The Gut Microbiome as Mediator Between Diet and its Impact on Immune Function

Abstract Background. Dietary habits may influence chronic low-grade inflammation in humans. Here we explore this interaction as well as the potential mediating role of the gut microbiome (GM), given that the GM is both involved in processing of dietary components and influences the immune system. Methods. A cross-sectional analysis of a sample of 482 healthy participants (207 males and 275 females) was performed. Dietary intake was assessed by a semiquantitative food questionnaire. Adipokines and soluble inflammatory mediators were assayed with multiple immunoassays and ELISA. Microbial DNA was extracted from frozen stool samples of the 471 participants. Polychoric correlation analysis was used to establish dietary patterns, and joint multivariate associations between these dietary patterns and immune biomarkers were studied using regression analyses with adjustment for sex, age, BMI, smoking, education levels and physical exercise and other dietary patterns. Non-parametric entropy mediation (NPEM) was applied to investigate whether diet-immune relationships are mediated by abundance of microbial species. Results. We identified 3 dietary patterns, characterized as “high-meat” (meat and sweetened drink), “prudent diet” (fish, fruit, legumes and vegetables) and “high alcohol” (higher alcohol consumption). Higher adherence to prudent diet was associated with a higher adiponectin level. The high alcohol pattern was associated with high concentrations of circulating concentrations of pro-inflammatory markers (CRP, IL-6, VEGF). Dialister invisus was found to mediate the relationship between a prudent dietary pattern and adiponectin, AAT, CRP, IL-6, and VEGF. Conclusion. A meat-based diet and a diet with high alcohol consumption were associated with high concentrations of biomarkers of chronic low-grade inflammation, and conversely, a prudent diet was associated with anti-inflammatory biomarkers. Diet-inflammation regulation may differ between sexes. Mediation analyses revealed that the association between prudent diet and immune function was partially mediated by the GM. Our study adds to our understanding of the associations between diet, the immune system and the GM in a healthy population.

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Regulation of Metabolism: A Cross Talk Between Gut Microbiota and Its Human Host

Physiology ◽

10.1152/physiol.00023.2012 ◽

2012 ◽

Vol 27 (5) ◽

pp. 300-307 ◽

Cited By ~ 33

Author(s):

Rémy Burcelin

Keyword(s):

Immune System ◽

Gut Microbiota ◽

Low Grade ◽

Gene Products ◽

Individual Level ◽

Obesity And Diabetes ◽

Regulation Of Metabolism ◽

Molecular Origin ◽

The Individual ◽

Low Grade Inflammation

The recent epidemic of obesity and diabetes and the diversity at the individual level could be explained by the intestinal microbiota-to-host relationship. More than four million gene products from the microbiome could interact with the immune system to induce a tissue metabolic infection, which is the molecular origin of the low-grade inflammation that characterizes the onset of obesity and diabetes.

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Cartilage-gut-microbiome axis: a new paradigm for novel therapeutic opportunities in osteoarthritis

RMD Open ◽

10.1136/rmdopen-2019-001037 ◽

2019 ◽

Vol 5 (2) ◽

pp. e001037 ◽

Cited By ~ 11

Author(s):

Jean-Marie Berthelot ◽

Jérémie Sellam ◽

Yves Maugars ◽

Francis Berenbaum

Keyword(s):

