Causal Relationship Between Diet, Lipids, Immune Cells, and Chronic Fatigue Syndrome: A Two-Mediation Mendelian Randomization Study, 2025, Li et al

[forestglip]

Causal Relationship Between Diet, Lipids, Immune Cells, and Chronic Fatigue Syndrome: A Two-Mediation Mendelian Randomization Study

Jixu Li, Qi Qin, Yiran Zhu, Yulu Qian, Jialu Yin, Xin Gao, Huijuan Wen, Pei Wang

[Line breaks added]

Abstract
Chronic fatigue syndrome (CFS) is a disorder characterized by severe unexplained fatigue and is associated with various factors including infections, immune responses, genetics, and environmental influences. However, the underlying mechanisms and possible interventions for CFS remain unclear. We used a two-mediated MR method to investigate causal relationships between diet, lipid levels, immune cells, and CFS.

Our findings suggest that certain lipids, specifically low-density cholesterol, apolipoprotein E, and apolipoprotein B, contribute to CFS development. Conversely, high-density lipoprotein cholesterol and apolipoprotein A1 may delay the onset of the syndrome.

Additionally, we explored how lipids affect fatigue through immune cell mediation. Factors, such as hematopoietic stem cell absolute count, the percentage of CD3-natural killer lymphocytes, and IgD presence on IgD+ CD38+ B cells may mediate the causal pathway linking lipids to CFS.

Furthermore, we examined the relationship between diet, lipids, and CFS. This indicated that specific dietary selections, like alcohol intake, a preference for chili peppers, and an affinity for breakfast, contributed to CFS. Conversely, cheese and pork consumption were protective factors against CFS. The protective effect of cheese consumption on CFS was mediated by apolipoprotein A1 and high-density lipoprotein cholesterol.

In conclusion, the study established an ecological chain: cheese consumption leads to increased high-density lipoprotein cholesterol and alters immune cell phenotypes—specifically, increasing the percentage of CD3-lymphocytes and IgD on IgD+ CD38+ B cells—ultimately influencing the development of CFS.

These findings enhance our understanding of how lipid levels and immune factors are related to CFS and how dietary choices can potentially mitigate the syndrome.

Link | PDF (Food Science & Nutrition) [Open Access]

 

[forestglip]

Mediation analysis of immune cells was conducted to determine whether they mediated the effects of lipids on CFS. Using two-step MR analysis, this study identified three immune cell characteristics that could mediate the causal relationship between lipids and CFS: hematopoietic stem cell absolute count, the percentage of NK CD3− lymphocytes, and IgD on IgD+ CD38+ B cells. The results from the two-step mediation analysis revealed a direct effect size of −0.080 for the impact of HDL-C on CFS.

Interesting that NK cells and CD38+ B cells popped up. Maybe some connection to daratumumab, which kills CD38 cells and apparently helped with ME/CFS symptoms, but only in those with high enough NK cell count.

 

[MeSci]

Not sure if I'm being thick as often nowadays, but the study seemed to find the opposite of what was reported.

Cheese consumption and HDL cholesterol were expected to reduce the risk of developing CFS, but they increased it?

 

[Simon M]

The usual question applies: how good is the underlying data? There is only one source of trustworthy ME/CFS GWAS data I know of, and it hasn't reported yet or made its data available more widely for GWAS analysis

 

[forestglip]

Cheese consumption and HDL cholesterol were expected to reduce the risk of developing CFS, but they increased it?

Could you quote where they said these increase risk?

They seem to consistently say cheese reduced risk of ME/CFS, except strangely in one spot they say:

Intriguingly, while total cheese consumption showed an overall positive association with CFS risk, fermented cheese subtypes exerted protective effects mediated by apo A1/HDL-C elevation.

I don't see any data about total vs. fermented. The tables only refer to "cheese consumption".

 

[MeSci]

It's the penultimate sentence in your first message:

"In conclusion, the study established an ecological chain: cheese consumption leads to increased high-density lipoprotein cholesterol and alters immune cell phenotypes—specifically, increasing the percentage of CD3-lymphocytes and IgD on IgD+ CD38+ B cells—ultimately influencing the development of CFS."

I gathered from that that they increased the risk? I'm not up to reading the whole paper at present.

 

[forestglip]

The usual question applies: how good is the underlying data? There is only one source of trustworthy GWAS data I know of, and it hasn't reported yet or made its data available more widely for GWAS analysis

Data sources

In this research, we explored the GWAS data for CFS, which was carefully sourced from the IEU GWAS database. This impressive dataset included insights from 7363 samples and featured 163,803,05 SNPs, providing a robust foundation for our findings.

