Multiple sclerosis and the Gut Microbiome: Some Preclinical Results

The gut microbiome is measured by assessing the prokaryotic DNA of a stool sample, which reflects the various types of bacteria that are generally commensal, beneficial residents of our gut in the normal human.

In the past 10 years it has become apparent that our gut microbiome can be quite different between individuals based on diet and region, and that persons with many different diseases can have characteristic differences in their gut microbiome from the average normal gut microbiome.

One hypothesis regarding these differences is that the gut microbiome in disease states is not reflecting the effect of disease, but instead may be one of its causes, especially as some type of enabling or modulating cause of a pertubation of immunity in autoimmune disease.

How do we tell cause from effect in such a case? One method is to see if a transfer of microbiome between healthy and diseased makes a difference.The study below reports results of such transfers (but to mice from human with MS).

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ABSTRACT

in PNAS October 3, 2017 vol. 114 no. 40 10713-10718

Gut bacteria from multiple sclerosis patients modulate human T cells and exacerbate symptoms in mouse models Egle Cekanaviciutea,1,2, Bryan B. Yoob,1, Tessel F. Runiaa,3, Justine W. Debeliusc, Sneha Singha, Charlotte A. Nelsona, Rachel Kannera, Yadira Bencosmed, Yun Kyung Leeb,4, Stephen L. Hausera, Elizabeth Crabtree-Hartmana, Ilana Katz Sandd, Mar Gaciasd, Yungjiao Zhud, Patrizia Casacciad,e, Bruce A. C. Creea, Rob Knightc, Sarkis K. Mazmanianb, and Sergio E. Baranzinia,5

Edited by Lawrence Steinman, Stanford University School of Medicine, Stanford, CA, and approved August 7, 2017 (received for review June 30, 2017)

Significance

We have experimentally investigated the immunoregulatory effects of human gut microbiota in multiple sclerosis (MS). We have identified specific bacteria that are associated with MS and demonstrated that these bacteria regulate T lymphocyte-mediated adaptive immune responses and contribute to the proinflammatory environment in vitro and in vivo. Thus, our results expand the knowledge of the microbial regulation of immunity and may provide a basis for the development of microbiome-based therapeutics in autoimmune diseases.

The gut microbiota regulates T cell functions throughout the body. We hypothesized that intestinal bacteria impact the pathogenesis of multiple sclerosis (MS), an autoimmune disorder of the CNS and thus analyzed the microbiomes of 71 MS patients not undergoing treatment and 71 healthy controls. Although no major shifts in microbial community structure were found, we identified specific bacterial taxa that were significantly associated with MS. Akkermansia muciniphila and Acinetobacter calcoaceticus, both increased in MS patients, induced proinflammatory responses in human peripheral blood mononuclear cells and in monocolonized mice. In contrast, Parabacteroides distasonis, which was reduced in MS patients, stimulated antiinflammatory IL-10–expressing human CD4+CD25+ T cells and IL-10+FoxP3+ Tregs in mice. Finally, microbiota transplants from MS patients into germ-free mice resulted in more severe symptoms of experimental autoimmune encephalomyelitis and reduced proportions of IL-10+ Tregs compared with mice “humanized” with microbiota from healthy controls. This study identifies specific human gut bacteria that regulate adaptive autoimmune responses, suggesting therapeutic targeting of the microbiota as a treatment for MS.

On the ontology of "Absence makes the heart grow fonder."

"What would not I give to wander
Where my old companions dwell?
Absence makes the heart grow fonder;
Isle of Beauty, fare thee well!"

-- Thomas Haynes Bayly, 1844

What is this thing called an absence? Does an absence exist?

Absences, like holes, have an uncertain kind of existence, since some deny they actually exist, except as conformations of the stuff around them, of which they they are holes, or absences. But no one can deny that holes and absences can be measured and counted. From a scientific point of view, holes thus exist as much as any other objective phenomena that can be measured and counted can be said to exist.

And holes, of course, are emergent. They could not exist without the stuff of which they are NOT made.

Diets containing more saturated fats may lower stroke risks according to newly published prospective study.

So, in this study published in the Lancet, diets lower in carbohydrate and higher in fat, including saturated fat, were associated with a lower risk of cardiovascular disease, and diets higher in saturated fats in particular seemed to carry less risk of stroke.

Note that "high carbohydrate" in this study usually meant a diet containing mostly sugars and grains or flours. Fruits and vegetables were not considered to be high in carbohydrates compared to sugars and grains.