Gut Microbiota ◽

Gut Microbiome ◽

Cartilage Degradation ◽

Low Grade ◽

New Paradigm ◽

Healthy Human ◽

Human Cartilage ◽

Intact Cartilage ◽

Low Grade Inflammation

DNA of gut microbiota can be found in synovium of osteoarthritis and rheumatoid arthritis. This finding could result from the translocation of still alive bacteria from gut to joints through blood, since the diversified dormant microbiota of healthy human blood can be transiently resuscitated in vitro. The recent finding of gut microbiome in human cartilage, which differed between osteoarthritis and controls, suggests that a similar trafficking of dead or alive bacteria from gut microbiota physiologically occurs between gut and epiphysial bone marrow. Subchondral microbiota could enhance cartilage healing and transform components of deep cartilage matrix in metabolites with immunosuppressive properties. The differences of microbiome observed between hip and knee cartilage, either in osteoarthritis or controls, might be the counterpart of subtle differences in chondrocyte metabolism, themselves in line with differences in DNA methylation according to joints. Although bacteria theoretically cannot reach chondrocytes from the surface of intact cartilage, some bacteria enter the vascular channels of the epiphysial growth cartilage in young animals, whereas others can infect chondrocytes in vitro. In osteoarthritis, the early osteochondral plate angiogenesis may further enhance the ability of microbiota to locate close to the deeper layers of cartilage, and this might lead to focal dysbiosis, low-grade inflammation, cartilage degradation, epigenetic changes in chondrocytes and worsening of osteoarthritis. More studies on cartilage across different ethnic groups, weights, and according to age, are needed, to confirm the silent presence of gut microbiota close to human cartilage and better understand its physiologic and pathogenic significance.

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Whole grain-rich diet reduces body weight and systemic low-grade inflammation without inducing major changes of the gut microbiome: a randomised cross-over trial

Gut ◽

10.1136/gutjnl-2017-314786 ◽

2017 ◽

Vol 68 (1) ◽

pp. 83-93 ◽

Cited By ~ 84

Author(s):

Henrik Munch Roager ◽

Josef K Vogt ◽

Mette Kristensen ◽

Lea Benedicte S Hansen ◽

Sabine Ibrügger ◽

...

Keyword(s):

Body Weight ◽

Insulin Sensitivity ◽

Gut Microbiome ◽

Inflammatory Markers ◽

Dietary Intervention ◽

Short Chain Fatty Acids ◽

Low Grade ◽

Whole Grain ◽

Intestinal Transit Time ◽

Low Grade Inflammation

ObjectiveTo investigate whether a whole grain diet alters the gut microbiome and insulin sensitivity, as well as biomarkers of metabolic health and gut functionality.Design60 Danish adults at risk of developing metabolic syndrome were included in a randomised cross-over trial with two 8-week dietary intervention periods comprising whole grain diet and refined grain diet, separated by a washout period of ≥6 weeks. The response to the interventions on the gut microbiome composition and insulin sensitivity as well on measures of glucose and lipid metabolism, gut functionality, inflammatory markers, anthropometry and urine metabolomics were assessed.Results50 participants completed both periods with a whole grain intake of 179±50 g/day and 13±10 g/day in the whole grain and refined grain period, respectively. Compliance was confirmed by a difference in plasma alkylresorcinols (p<0.0001). Compared with refined grain, whole grain did not significantly alter glucose homeostasis and did not induce major changes in the faecal microbiome. Also, breath hydrogen levels, plasma short-chain fatty acids, intestinal integrity and intestinal transit time were not affected. The whole grain diet did, however, compared with the refined grain diet, decrease body weight (p<0.0001), serum inflammatory markers, interleukin (IL)-6 (p=0.009) and C-reactive protein (p=0.003). The reduction in body weight was consistent with a reduction in energy intake, and IL-6 reduction was associated with the amount of whole grain consumed, in particular with intake of rye.ConclusionCompared with refined grain diet, whole grain diet did not alter insulin sensitivity and gut microbiome but reduced body weight and systemic low-grade inflammation.Trial registration numberNCT01731366; Results.

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How Immunosenescence and Inflammaging May Contribute to Hyperinflammatory Syndrome in COVID-19

International Journal of Molecular Sciences ◽

10.3390/ijms222212539 ◽

2021 ◽

Vol 22 (22) ◽

pp. 12539

Author(s):

Ludmila Müller ◽

Svetlana Di Benedetto

Keyword(s):

