Linking the Human Gut Microbiome to Inflammatory Cytokine Production Capacity

Abstract

SummaryGut microbial dysbioses are linked to aberrant immune responses, which are often accompanied by abnormal production of inflammatory cytokines. As part of the Human Functional Genomics * Correspondence: xavier@molbio.mgh.harvard.edu (R.J.X.), mihai.netea@radboudumc.nl (M.G.N.). Lead ContactPublisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Author ContributionsMS performed the metagenomics data analyses and correlation analyses. SPS, MJ, MO, AK, and MJB performed the immunological assays and processed and analyzed the data. MS, HV, EAF, CH, MGN, and RJX interpreted the results. MS, EAF, and CH led the computational methods and research development. SPS, MJ, and MO collected clinical samples. SPS, TJ, and LJ performed functional validation experiments. MS, SPS, HV, CH, MGN, and RJX assembled and wrote the paper. MS, HV, MGN, and RJX served as project leaders. JF, AZ, LABJ, CW, MGN, and RJX designed the cohort study. CH, CW, MGN, and RJX served as principal investigators. Table S1. Related to Figure 3. Correlation coefficients for all significant species associations Table S2. Related to Figure 3. FDR values for all significant species associations Table S3. Related to Figure 3. Correlation coefficients for all significant genus associations Table S4. Related to Figure 3. FDR values for all significant genus associations Table S5. Related to Figure 4. Correlation coefficients for all significant pathway associations Table S6. Related to Figure 4. FDR values for all significant pathway associations Table S7. Related to Figure 4. Correlation coefficients for all significant GO category associations Table S8. Related to Figure 4. FDR values for all significant GO category associations HHS Public Access Author Manuscript Author ManuscriptAuthor Manuscript Author ManuscriptProject (HFGP), we investigate how differences in composition and function of gut microbial communities may contribute to inter-individual variation in cytokine responses to microbial stimulations in healthy humans. We observe microbiome-cytokine interaction patterns that are stimulus-specific, cytokine-specific, and cytokine-and stimulus-specific. Validation of two predicted host-microbial interactions reveal that TNFα and IFNγ production are associated with specific microbial metabolic pathways: palmitoleic acid metabolism and tryptophan degradation to tryptophol. Besides providing a resource of predicted microbially-derived mediators that influence immune phenotypes in response to common microorganisms, these data can help to define principles for understanding disease susceptibility. The three HFGP stud...

Host and Environmental Factors Influencing Individual Human Cytokine Responses

“…The accompanying study by Yang et al demonstrates that genetic variability of the host has a strong effect on cytokine responses, again with the impact depending on the type of pathogen and cytokine studied (Li et al, 2016). In addition, a role of non-genetic factors for the modulation of cytokine responses is supported by the identification of important microbiome components that modulate cytokine responses, as described in the accompanying manuscript by Schirmer et al (Schirmer et al, 2016). These effects are likely mediated by microbial components, or through diverse metabolites released by microbiota-diet interaction.…”

“…We systematically investigated the factors that influence the human cytokine responses in the 500 Functional Genomics (500FG) cohort of healthy volunteers within HFGP, after stimulation of their leukocytes with bacterial, fungal, viral and non-microbial metabolic stimuli; while the present study assessed the impact of environmental and non-genetic host factors on cytokine responses, complementary studies investigated the impact of the genetic (Li et al, 2016) and microbiome (Schirmer et al, 2016) variability on cytokine production.…”

“…The current manuscript is the first in a series of three studies presented in this issue of Cell, that aim to provide a systematic assessment of the impact of various intrinsic and environmental factors (this manuscript), the host genome (Li et al, 2016), and the gut microbiome (Schirmer et al, 2016), on cytokine production and baseline immune parameters in a systems biology-based approach. See also Table S1, S2 and Figure S1.…”

“…The 500FG study has two important advantages compared to previous studies: firstly, it comprises the largest cohort of healthy individuals studied to date, and secondly, the cytokine production was assessed in response to a large panel of microbial and metabolic stimuli and in three different cellular systems. The current manuscript is the first in a series of three studies presented in this issue of Cell, that aim to provide a systematic assessment of the impact of various intrinsic and environmental factors (this manuscript), the host genome (Li et al, 2016), and the gut microbiome (Schirmer et al, 2016), on baseline immune status and cytokine production in a systems biology-based approach. A schematic overview of these three studies on the 500FG cohort is presented in Figure 1.…”

The immunopathology of sepsis and potential therapeutic targets

“…Conversely, dysbiosis in the gut has been linked to the subsequent hospitalization of patients with sepsis, which suggests an association between the composition of the gut microbiota and sepsis susceptibility 74 . The composition of the gut microbiome of healthy individuals influences cytokine release by blood leukocytes in a stimulus-specific and cytokinespecific way 75 . Preclinical studies have demonstrated that disruption of the gut microbiome by broad-spectrum antibiotics impairs host defence during sepsis, and this impairment might be due to several mechanisms [76][77][78] .…”