This study can be seen as yet another nail in the coffin of the old, now seeming quite incorrect "saturated fats bad, unsaturated fats good" dogma. When dietary components are broken down by animal type, beef and pork still seem to be less good for longevity than fish and poultry, though.

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ABSTRACT

Associations of fats and carbohydrate intake with cardiovascular disease and mortality in 18 countries from five continents (PURE): a prospective cohort study

Dr Mahshid Dehghan, PhD'Correspondence information about the author Dr Mahshid DehghanEmail the author Dr Mahshid Dehghan, Andrew Mente, PhD, Xiaohe Zhang, MSc, Sumathi Swaminathan, PhD, Prof Wei Li, PhD, Prof Viswanathan Mohan, MD, Romaina Iqbal, PhD, Prof Rajesh Kumar, MD, Edelweiss Wentzel-Viljoen, PhD, Prof Annika Rosengren, MD, Leela Itty Amma, MD, Prof Alvaro Avezum, MD, Jephat Chifamba, DPhil, Rafael Diaz, MD, Rasha Khatib, PhD, Prof Scott Lear, PhD, Prof Patricio Lopez-Jaramillo, MD, Xiaoyun Liu, PhD, Prof Rajeev Gupta, MD, Noushin Mohammadifard, PhD, Nan Gao, BSc, Aytekin Oguz, MD, Anis Safura Ramli, MD, Pamela Seron, PhD, Yi Sun, MSc, Prof Andrzej Szuba, MD, Lungiswa Tsolekile, MPH, Prof Andreas Wielgosz, MD, Rita Yusuf, PhD, Afzal Hussein Yusufali, MD, Prof Koon K Teo, MD, Sumathy Rangarajan, MSc, Gilles Dagenais, MD, Shrikant I Bangdiwala, PhD, Shofiqul Islam, MSc, Prof Sonia S Anand, Prof Salim Yusuf, DPhil on behalf of the show Prospective Urban Rural Epidemiology (PURE) study investigators

Published: 29 August 2017

DOI: http://dx.doi.org/10.1016/S0140-6736(17)32252-3 |

Background

The relationship between macronutrients and cardiovascular disease and mortality is controversial. Most available data are from European and North American populations where nutrition excess is more likely, so their applicability to other populations is unclear.

Methods

The Prospective Urban Rural Epidemiology (PURE) study is a large, epidemiological cohort study of individuals aged 35–70 years (enrolled between Jan 1, 2003, and March 31, 2013) in 18 countries with a median follow-up of 7·4 years (IQR 5·3–9·3). Dietary intake of 135 335 individuals was recorded using validated food frequency questionnaires. The primary outcomes were total mortality and major cardiovascular events (fatal cardiovascular disease, non-fatal myocardial infarction, stroke, and heart failure). Secondary outcomes were all myocardial infarctions, stroke, cardiovascular disease mortality, and non-cardiovascular disease mortality. Participants were categorised into quintiles of nutrient intake (carbohydrate, fats, and protein) based on percentage of energy provided by nutrients. We assessed the associations between consumption of carbohydrate, total fat, and each type of fat with cardiovascular disease and total mortality. We calculated hazard ratios (HRs) using a multivariable Cox frailty model with random intercepts to account for centre clustering.

Findings

During follow-up, we documented 5796 deaths and 4784 major cardiovascular disease events. Higher carbohydrate intake was associated with an increased risk of total mortality (highest [quintile 5] vs lowest quintile [quintile 1] category, HR 1·28 [95% CI 1·12–1·46], ptrend=0·0001) but not with the risk of cardiovascular disease or cardiovascular disease mortality. Intake of total fat and each type of fat was associated with lower risk of total mortality (quintile 5 vs quintile 1, total fat: HR 0·77 [95% CI 0·67–0·87], ptrend<0·0001; saturated fat, HR 0·86 [0·76–0·99], ptrend=0·0088; monounsaturated fat: HR 0·81 [0·71–0·92], ptrend<0·0001; and polyunsaturated fat: HR 0·80 [0·71–0·89], ptrend<0·0001). Higher saturated fat intake was associated with lower risk of stroke (quintile 5 vs quintile 1, HR 0·79 [95% CI 0·64–0·98], ptrend=0·0498). Total fat and saturated and unsaturated fats were not significantly associated with risk of myocardial infarction or cardiovascular disease mortality.