Immune System ◽

Elderly People ◽

Immune Cells ◽

Peripheral Circulation ◽

Low Grade ◽

Thymic Involution ◽

Cell Repertoire ◽

Chronic Stressors ◽

Low Grade Inflammation ◽

With Memory

Aging is characterized by the dynamic remodeling of the immune system designated “immunosenescence,” and is associated with altered hematopoiesis, thymic involution, and lifelong immune stimulation by multitudinous chronic stressors, including the cytomegalovirus (CMV). Such alterations may contribute to a lowered proportion of naïve T-cells and to reduced diversity of the T-cell repertoire. In the peripheral circulation, a shift occurs towards accumulations of T and B-cell populations with memory phenotypes, and to accumulation of putatively senescent and exhausted immune cells. The aging-related accumulations of functionally exhausted memory T lymphocytes, commonly secreting pro-inflammatory cytokines, together with mediators and factors of the innate immune system, are considered to contribute to the low-grade inflammation (inflammaging) often observed in elderly people. These senescent immune cells not only secrete inflammatory mediators, but are also able to negatively modulate their environments. In this review, we give a short summary of the ways that immunosenescence, inflammaging, and CMV infection may cause insufficient immune responses, contribute to the establishment of the hyperinflammatory syndrome and impact the severity of the coronavirus disease 2019 (COVID-19) in elderly people.

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Aging and serum MCP-1 are associated with gut microbiome composition in a murine model

10.7287/peerj.preprints.1754v1 ◽

2016 ◽

Author(s):

Melissa N. Conley ◽

Carmen P. Wong ◽

Kyle M. Duyck ◽

Norman Hord ◽

Emily Ho ◽

...

Keyword(s):

Immune System ◽

Murine Model ◽

Gut Microbiome ◽

Inflammatory Marker ◽

Low Grade ◽

Host Immune System ◽

Cancer Type ◽

Microbiome Composition ◽

Aged Mice ◽

Age Related

Introduction Age is the primary risk factor for major human chronic diseases, including cardiovascular disorders, cancer, type 2 diabetes, and neurodegenerative diseases. Chronic, low-grade, systemic inflammation is associated with aging and the progression of immunosenescence. Immunosenescence may play an important role in the development of age-related chronic disease and the widely observed phenomenon of increased production of inflammatory mediators that accompany this process, referred to as “inflammaging”. While it has been demonstrated that the gut microbiome and immune system interact, the relationship between the gut microbiome and age remains to be clearly defined, particularly in the context of inflammation. The aim of the study was to clarify the associations between age, the gut microbiome, and pro-inflammatory marker serum MCP-1 in a C57BL/6 murine model. Results We used 16S rRNA gene sequencing to profile the composition of fecal microbiota associated with young and aged mice. Our analysis identified an association between microbiome structure and mouse age, and revealed specific groups of taxa whose abundances stratify young and aged mice. This includes the Ruminococcaceae, Clostridiaceae, and Enterobacteriaceae. We also profiled pro-inflammatory serum MCP-1 levels of each mouse and found that aged mice exhibited elevated serum MCP-1, a phenotype consistent with inflammaging. Robust correlation tests identified several taxa whose abundance in the microbiome associates with serum MCP-1 status, indicating that they may interact with the mouse immune system. We find that taxonomically similar organisms can exhibit differing, even opposite, patterns of association with the host immune system. We also find that many of the OTUs that associate with serum MCP-1 also stratify individuals by age. Discussion Our results demonstrate that gut microbiome composition is associated with age and the pro-inflammatory marker, serum MCP-1. The correlation between age, relative abundance of specific taxa in the gut microbiome, and serum MCP-1 status in mice indicates that the gut microbiome may play a modulating role in age-related inflammatory processes. These findings warrant further investigation of taxa associated with the inflammaging phenotype and the role of gut microbiome in the health status and immune function of aged individuals.

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The Gut Microbiome, Metformin, and Aging

The Annual Review of Pharmacology and Toxicology ◽

10.1146/annurev-pharmtox-051920-093829 ◽

2021 ◽

Vol 62 (1) ◽

Cited By ~ 1

Author(s):

Sri Nitya Reddy Induri ◽

Payalben Kansara ◽

Scott C. Thomas ◽

Fangxi Xu ◽

Deepak Saxena ◽

...

