I’ve illustrated this post with a picture of Janus, the Roman god of, among other things, duality. Every time I read about short chain fatty acids (SCFAs), I think of him.
Over the years, I’ve written about the benefits of SCFAs many times. (Here’s just one of many such examples.) I’ve also written about the massive amount of research that suggests that too much of a good thing, including SCFAs, are neurotoxic and extremely detrimental to health. (For example, here.)
I’ve commented before about how I find this idea of balance particularly interesting. SCFAs are critically important for good health as long as you have the right amount; and to make this even more complex, the timing is critical: they are good in the right amount at the right time. Just as excess levels are associated with disease, so are low levels. Since SCFAs are produced by gut bacteria, it’s easy to imagine how alterations in the microbiota can alter levels of these metabolites to influence the development of various illnesses.
The human biome is insanely complex.
A week ago or so, a paper was published in the journal, Cell, which explored how propionate (also called propionic acid, or PPA) “shapes” the course of multiple sclerosis (MS) by influencing the immune system.[i]
Like other autoimmune diseases, MS involves an increase in inflammatory immune cells and a decrease in regulatory ones (Treg, which modulate inflammation). This hyper inflammatory response leads the body to mistakenly attack the myelin sheaths of nerve fibers, which is a protective layer surrounding the nerves. This hampers the ability of nerves to send and receive signals properly.
In this study, the blood and stool of almost 300 people with MS were examined: the results showed low levels of PPA, no matter what type of MS the person had (i.e. relapsing-remitting, progressive, etc.) The bacterial species which produce PPA were found at lower levels; bacterial species associated with disease, like Shigella, were found to be at higher levels. The microbiome composition of the MS patients also varied according to the course of their disease, and this paralleled the fact that those newly diagnosed had the lowest levels of PPA, “…indicating that alterations in the gut microbiome might affect the severity of MS and that successful interventions might involve restoration of gut homeostasis.”
Thus, these scientists hypothesized that supplementing PPA, with its anti-inflammatory capabilities, might have a beneficial effect on those with MS, the hope being that the metabolite could boost levels of regulatory cytokines. 91 patients and 24 controls were given 1000 mg of PPA daily for 14 days. After these 2 weeks, Treg (including IL-10, one of the most important) rose by 25% in the control group and by 30% in the MS patients. 52 patients continued to take the PPA after the study concluded, and the improvement in Treg remained. This experiment was repeated in a 2nd group of patients and the results were the same. To boot, high levels of pro-inflammatory immune cells dropped significantly.
Long-term PPA supplement use was also studied. 41.2% of those on PPA had a lower annual relapse rate; 47.4% had a stable relapse rate; 11.3% had an increased rate of relapse. And one more interesting finding: 22 patients, who remained on the PPA for a year and a half, underwent brain MRIs: “…the striatum, a region known to shrink (brain atrophy) in MS, actually increased in volume compare to scans taken before starting this treatment.”[ii] This correlated with an improvement in clinical symptoms: “This improved Treg cell function correlates with alleviation of clinical symptoms in MS patients. In a retrospective setting, we observed a decrease in relapse rate and stabilization of disability during long-term [propionic acid] supplementation.”
By the way, no adverse effects to the PPA supplementation were reported.
The researchers conclude that their study saying that it “…provides further evidence of the hypothesis that SCFAs are reduced in autoimmune diseases, such as MS, as a consequence of an altered gut microbiome.… [PPA] supplementation had a beneficial effect on immunological, neurodegenerative, and clinical parameters in MS patients, including relapse rate and disability progression.”
This is very preliminary research, so rest assured, I will follow it. This this may well apply to other autoimmune diseases and help many people.
Today’s post describes what may be a critical finding in defining at least one mechanism whereby gut microbes directly affect the brain. Those interested in developmental disorders, like autism; Parkinson’s; Alzheimer’s; chronic fatigue; etc. should pay particular attention as, according this article, this information is likely applicable to those illnesses, and many more.
The relationship of neurological disorders to the gut bacteria is well established, as you know. This includes the developmental disorders and diseases mentioned above, as well as the development of anxiety, depression, etc. However, “…evidence of causality and identity of microbiome-derived compounds that mediate gut-brain axis interaction remain elusive.” Thus, it’s a major step forward that scientists at the University of Glasgow have discovered two new molecules that are produced by gut bacteria and that can travel directly to the brain, crossing the blood-brain barrier.[i] These molecules structurally greatly resemble carnitine, a compound derived from amino acids, which is critical in transporting fatty acids into the mitochondria of cells, where the fats are “burned” to produce energy. In looking like carnitine, these molecules essentially take the place of the real compound, thereby preventing real carnitine from performing its essential functions, “…leading to inhibition of brain cell function.”
