Suppressed immune and metabolic responses to intestinal damage-associated microbial translocation in myalgic encephalomyelitis/chronic fatigue syndrome

Melanie Uhde; Alyssa C Indart; Peter H R Green; Robert H Yolken; Dane B Cook; Sanjay K Shukla; Suzanne D Vernon; Armin Alaedini

doi:10.1016/j.bbih.2023.100627

Suppressed immune and metabolic responses to intestinal damage-associated microbial translocation in myalgic encephalomyelitis/chronic fatigue syndrome

Brain Behav Immun Health. 2023 Apr 27:30:100627. doi: 10.1016/j.bbih.2023.100627. eCollection 2023 Jul.

Authors

Melanie Uhde¹, Alyssa C Indart¹, Peter H R Green^{1

2}, Robert H Yolken³, Dane B Cook⁴, Sanjay K Shukla⁵, Suzanne D Vernon⁶, Armin Alaedini^{1

7

2

8}

Affiliations

¹ Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, New York, NY, USA.
² Celiac Disease Center, Columbia University, New York, NY, USA.
³ The Stanley Laboratory of Developmental Neurovirology, Johns Hopkins University, Baltimore, MD, USA.
⁴ Department of Kinesiology, University of Wisconsin - Madison, Madison, WI, USA.
⁵ Center for Human Genetics, Marshfield Clinic Research Institute, Marshfield, WI, USA.
⁶ Bateman Horne Center, Salt Lake City, UT, USA.
⁷ Institute of Human Nutrition, Columbia University, New York, NY, USA.
⁸ Division of Infectious Diseases, Department of Medicine, New York Medical College, Valhalla, NY, USA.

Abstract

The etiology and mechanism of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are poorly understood and no biomarkers have been established. Specifically, the relationship between the immunologic, metabolic, and gastrointestinal abnormalities associated with ME/CFS and their relevance to established symptoms of the condition remain unclear. Relying on data from two independent pairs of ME/CFS and control cohorts, one at rest and one undergoing an exercise challenge, we identify a state of suppressed acute-phase innate immune response to microbial translocation in conjunction with a compromised gut epithelium in ME/CFS. This immunosuppression, along with observed enhancement of compensatory antibody responses to counter the microbial translocation, was associated with and may be mediated by alterations in glucose and citrate metabolism and an IL-10 immunoregulatory response. Our findings provide novel insights into mechanistic pathways, biomarkers, and potential therapeutic targets in ME/CFS, including in the context of exertion, with relevance to both intestinal and extra-intestinal symptoms.

Keywords: Acute-phase innate immune response; Antibody; B cell; Citrate; Glucose; Gut epithelial barrier; IL-10; Immunoregulation; Inflammation; Metabolism; Microbial translocation; Microbiota; Myalgic encephalomyelitis/chronic fatigue syndrome; TLR4.