Effect of gut microbiome modulation on muscle function and cognition | Hacker News Reader

Effect of gut microbiome modulation on muscle function and cognition

nature.com

58 pointsgnabgib33 comments

This was an interesting read.

In essence, a randomised controlled trial looked at the effects of gut microbiome modulation on muscle function and cognition in older adults. Participants in the trail received either a prebiotic or a placebo.

My takeaways: - The prebiotic improved cognitive function, but not muscle function, for members of the trial.

- The gut microbiome composition changed in the prebiotic group, with an increase in Bifidobacterium abundance. (Was not clear on a first read if that is necessarily always positive).

- The trial suggests that microbiome modulation might be a target for improving cognitive function in older adults.

- Prebiotics the trial mentions: inulin and FOS

> an increase in Bifidobacterium abundance. (Was not clear on a first read if that is necessarily always positive).

The total effect of a microbiome is not an additive function of the individual species. These species interact in highly complex ways. Some species might normally release factors that are detrimental to health, but their behaviour is suppressed by other species present in the flora. Therefore the individual species are not of therapeutic relevance; due to limitations in our understanding, each flora must be considered as a whole.

> Therefore the individual species are not of therapeutic relevance

Wanted to point out that this does not hold true for babies, where Bifidobacterium abundance generally does correlate with healthy microbiota and the strain B. infantis is relevant therapeutically and has evolved to metabolize milk sugars into short chain fatty acids.

B infantis ferments lactose into lactate, which is afterwards utilised by lactate-consuming bacteria to kickstart butyrate production. In general, the infant gut is about striking a balance between lactate-producing and lactate-using bacteria. While bifidobacterium is usually dominant on the lactate-producing side, the same function can be (and is) fulfilled by other primary colonisers, such as Staphylococcus.

The point here is that individual strains are only "beneficial" in so far as they interact positively with others.

> The prebiotic improves cognition (factor score versus placebo (β = −0.482; 95% CI,−0.813, −0.141; p = 0.014))

Always difficult to interpret the effect size of medical studies. Can an expert chime in here? What does this translate to in percentage terms, or number of standard deviations? How can we tell if this is a clinically meaningful delta?

More broadly - why the obsession in medical papers with statistical significance rather than actual, interpretable effect size?

I'll chime in:

(β = −0.482; 95% CI, −0.813, −0.141; p = 0.014): The "β" represents the change in the factor score due to the prebiotic. A negative number here (-0.482) likely means that the prebiotic reduced some kind of negative score associated with poorer cognition, thus improving cognitive function. The "95% CI" stands for the 95% confidence interval, which is a range of values (-0.813 to -0.141) that likely contains the true effect size. The smaller this range, the more precise the estimate. The "p-value" (p = 0.014) tells us the probability that the observed results could have occurred by chance. A p-value of 0.014 means there's a 1.4% chance the results are due to random variation, which is low, so the results are considered statistically significant.

In simpler terms, that study found the prebiotic to significantly improve mental functions compared to not taking anything, with a high level of confidence that this result is not due to chance.

HOWEVER, when you look at the size of the study, it's unimpressive. A larger RCT will be needed. Also, it was a 'remote' study, so they could not measure muscle mass. Also, analyzing stool samples has serious limitations, as there are quite a few species that cannot be cultured (or identified).

That confidence interval seems large, no?

In such a limited RCT, yeah. It does.

Not expert in medical science.

Here's my understanding β is coefficient (slope) for the linear mixed model and 95% CI is the confidence interval for the coefficient. There are no effect sizes given, my guess is it's harder to calculate for linear mixed models when models gets complicated. It's not easy/useful to interpret from coefficient here.

Rather see Table 3 for mean and SD. The mean(SD) change for cognition for Treatment group was 0.40 (0.83) and for placebo was 0.19 (0.70). Linear mixed model showed this was significant when other factors held constant.

Not an expert, but see table 3. They use CANTAB as the test of cognition. Scores range from 0 (worst) to 1 (best). β = the standardized beta coefficient. You do a linear regression, where the cognition score is the dependent variable, and prebiotic status is an independent variable. The values are standardized first (x - mean)/(standard deviation). β is the slope of the regression line. They use the prebiotic group as the reference group.

It is interesting that they achieved any positive results with prebiotics. The animal study evidence suggests that these are weak interventions compared to fecal microbiota transplant (FMT) from a young individual or flagellin immunization. Weak in the sense that they don't last long for one dose, whereas both FMT and flagellin immunization are essentially years-long to permanent effects, and also weak in the sense of a small effect size on the gut microbiome and health measures compared to FMT and flagellin immunization.

In principle it should be possible to produce some sort of one-time high dose oral probiotic that produces results that are in the same ballpark for effect size and duration as FMT. In practice, it doesn't look like anyone is rushing to get that done, and it might turn out to be very expensive to manufacture 100-200+ distinct microbial populations into a probiotic mix. No-one seems to know whether it would take that many, or whether there are a lynchpin few dozen species one could focus on to get an 80/20 outcome. But that sounds like a question that could be answered in the next decade or two at the present pace.

This is another positive results using human milk oligosaccharides (HMOs), which I'd consider a prebiotic https://www.sciencedirect.com/science/article/pii/S193131282...

They used EVC001, a robust strain of B. infantis that came out of UC Davis research, and HMOs, which are a symbiotic that it can metabolize into short chain fatty acids, to achieve reversible engraftment without the use of antibiotics. The insurance hypothesis has kind of conflated diversity with function, but it could be possible to have a stable microbiome with less diversity but high function using symbiotics and strains we have identified as contributing to improved function [1].

1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7171047/

What I remember about the microbiome: it's rather specific and we won't get one mix to suit us all. Ah yes, here:

> A significant proportion of the infant gut microbiome is considered to be acquired from the mother during and after birth. Thus begins a lifelong and dynamic relationship with microbes that has an enduring impact on host health. https://www.nature.com/articles/s41467-023-38694-0

When reading table 3, I am wrong to think the improvement occurred in both branches of the clinical trial and only marginal?

For example: Pattern recognition memory test (% correct)

* At Baseline:

Treatment branch :86 (12%)

Placebo branch :91 (9%)

* At study End:

Treatment branch :97 (7%)

Placebo branch :93 (7%)

https://www.nature.com/articles/s41467-024-46116-y/tables/3

Treatment Branch = 86.74 -> 97.44 => 12.33% increase

Placebo Branch = 91.32 -> 93.59 => 2.48% increase

Unless im reading it wrong, it seems like a 10% difference between both. Which in my books is not "marginal".

not really surprising, as people with gut microbiome issues will tell you that fatigue and mental fog are very common symptoms. Of course proper research and validation is always welcome.

So what should I eat now?

A diverse diet with lots of plants, vegetables and fiber. This doesn’t change that.

What about fermented food?

That’s probably good on balance, except for alcohol. But this article doesn’t meaningfully change this recommendation (it’s an extra pebble on a large mountain).

that's a bit broad, as it includes sauerkraut, bread, cheese and beer.

So what I'm taking away from your comment is that I should indulge myself this Oktoberfest for health reasons.