These 2 molecules appear to be made by certain members of the Clostridiales family (C. clostridioforme and C. symbiosum). The authors of this paper theorize that these bacteria produce these “fake carnitine” molecules to give themselves a competitive advantage against species that do poorly in the presence of carnitine. Not much is known about these two species, except that their presence “…in the gut microbiome is associated with low microbial diversity, while C. symbiosum presence could further distinguish obese from lean participants.” We also know that these 2 strains are increased in the guts of those with autism, and completely absent in controls in studies comparing the two populations.
Mitochondrial dysfunction is well established in autism, as well as in Parkinson’s and Alzheimer’s. In autism, carnitine has been looked at as a potential treatment for a subgroup of those on the spectrum. A 2019 paper states, “Autism onset can be connected with various factors such as metabolic disorders: including carnitine deficiency….Some people with autism (less than 20%) seem to have L-carnitine metabolism disorders and for these patients, a dietary supplementation with L-carnitine is beneficial.”[ii] Another 2019 review describes the few clinical trials yet done on the population, which, while small, also showed consistency in results: there was improvement, often significant improvement, in the symptoms of autism. (The doses and duration of treatment varied greatly in these trials, so the fact that there was general consensus as to the benefits of carnitine treatment, I’d think, make the results that much more significant.)[iii]
In digging around, I also found that some evidence of carnitine’s protective role in Parkinson’s, heart disease, type 2 diabetes, etc. I also found studies linking low levels of carnitine with depression and anxiety.
Back to autism for one last thought: as you know, from reading my many posts (two of many examples, here and here) on the work of Dr. Derrick MacFabe and others in the field, the short-chain fatty acid, propionate (PPA) is now generally accepted to play a significant role in the development of many cases of autism. Abnormal gut bacteria, which includes high levels of clostridia (PPA producers, as well as the producers of these carnitine-like molecules), in the population – possibly combined with food sources (PPA is a common preservative) are likely to blame. High levels of PPA cause a reduction in carnitine levels: “PPA is thought to affect mitochondrial fatty acid metabolism by sequestering carnitine.”[iv] So now we are faced, thanks to this altered gut microbiota, with both a reduction of carnitine levels and these carnitine-analogs which replace what little carnitine is available, further destroying normal mitochondrial function. This, in turn, affects the way energy is produced in the cell and thus, the way the brain develops and functions.
Animal (dairy, meat, fish) products contain carnitine. If you tend to avoid these in your diet, and are among the susceptible population, you may want to consider supplementation. (Of course, talk to your health care practitioner first.) Carnitine (best taken in the form acetyl-l-carnitine) is a very low risk supplement. Only in high doses, 3000 mg per day or more, can it have side effects including nausea and vomiting. Strikes me that this may be another can’t-hurt-could-help kind of thing.
[iv] Thomas, RH, Foley, KA, Mepham, JR, Tichenoff, LR, Possmayer, F, MacFabe, DF. Altered brain phospholipid and acylcarnitine profiles in propionic acid infused rodents: further development of a potential model of autism spectrum disorders. Journal of Neurochemistry. 2010;113:515-529. oi: 10.1111/j.1471-4159.2010.06614.x
I’ve been keeping an eye out for anything new and interesting in the realm of the biome and arthritis – any kind of arthritis. Following are some highlights from a recent article on the two way communication between the gut immune system and the resident bacteria, and its association to rheumatoid arthritis (RA), osteoarthritis (OA), and inflammatory spondylitis (SpA) conditions like psoriatic arthritis and ankylosing spondylitis.[i]
The authors start by emphasizing that while exact mechanisms of action are as yet unknown, evidences continues to mount that these illnesses are directly related to alterations in the gut bacteria, and that those alterations are may well be causative.
These authors conclude that it is now clear that “…unfavorable dysbiosis-mediated immune alterations precede the development of these disorders, suggesting causal relationships in this link [between the microbiota and the immune system].” This is exactly the same phenomenon I described on Tuesday, seen in those with Parkinson’s.
We have to hope that soon there will be regular testing of our biomes. Perhaps if we can catch these changes early on, someday soon we’ll be able to prevent all these diseases from developing in the first place.
[i] Kalinkovich, A, and Livshits, G. A cross talk between dysbiosis and gut-associated immune system governs the development of inflammatory arthropaties. Seminars in Arthrisi and Rheumatism. 2019; 49 (3), 474-484. DOI: 10.1016/j.semarthrit.2019.05.007
I haven’t given you a Parkinson’s-and-the-biome update in several months now, and as yesterday I read a great review of the current status of our knowledge on the connection between the two, I figured it was time.[i]
I am sure that most of you are very familiar with Parkinson’s Disease (PD), which is the 2nd most common neurodegenerative disorder after Alzheimer’s. We have known for several years now, that it appears that the disease starts in the gut, although the exact mechanism of action is still unknown. It seems, reading this paper, that the generally accepted (simplified) scenario right now is the following:
An unknown pathogen damages the nerves of the GI tract, resulting in the mis-folding (distortion) of a protein called α-synuclein (also known as Lewy bodies or Lewy neurites). These Lewy bodies first accumulate in the gut. Through various mechanisms, including the vagus nerve (which connects the brain to the gut’s nervous system), they move into the brain, including the substantia nigra, destroying the dopamine-producing cells there, resulting in the symptoms of the disease.