7363 is a lot of samples. I'm also curious where they're from. I'm not sure what IEU is. Maybe this: https://gwas.mrcieu.ac.uk/

 

[forestglip]

ultimately influencing the development of CFS

I don't think "influencing" necessarily means increasing risk. They worded it differently in the paper:

Specifically, cheese consumption increased HDL-C levels, which then influence three immune phenotypes: hematopoietic %CD3− lymphocytes and IgD present in IgD+ CD38+ B cells. This interaction helps to mitigate the onset of CFS (Figure 1, Table 1).

 

[Jonathan Edwards]

I find this completely implausible and I continue to take the view that if people write completely impenetrable abstracts with no actual data the paper probably isn't worth looking at further.

All I can see is people hiding behind jargon. As far as i can make out they are saying that if we assume P causes Q which then causes R then we get a number like 0.080. But they don't tell you what number you get if you assume that R causes P which causes Q or Q causes R which causes P. Or what it would mean.

 

[Yann04]

Maybe this: https://gwas.mrcieu.ac.uk/thi

The page gives me a cloudflare error

 

[forestglip]

The page gives me a cloudflare error

Oops, fixed link, thanks.

 

[Simon M]

Data sources


7363 is a lot of samples. I'm also curious where they're from. I'm not sure what IEU is. Maybe this: https://gwas.mrcieu.ac.uk/

Yes, I found the same thing. But how do we know the cases really do have ME/CFS? UKB has over 5000 CFS cases, but the recent Samms/Ponting paper on cohort quality, showed there were numerous concerning features of the data. I'm not sure there is better data out there (though there is a Finnish database, about which I know very little, and it doesn't seem to be the one used here).
I mean, how many large well defined cohorts oME/CFS are there? Without a clear description of the data, I'm not inclined to take the study seriously.

 

[BrightCandle]

This indicated that specific dietary selections, like alcohol intake, a preference for chili peppers, and an affinity for breakfast, contributed to CFS. Conversely, cheese and pork consumption were protective factors against CFS.

Didn't drink alcohol, don't particular care for chillis, usually didn't and still don't eat breakfast and I love cheese but not so much pork. So I did just about everything "right" according to this and still ended up with ME/CFS and the consumption of cheese and pork not and avoiding those other things makes no difference now other than alcohol which I am extremely intolerant to.

 

[Jonathan Edwards]

I would be surprised if there were accurate data on the chilli and cheese eating habits and breakfast preferences of 7363 DNA donors. And how do we know that they don't eat loads of tacos too?

 

[MrMagoo]

I would be surprised if there were accurate data on the chilli and cheese eating habits and breakfast preferences of 7363 DNA donors. And how do we know that they don't eat loads of tacos too?

And further necessary questions
Do they smoke???
Did their parents divorce in their childhood?
How many of them are Sagittarius?
Who has blue eyes?

 

[lunarswirls]

I wonder if this paper was even written by humans. Doesn't seem like it...

Low-quality papers are surging by exploiting public data sets and AI
Paper mills are also likely contributing to “false discoveries”

 

[Murph]

Why's it always Chinese teams doing Mendelian randomisations? Did they just rediscover the technique?

Mendelian randomisation must be okay right? It must be a legitimate technique? I am always suspicious because the very first one I read tested a link from long covid to mecfs and found none, but the samples were all taken pre covid. It made literally no sense to me, even prima facie, and I emailed some experts and they agreed:

No Causal Effects Detected in COVID-19 and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Two Sample Mendelian Randomization Study - PMC

New clinical observational studies suggest that Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a sequela of COVID-19 infection, but whether there is an exact causal relationship between COVID-19 and ME/CFS remains to be verified. To ...

pmc.ncbi.nlm.nih.gov

 

[Murph]

hmmm. Affinity for breakfast is a novel concept in medical literature.



This is the sort of groundbreaking research we need. We should petition to get the name of this illness changed to breakfast affinity syndrome.

[SARCASM TAG INCLUDED HERE FOR FEAR OF MISUNDERSTANDING !!]

 

[forestglip]

Mendelian randomisation must be okay right? It must be a legitimate technique?

I read a couple resources about MR from an expert in the field, Steven Burgess, and posted them previously:

- https://mendelianrandomisation.com/index.php/what-is-mr

Use of Mendelian Randomization to assess the causal status of modifiable exposures for rheumatic diseases, 2024, Zhao et al

What he appears to try to get across is that using MR for traits that aren't known to be specifically controlled directly by genes is an iffy use of MR as it's hard to be sure that the SNPs associated with the trait don't cause the outcome through a different pathway.

So mutation in gene for CRP known to cause CRP to increase, in an MR study to see if high CRP causes something else? Great.

Mutations associated with eating breakfast to see if eating breakfast causes something else? Probably too shaky of a connection between the mutations and breakfast to be sure the causal pathway is (mutation > breakfast > CFS), and not (mutation > CFS and mutation > breakfast), or (mutation > CFS > breakfast).

(> means causes.)

 

[Snow Leopard]

Classic case of association not being causation.