Interpretation

High carbohydrate intake was associated with higher risk of total mortality, whereas total fat and individual types of fat were related to lower total mortality. Total fat and types of fat were not associated with cardiovascular disease, myocardial infarction, or cardiovascular disease mortality, whereas saturated fat had an inverse association with stroke. Global dietary guidelines should be reconsidered in light of these findings.

Digression: Total Eclipse of the Sun

This week we are visiting relatives on the mainland. While visiting my mother, sisters, and brother at a reunion in Illinois, we saw the total eclipse at Fern Cliffe State Park. Video (handheld point-and-shoot camera)) on YouTube is below!

An alternative to Kim's physicalism

In his book Physicalism, or Something Near Enough, Jaegwon Kim says:
The final picture that has emerged is this: P is a cause of P*, with M and M* supervening respectively on P and P*. There is a single underlying causal process in this picture, and this process connects two physical properties, P and P*. The correlations between M and M* and between M and P* are by no means accidental or coincidental; they are lawful and counterfactual-sustaining regularities arising out of M's and M*'s supervenience on the causally linked P and P*. These observed correlations give us an impression of causation; however, that is only an appearance, and there is no more causation here than between two successive shadows cast by a moving car, or two successive symptoms of a developing pathology. This is a simple and elegant picture, metaphysically speaking, but it will prompt howls of protest from those who think that it has given away something very special and precious, namely the causal efficacy of our minds. Thus is born the problem of mental causation[...] Causal efficacy of mental properties is inconsistent with the joint acceptance of the following four claims: (i) physical causal closure, (ii) causal exclusion, (iii) mind-body supervenience, and (iv) mental/physical property dualism--the view that mental properties are irreducible to physical properties.

Here P stands for physical properties and states and M stands for mental properties and states. P* and M* are states that follow after (or from) the prior physical and mental states, respectively. Kim asserts that under his stipulated physicalism the only arrow in the below diagram that has any real ability to change the world is the causal arrow from P to P*, because only physical causation is needed for the world to look the way it does: mental phenomena must then be epiphenomenal, and mental causation illusion. Kim's diagram is as follows:

How can the inconsistency with common experience of Kim's conclusions be avoided? One way is by loosening the requirement that M is directly caused by P. In Kim's view, the brain's nature is constituted by its physical properties. What if the person (and/or their brain) is something beyond (or maybe just underneath) their physical properties?

If so, we can instead assert that we have an entity-- say the brain, or the person-- with both physical and mental properties that are not connected by P causing M, but by the underlying entity causing both its P properties and its M properties:

In this case, the entity has both physical and mental properties, but the causation is brain changing its own physical properties and its own mental properties, in parallel, rather than the physical changes of the brain, seen as the "all there is" of brain function, determining the changing mental events, as in physicalism.

It might be objected that this loosens the cause and effect of physical changes on the mental (a blow to the head causes concussion, for example, and there are experimentally measurable physical brain correlates to our mental states). But the loosening of the token identity or type identity of exact physical to mental property matches is useful, for it allows for the empirically demonstrated variability and dynamism of the brain of even the smallest organisms. Even flies do not generally have identical brain state or behavioral experimental correlates to repeated events, only similar ones, even in a seemingly identically repeated experimental setting. Changing our theory of causality of mental states in this fashion would not invalidate any experimental data, and it might fit some of that data better than a strict physical-to-mental causal chain.

Another objection would be that rational thought requires that the conclusion follow the reasoning by one mental event causing another, but I think this confuses the reason with the reasoner: our thoughts do not think themselves, we think them.

Socioeconomic conclusions versus EEG sampling protocol error: A skeptical look at a recent bioRxiv preprint.

In the preprint below, the authors propose a new finding: the EEG alpha pattern correlates with educational level and familiarity with modern technologies. Yet (as also pointed out 4 months ago by Niko Bush in the comments on the paper on bioRxiv), EEG tracings were originally done in Germany in the 1920's and at MIT in the 1930's, and alpha was described well in persons in the US and in Germany during the early 20th century, a time when the technology felt relevant by the authors of the preprint was rare to nonexistent, and when most persons had only what the current authors would have seen as a low amount of education. Berger, writing in 1929, described alpha with average amplitudes of 15 to 20 micro-volts, using a primitive string galvanometer which might have attenuated voltages by a perhaps a third (see H. Berger, Uber das Elektrenkephalogramm des Menschen, Arch Psychiat Nervenkr 87:527-570, 1929).

