answer? Check out these 3 areas of interesting research happening on the FMT/allergy front, followed by a few thoughts from me, and a few from Dr. Ty Vincent.
- A January 2019 study used an interesting method of studying the effects of the human microbiome on milk allergy: give animals FMT from either healthy or allergic infants. They found that simply receiving FMT from an allergic child was enough to induce a severe reaction to milk in a mouse not previously intolerant to it. Upon genomic analysis of the gut microbiomes of healthy versus milk-allergic infants, a Firmicutes butyrogen from the increasingly famous group of Clostridial ‘commensals with benefits’ called Anaerostipes caccae was identified as the primary protective factor differentiating who became sensitized to milk and who did not—at least in this experiment. A. caccae has been found to join forces with the desirable Akkermansia muciniphila to the benefit of both; previous research on other Clostridial commensals showed that their gut presence might even prevent allergic sensitization to nuts through inducing IL-22 production and improving gut barrier function.
- A June 2019 study chimes in: mice with severe egg allergy given FMT from healthy infants were spared anaphylaxis while those provided FMT from allergic infants were not. Really important point: researchers additionally discovered that combinations of bacteria from either the Clostridium cluster of Firmicutes commensals (as in the January 2019 study) or the order Bacteroidales given as a probiotic had an analogous protective effect—as did a Firmicutes phylum newcomer on the scene, Subdoligranulum variabile. These bacteria heightened T-reg cell expression within the IgE-imbalanced allergic milieu, drawing it back towards better immune tolerance. The fecal microbiomes of allergic and non-allergic infants had shown significant differences in S. variabile as well as in some Clostridia; the researchers speculated that a “deficiency” in S. variabile may even have been a trigger for developing intolerance. An intriguing finding was that the effective microbes appeared to induce a particular T-reg cell possessing a specialized member of the retinoic acid-related orphan receptor (ROR) family called RORγt, which can influence whether naïve T cells develop into Th1/Th2-modulating T-regs or immune-activating T17 cells, and so is thought to play important roles in atopy and autoimmunity. It’s worth noting that RORγt comes into play as a result of pro- versus anti-inflammatory influences experienced by an immune cell—and that dietary vitamin A gives the ‘thumbs up’ to RORγt-positive T-regs rather than to Th17 cells.
- Humans: The first, phase 1 trial using encapsulated FMT for food allergy is currently recruiting subjects. Happening at Boston Children’s Hospital, this study is limited to ten individuals (10-40 years old) who fail a screening food challenge to peanuts. Oral FMT will be given over two days, followed by two additional oral peanut challenge tests. Biological specimen will also be collected to evaluate (I am guessing) microbiome baseline and changes; IgE status and other immunological biomarkers.
Thinking of the aforementioned animal studies, what critters reside in the OpenBiome FMT being used in the study? Has it been/will it be tested for those players – such as the Clostridia “commensals with benefits” species that were so important in protecting the animals from milk allergy? Or the different Clostridia (and Firmicutes) commensals in the egg allergy study? What about the dose and duration of the FMT? And the lack of uniformity among donors? What about the (apparent) lack of other interventions (such as vitamin D) that we in FxMed would consider essential to any allergy protocol? I have loads of questions. They are easy to come by in assessing someone else’s trial. Buuuuut having JUST finished our own clinical research study, and diving into data analysis now, I understand that the conversation Just. Needs. To be. Started. It will never be perfect. And some scientists- traditional ones- would argue that investigating multiple variables (like say, FMT and D) would muddy the research waters.
Thinking about the LPS exposure and tolerance (mentioned in the second paragraph), it’s long been understood that INF-y turns on Th1 and inhibits Th2, which reduces the incidence of allergy (the foundational idea of the hygiene hypothesis: get exposed to bugs that turn on INF-y and Th1, you don’t get allergies and atopy.). In fact, it was in part this discovery years ago that created the Th1/2 paradigm that we learned in medical training. While that paradigm has evolved (enter Th17 , Th9 into the mix), this understanding of attenuating the different arms of our immune system via interaction remains a fundamental. In 2013, LPS, one of the most potent inducers of Th1 inflammation, was shown to inhibit or attenuate Th2 lung inflammation (including eosinophil recruitment and Th2 cytokines) caused by house dust mite allergens in mice in a dose-dependent manner.
Pretty interesting. But it trends logical if you think about it: Why wouldn’t LPS, a major driver of INF-y, turn down Th2? It makes sense that we might rely on the ubiquitous LPS for some useful purpose. (But make no mistake: I am clear that LPS is exquisitely toxic- and that we perhaps see intestinal permeability and dysbiosis driving higher amounts of LPS into circulation thereby promoting systemic inflammation (endotoxemia), and thus LPS is more classically a bad guy.
But why not think way outside of the box, and look at using microamounts of LPS in oral immunotherapy for allergies?
LPS as an “adjuvant” to allergy oral immunotherapy?
Turns out, yeah, maybe. It’s in development.
We work with a lot of tough allergy patients here. Thus, we’re spending a reasonable amount of time thinking beyond the box. Fundamentally, our best and first intervention is using full functional approach. Onto that, we use oral immunotherapy or sublingual immunotherapy; all of the myriad botanicals with antihistamine properties, key nutrients, etc. And we’ve got our eyes trained on what might be next. Thus, I am paying attention to the FMT research, and LPS side story.
In fact, if you are familiar with low dose allergy therapy (LDA), a novel form of immunotherapy, delivered most commonly via subcutaneous injection, but also sublingually, you probably know who Dr. Ty Vincent is. Ty has been using and training clinicians on LDA for a decade plus.
I pinged him on FMT and the idea of LPS as an adjuvant.
He was not impressed. Of FMT, he said: Not likely to work, no. Even people with fancy poop inside them still have allergies…
OK.
What about sub-physiologic exposures to LPS along with LDA?
He said: It’s a common observation that “immune distraction” of various forms can mitigate allergies or chronic immune issues.
– Autistic kids who are nonverbal will start speaking in sentences when they run a fever during viral illness.
– Intestinal worm therapies are used to treat autoimmune and chronic inflammatory conditions
– BCG vaccine sometimes reduces the autoimmunity and advancement of disease in Type 1 diabetes
So it would make sense that LPS might redirect some of the immune systems attention/resources and secondarily mitigate chronic immune conditions.
I don’t think that’s a very successful way to treat these conditions at all. If it does work well it isn’t likely to work for very long.
Focusing on restoring tolerance to the inciting immune target makes a lot more sense to me.
I appreciate Dr. Vincent’s comments, and his expertise. I refer folks to him for LDA with some regularity and we are also looking forward to hosting him for a Teach-In in our Clinic Immersion program in December this year (click here to learn how you can access).That said, my eyes remain open on these exciting next ventures.
A few links into our allergy archives:
https://www.drkarafitzgerald.com/2019/04/08/allergies-why-our-approach-to-hygiene-has-been-so-wrong/
https://www.drkarafitzgerald.com/dr-kfs-seasonal-allergy-relief-program/