There is a large body of research now supporting this model:
If this subject particularly interests you, as it does me (seeing as I have multiple friends who have developed the damn disease in their 40s and 50s – INSANE), take some time to check out some of my other posts on the subject. There are a lot!
[i] Yang, D, et. al. The role of the gut microbiota in the pathogenesis of Parkinson’s Disease. Frontiers in Neurology. 2019. DOI: 10.3389/fneur.2019.01155.
My regular readers know that I am always on the lookout for “things you can do now,” and that I get very excited when I find something that actually makes sense, even if it’s not entirely proven or the mechanism of action fully understood. Yesterday, I came across research out of the University of Texas looking at the effects of eating mango on inflammatory bowel disease.[i]
Besides, it is one of my all-time favorite foods, so it’s a pleasure to wax lyrical on the delight that is a ripe mango.
Believe it or not, something as simple as eating 200-400 grams (approximately 7-14 ounces) per day of mango appears to make a measurable difference in alleviating the symptoms of inflammatory bowel disease (IBD). These researchers conducted a small pilot study on 10 volunteers (3 with Crohn’s disease and 7 with ulcerative colitis, all currently on drugs for their illnesses) with mild to moderate IBD, and had them eat mango daily for 8 weeks.
Their justification for the research: mango contains polyphenols, natural plant compounds that act as antioxidants, and have been shown in many studies to protect against cancer and other diseases. Some of the polyphenols you may be familiar with include flavonoids and phenolic acids. Their presence is one of the reasons a plant-based diet is so healthy. Previous studies have shown that mango polyphenols “…possess anti-inflammatory, anti-obesogenic [obesity] and anti-cancer activities, indicating their potential in modulating risk factors for intestinal disease.” In animal studies, in which colitis has been chemically induced in rodents, a mango-based beverage attenuated inflammation.
Results of this study:
Obviously, this was a tiny study (it was only a proof-of-concept, after all), so the results should be interpreted with caution. Still, it is nice to report some good news. I don’t have IBD, but what the hell?! It’s not like you have to twist my arm to convince me to eat my mango daily.
[i] H. Kim, V.P. Venancio, C. Fang, et al., Mango (Mangifera indica
L.) polyphenols reduce IL-8, GRO, and GM-SCF plasma levels and increase Lactobacillus species in a pilot study in patients with inflammatory bowel disease, Nutrition Research(2020), https://doi.org/10.1016/j.nutres.2020.01.002
Back in January, I wrote about how bile acids are regulators of inflammation and thus, when dysregulated (either too high or too low), this dysregulation can lead to disease. Bile is produced by the liver and excreted into the intestines to digest fat. Gut bacteria convert these primary bile acids into secondary bile acids, which are, in turn, immune signaling molecules, and I described research out of Harvard looking at the exact mechanism of action. In that post, I also wrote about a second paper, also from Harvard, that looked at how diet and the gut bacteria work together to modify these immune-mediating bile acids. I mention that “…low levels of bile acids make the mice prone to developing inflammatory conditions, like IBD.”
Well, new research out of Stamford University has zeroed in on a particular kind of bacteria missing from those with ulcerative colitis (UC) which may be responsible for the development of the disease.[i] The study consisted of 2 groups of patients, 17 with UC who had undergone surgery to remove the colon and rectum. The surgeons then reposition the lower end of the small intestine to create a pouch that acts as a rectum. Unfortunately, half of these UC patients develop a condition called pouchitis, which is inflammation of this pouch similar to the UC itself. The second group of patients had a rare genetic condition which leads to that same surgery but almost never develop pouchitis. In comparing the two groups, they noted that those with UC had markedly lower levels of both microbial diversity and secondary bile acids, including the two most prominent, deoxycholic acid and lithocholic acid, mirroring the Harvard research. They noted too that the family of bacteria called Ruminoccoccaceae was significantly low in the UC patients versus the others. These bacteria, along with several other kinds, carry the genes to create secondary bile acids. Ruminococcaceae are a family of bacteria within the class of Clostridia.[ii]
In fact, when primary bile acids were incubated in stool samples from the patients with the genetic condition, secondary bile acids were created. This did not happen with the same procedure using stool samples from the UC patients. And in 3 different animal studies, when mice with IBD were supplemented with these 2 bile acids, markers for inflammation markedly improved.