So the low tech, low education contingent in the 21st century must differ in some other way. Is it due to low intelligence? But in these days of a commercial digital EEG of uncertain utility being commonly utilized by many psychologists, it's well documented that except in pathological cases of retardation the alpha is well seen in about 80% of normal EEG tracings, with about 20% showing lower amplitudes of less than 20 micro-volts and with about 4% showing only fast variant activity and no measurable alpha band (Niedermeyer and Da Silva, Elecroencephalography, Urban & Schwarzenberg Press, 1987).

Are the results reported in the current study related to technique of the EEG acquisition? Here, we may have found some clues. The study being considered used EEG hardware which was not set to acquire the actual amplitudes of the raw data. Rather, what was analyzed was a digital spectrum analysis of the data. This means that a normal alpha rhythm might have been unseen if sufficient muscle or movement artifact was present. Perhaps this explains the large degree to which the reported alpha "energy" calculation varied (10 to 1350, no units given). Of course, this would not yet explain the difference by educational and technlogical familiarity described in the study.

Further perusal of the Materials and Methods section does provide further clues. The equipment used was an Emotiv EPOC device which was used for EEG recording of duration 3 minutes per individual sample. The study states that "Participants answered a series of questions regarding their demographic, communication and mobility behavior in addition to having EEG recorded for three minutes while they were awake and seated with their eyes closed" which suggests that the sampling might have been set up and was finished within several minutes.

With standard clinical EEG acquisition, the EEG is set up over a period of 10 to 20 minutes, with the patient encouraged to relax and the patient often kept comfortably reclining or supine in a dimly lit room to promote sleep. The EEG alpha rhythm and amplitude is well known to be sensitive to anxiety, with about 3 times more subjects with anxiety showing low alpha voltage than in subjects who were not anxious (eg., Enoch, M.-A., White, K. V., Harris, C. R., Robin, R. W., Ross, J., Rohrbaugh, J. W. and Goldman, D. (1999), Association of Low-Voltage Alpha EEG With a Subtype of Alcohol Use Disorders. Alcoholism: Clinical and Experimental Research, 23: 1312–1319).

It seems quite likely to this writer that it is exactly that group of people who might be those of lower education, who were lower in familiarity with technology, who would also tend to be more anxious when multiple electrodes were first placed on their head. One wonders what the alpha power spectrum might have been if those individuals had been given more time to be less threatened by the EEG procedure, and the sampling done only after they were felt to be more relaxed as a result of taking that extra time.

ABSTRACT

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Modernization, Wealth And The Emergence Of Strong Alpha Oscillations In The Human EEG

Dhanya Parameshwaran, Tara C. Thiagarajan

doi: https://doi.org/10.1101/125898

Abstract

Oscillations in the alpha range (8-15 Hz) have been found to appear prominently in the EEG signal when people are awake with their eyes closed, and since their discovery have been considered a fundamental cerebral rhythm. While the mechanism of this oscillation continues to be debated, it has been shown to bear positive relation to memory capacity, attention and a host of other cognitive outcomes. Here we show that this feature is largely undetected in the EEG of adults without post-primary education and access to modern technologies. Furthermore, we show that the spatial extent and energy of the oscillation have wide variation, with energy ranging over a thousand fold across the breath of humanity with no centralizing mean. This represents a divergence in a fundamental functional characteristic of an organ demonstrating both that modernization has had a profound influence on brain dynamics and that a meaningful average human brain does not exist in a dynamical sense.

On the Deontology of Immunization

In the US today, there is a one in a million chance that any particular person who is not immunized against measles will contract measles this year. Why is this so? Herd immunity: if all with whom I share air do not have measles because they are immune, I cannot contract the disease from them.

But why do we immunize? After all, currently there is about a 1 in 100,000 chance of a severe reaction to the vaccine, but only about a 1 in 1,000,000 per year chance that the child we immunize will get measles if we do not give the vaccine to them.

We immunize because it is our duty to the entire population to keep up that herd immunity! After all, if we stopped giving immunizations, the chance of contracting measles in the younger population would rise within a generation to its 19th century value of close to 1.0! And the serious and even fatal consequences to many of those who then got measles would far outstrip the rare problems of our present day with the vaccines.

So we have a duty to society to immunize that benefits all, but indirectly. Duty to the "herd," our society and country, requires that all, or almost all, individuals take that small risk individually. In addition, the immunized person does benefit: because they and others like them are all immune to the disease, they and others like them are better off, because they will not get sick from measles.

Multiple sclerosis and the Gut Microbiome: Some Preclinical Results

The gut microbiome is measured by assessing the prokaryotic DNA of a stool sample, which reflects the various types of bacteria that are g...