Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2024 Apr 17:18:1369996.
doi: 10.3389/fnins.2024.1369996. eCollection 2024.

Multiple reports on the causal relationship between various chronic pain and gut microbiota: a two-sample Mendelian randomization study

Yuxin Cai  1   2 , Shuyang Wen  1   2   3 , Jinjing Hu  1   2 , Ziyi Wang  4 , Guozhi Huang  1   2 , Qing Zeng  1   2 , Jihua Zou  1   2   5
Affiliations

Multiple reports on the causal relationship between various chronic pain and gut microbiota: a two-sample Mendelian randomization study

Yuxin Cai et al. Front Neurosci. .

Abstract

Background: Previous evidence suggests a link between gut microbiota and chronic pain, but the causal relationship is not yet fully understood.

Methods: We categorized gut microbiota based on phylum, class, order, family, and genus levels and gathered pain-related information from the UKB and FinnGen GWAS project. Then, we conducted MR analysis to explore the potential causal relationship between gut microbiota and chronic pain at 12 specific locations.

Results: We have discovered a direct connection between genetic susceptibility in the gut microbiota (gut metabolites) and pain experienced at 12 specific locations. Notably, Serotonin (5-HT) and Glycine were found to be associated with a higher risk of pain in the extremities. On the other hand, certain microbial families and orders were found to have a protective effect against migraines. Specifically, the family Bifidobacteriaceae (IVW, FDR p = 0.013) was associated with a lower risk of migraines. Furthermore, the genus Oxalobacter (IVW, FDR p = 0.044) was found to be linked to an increased risk of low back pain. Importantly, these associations remained significant even after applying the Benjamini-Hochberg correction test. Our analysis did not find any heterogeneity in the data (p > 0.05), as confirmed by the Cochrane's Q-test. Additionally, both the MR-Egger and MR-PRESSO tests indicated no significant evidence of horizontal pleiotropy (p > 0.05).

Conclusion: Our MR analysis demonstrated a causal relationship between the gut microbiota and pain, highlighting its potential significance in advancing our understanding of the underlying mechanisms and clinical implications of microbiota-mediated pain.

Keywords: Mendelian randomization; chronic pain; genetics; gut microbiota; single-nucleotide polymorphisms (SNPs).