There is a phase 2 clinical trial happening at Stamford right now on 15 patients with UC who have had this pouch surgery; they are being given a naturally occurring secondary bile acid which is already approved by the FDA for other conditions. I will absolutely keep an eye out for those results. However, looking at Clinical Trials.gov, it looks like the primary completion date of the study isn’t until December 2025. (I wish that there were a trial ongoing for those who have not as yet lost the bottom of their colon/rectum. It would be great to see if this treatment could help prevent that horrible surgery in the first place.)
A postscript: as I was getting ready to post this, I spotted breaking news about a brand new study out of Michigan State University about the discovery of brand new bile acids that are produced only by our gut microbes, not by our own bodies.[iii] The discovery has apparently rocked the scientific world in that, no new bile acids have been found since their initial discovery in 1848: “This discovery will change how medical textbooks address digestion, and it contributes to an ever-growing body of knowledge supporting the importance of the microbiome…” And these new bile acids are “…particularly abundant in the guts of people suffering with gastrointestinal diseases, such as Crohn’s…”
This is really a developing story: the recognition of a completely altered bile acid composition in those with diseases involving intestinal inflammation. Definitely stay tuned!
[i] Sidhartha R. Sinha, Yeneneh Haileselassie, Linh P. Nguyen, Carolina Tropini, Min Wang, Laren S. Becker, Davis Sim, Karolin Jarr, Estelle T. Spear, Gulshan Singh, Hong Namkoong, Kyle Bittinger, Michael A. Fischbach, Justin L. Sonnenburg, Aida Habtezion. Dysbiosis-Induced Secondary Bile Acid Deficiency Promotes Intestinal Inflammation. Cell Host & Microbe, 2020; DOI: 10.1016/j.chom.2020.01.021
Remember last Thursday, when I wrote about the relationship of the gut bacteria to the structure and function of the brain? I mentioned in that post that, “In Western populations, Bacteroides and Prevotella species tend to dominate, with the former outnumbering the latter –as they did in this sample of women. A diet high in fat and animal protein (i.e. a standard Western diet) is more associated with higher Bacteroides species than Prevotella…” I went on to point out that, “Prevotella levels are markedly higher in non-Westernized societies, which consume plant-based diets, where people are actually less prone to ‘mental’ illnesses like depression or anxiety. And don’t forget, low levels of Prevotella have also been associated with leaky gut and also, Parkinson’s disease. So the likelihood is that higher Prevotella amounts are better for health.”
With that fresh in mind, yesterday morning I spotted an article[i] that looked at the composition of the bacterial microbiome in infancy and its relationship to the development of anxiety issues in toddlers, and the findings should come as no surprise: “…we found a clear association between decreased normalised abundance of Prevotella in faecal samples collected at 12 months of age and increased behavioural problems at 2 years…”
This finding held even when other variables were accounted for, like mode of birth, pet ownership, maternal smoking, breast feeding, and so forth.
The test group tested consisted of 201 infants, selected from an Australian birth cohort of over 1000 babies. Stool samples were collected at 1, 6 and 12 months, and when the babies reached 2 years of age, their parents filled out extensive questionnaires. No association was found in behavioral differences based upon the first 2 stool collections, but the 12-month sample found significant associations. Believe it or not, Prevotella was found in only 4% of the children who went on to have anxiety issues versus 44% of the children without any problems. (Lacnospiraceae species were also altered in the behavior group, although when other factors as mentioned above were accounted for, this was somewhat less significant.)
The main factor leading to lower levels of Prevotella? You guessed it: antibiotic use. However, the behavior group’s antibiotic use was not different from the non-behavioral group with low levels of Prevotella, so this was not considered significant in terms of predicting behavior.
The mechanisms are still unknown but there are numerous possibilities: stimulation of the vagus nerve, various enzymes or cytokines, tryptophan metabolism, the immune system, and so forth. Studies are already underway to replicate these findings and to delve into causality. The implications of this work may be huge: as these authors state, this work “…adds support to evidence that the human gut microbiota may have long-term neurodevelopmental consequences, conferring protection or vulnerability to behavioural and mental health outcomes in later life…” This work, therefore, may have tremendous relevance not only to anxiety disorders (which are on the increase in industrialized nations) and other mental health issues, but also autism (remember the fecal microbiota transplant study – FMT led to higher levels of good bacteria, including Prevotella, which is low in those with autism), and potentially illnesses that tend to hit in later life, like Parkinson’s disease. It’s looking more and more like eating right from the moment of birth is crucial for long-term physical and mental health.
Hopefully there will be more to report to you in the near future. In the meantime, eat that plant-based diet!