PubMed Disclaimer

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Study design.
Figure 2
Figure 2
From outside to inside, the p-values of IVW, MR Egger, WM, SM, and Wmode represented, respectively. IVW, inverse variance weighted; WM, weighted median; SM, simple mode; Wmode weighted mode. (A) Causal effect of the gut microbiome on headache. (B) Causal effect of the gut microbiome on migraine in FinnGen Biobank based on MR analyses.
Figure 3
Figure 3
Causal effect of the gut microbiome on Ocular pain in FinnGen Biobank based on MR analyses. From outside to inside, the p-values of IVW, MR Egger, WM, SM, and Wmode represented, respectively. IVW, inverse variance weighted; WM, weighted median; SM, simple mode; Wmode weighted mode.
Figure 4
Figure 4
From outside to inside, the p-values of IVW, MR Egger, WM, SM, and Wmode represented, respectively. IVW, inverse variance weighted; WM, weighted median; SM, simple mode; Wmode weighted mode. (A) Causal effect of the gut microbiome on Atypical facial pain (FinnGen Biobank). (B) Causal effect of the gut microbiome on Facial pains (UK Biobank) based on MR analyses.
Figure 5
Figure 5
Causal effect of the gut microbiome on neck or shoulder pain (UK Biobank) on MR analyses. From outside to inside, the p-values of IVW, MR Egger, WM, SM, and Wmode represented, respectively. IVW, inverse variance weighted; WM, weighted median; SM, simple mode; Wmode weighted mode.
Figure 6
Figure 6
From outside to inside, the p-values of IVW, MR Egger, WM, SM, and Wmode represented, respectively. IVW, inverse variance weighted; WM, weighted median; SM, simple mode; Wmode weighted mode. (A) Causal effect of the gut microbiome on low back pain (FinnGen Biobank). (B) Causal effect of the gut microbiome on sciatica (FinnGen Biobank) based on MR analyses.
Figure 7
Figure 7
Causal effect of the gut microbiome on knee pain (UK Biobank) on MR analyses. From outside to inside, the p-values of IVW, MR Egger, WM, SM, and Wmode represented, respectively. IVW, inverse variance weighted; WM, weighted median; SM, simple mode; Wmode weighted mode.
Figure 8
Figure 8
Causal effect of the gut microbiome on hip pain (UK Biobank) on MR analyses. From outside to inside, the p-values of IVW, MR Egger, WM, SM, and Wmode represented, respectively. IVW, inverse variance weighted; WM, weighted median; SM, simple mode; Wmode weighted mode.
Figure 9
Figure 9
Causal effect of the gut microbiome on limb pain (FinnGen Biobank) on MR analyses. From outside to inside, the p-values of IVW, MR Egger, WM, SM, and Wmode represented, respectively. IVW, inverse variance weighted; WM, weighted median; SM, simple mode; Wmode weighted mode.
Figure 10
Figure 10
Causal effect of the gut microbiome on joint pain (FinnGen Biobank) on MR analyses. From outside to inside, the p-values of IVW, MR Egger, WM, SM, and Wmode represented, respectively. IVW, inverse variance weighted; WM, weighted median; SM, simple mode; Wmode weighted mode.
Figure 11
Figure 11
Causal efect of the gut microbiome on Fibromyalgia (FinnGen Biobank) on MR analyses. From outside to inside, the p-values of IVW, MR Egger, WM, SM, and Wmode represented, respectively. IVW, inverse variance weighted; WM, weighted median; SM, simple mode; Wmode weighted mode.
Figure 12
Figure 12
Causal effect of the gut microbiome on Pain in thoracic spine (FinnGen Biobank) on MR analyses. From outside to inside, the p-values of IVW, MR Egger, WM, SM, and Wmode represented, respectively. IVW, inverse variance weighted; WM, weighted median; SM, simple mode; Wmode weighted mode.
Figure 13
Figure 13
Causal effect of the gut microbiome on Pain (limb, back, neck, head abdominally) (FinnGen Biobank) on MR analyses. From outside to inside, the p-values of IVW, MR Egger, WM, SM, and Wmode represented, respectively. IVW, inverse variance weighted; WM, weighted median; SM, simple mode; Wmode weighted mode.
Figure 14
Figure 14
Causal links between gut microbiota and pain at 12 specific sites.
Figure 15
Figure 15
Summary of the main findings in the univariate MR Study. Combined with the available evidence, we consistently found causal effects of (A) genus.Lachnospira, (B) genus.Roseburia, (C) family.Christensenellaceae, (D) phylum.Bacteroidetes, (E) genus.Bifidobacterium, (F) genus.Dialister on painBlack solid arrows indicate known evidence and red solid arrows indicate our findings in this study.
See this image and copyright information in PMC

References

    1. Acharya C., Betrapally N. S., Gillevet P. M., Sterling R. K., Akbarali H., White M. B., et al. . (2017). Chronic opioid use is associated with altered gut microbiota and predicts readmissions in patients with cirrhosis. Aliment. Pharmacol. Ther. 45, 319–331. doi: 10.1111/apt.13858, PMID: - DOI - PubMed
    1. Amaral F. A., Sachs D., Costa V. V., Fagundes C. T., Cisalpino D., Cunha T. M., et al. . (2008). Commensal microbiota is fundamental for the development of inflammatory pain. Proc. Natl. Acad. Sci. USA 105, 2193–2197. doi: 10.1073/pnas.0711891105, PMID: - DOI - PMC - PubMed
    1. Amin N., Liu J., Bonnechere B., MahmoudianDehkordi S., Arnold M., Batra R., et al. . (2023). Interplay of metabolome and gut microbiome in individuals with major depressive disorder vs control individuals. JAMA Psychiat. 80, 597–609. doi: 10.1001/jamapsychiatry.2023.0685, PMID: - DOI - PMC - PubMed
    1. Auton A., Brooks L. D., Durbin R. M., Garrison E. P., Kang H. M., Korbel J. O., et al. . (2015). A global reference for human genetic variation. Nature 526, 68–74. doi: 10.1038/nature15393, PMID: - DOI - PMC - PubMed
    1. Backhed F., Ley R. E., Sonnenburg J. L., Peterson D. A., Gordon J. I. (2005). Host-bacterial mutualism in the human intestine. Science 307, 1915–1920. doi: 10.1126/science.1104816, PMID: - DOI - PubMed

LinkOut - more resources