Keyword(s):

Gut Microbiome ◽

Healthy Aging ◽

Bacterial Species ◽

Annual Review ◽

Publication Date ◽

Low Grade ◽

Host Interactions ◽

Age Related ◽

Low Grade Inflammation

Metformin has been extensively used for the treatment of type 2 diabetes, and it may also promote healthy aging. Despite its widespread use and versatility, metformin's mechanisms of action remain elusive. The gut typically harbors thousands of bacterial species, and as the concentration of metformin is much higher in the gut as compared to plasma, it is plausible that microbiome-drug-host interactions may influence the functions of metformin. Detrimental perturbations in the aging gut microbiome lead to the activation of the innate immune response concomitant with chronic low-grade inflammation. With the effectiveness of metformin in diabetes and antiaging varying among individuals, there is reason to believe that the gut microbiome plays a role in the efficacy of metformin. Metformin has been implicated in the promotion and maintenance of a healthy gut microbiome and reduces many age-related degenerative pathologies. Mechanistic understanding of metformin in the promotion of a healthy gut microbiome and aging will require a systems-level approach. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 62 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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Epigenetics meets proteomics in an epigenome-wide association study with circulating blood plasma protein traits

Nature Communications ◽

10.1038/s41467-019-13831-w ◽

2020 ◽

Vol 11 (1) ◽

Cited By ~ 8

Author(s):

Shaza B. Zaghlool ◽

Brigitte Kühnel ◽

Mohamed A. Elhadad ◽

Sara Kader ◽

Anna Halama ◽

...

Keyword(s):

Dna Methylation ◽

Immune System ◽

Association Study ◽

Underlying Disease ◽

Low Grade ◽

Complex Disorders ◽

Clinical Endpoints ◽

Personalized Approach ◽

Level Of Significance ◽

Low Grade Inflammation

AbstractDNA methylation and blood circulating proteins have been associated with many complex disorders, but the underlying disease-causing mechanisms often remain unclear. Here, we report an epigenome-wide association study of 1123 proteins from 944 participants of the KORA population study and replication in a multi-ethnic cohort of 344 individuals. We identify 98 CpG-protein associations (pQTMs) at a stringent Bonferroni level of significance. Overlapping associations with transcriptomics, metabolomics, and clinical endpoints suggest implication of processes related to chronic low-grade inflammation, including a network involving methylation of NLRC5, a regulator of the inflammasome, and associated pQTMs implicating key proteins of the immune system, such as CD48, CD163, CXCL10, CXCL11, LAG3, FCGR3B, and B2M. Our study links DNA methylation to disease endpoints via intermediate proteomics phenotypes and identifies correlative networks that may eventually be targeted in a personalized approach of chronic low-grade inflammation.

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Can Exercise-Induced Muscle Damage Be a Good Model for the Investigation of the Anti-Inflammatory Properties of Diet in Humans?

Biomedicines ◽

10.3390/biomedicines9010036 ◽

2021 ◽

Vol 9 (1) ◽

pp. 36

Author(s):

Spyridon Methenitis ◽

Ioanna Stergiou ◽

Smaragdi Antonopoulou ◽

Tzortzis Nomikos

Keyword(s):

Muscle Damage ◽

Dietary Patterns ◽

Inflammatory Responses ◽

Low Grade ◽

Inflammatory Stimuli ◽

Methodological Approaches ◽

Anti Inflammatory ◽

Exercise Induced ◽

Low Grade Inflammation ◽

Inflammatory Effect

Subclinical, low-grade, inflammation is one of the main pathophysiological mechanisms underlying the majority of chronic and non-communicable diseases. Several methodological approaches have been applied for the assessment of the anti-inflammatory properties of nutrition, however, their impact in human body remains uncertain, because of the fact that the majority of the studies reporting anti-inflammatory effect of dietary patterns, have been performed under laboratory settings and/or in animal models. Thus, the extrapolation of these results to humans is risky. It is therefore obvious that the development of an inflammatory model in humans, by which we could induce inflammatory responses to humans in a regulated, specific, and non-harmful way, could greatly facilitate the estimation of the anti-inflammatory properties of diet in a more physiological way and mechanistically relevant way. We believe that exercise-induced muscle damage (EIMD) could serve as such a model, either in studies investigating the homeostatic responses of individuals under inflammatory stimuli or for the estimation of the anti-inflammatory or pro-inflammatory potential of dietary patterns, foods, supplements, nutrients, or phytochemicals. Thus, in this review we discuss the possibility of exercise-induced muscle damage being an inflammation model suitable for the assessment of the anti-inflammatory properties of diet in humans.

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Vitamin D and inflammation in the prevention of type 2 diabetes: public health relevance

Reviews in Health Care ◽

10.7175/rhc.26934243-255 ◽

2012 ◽

Vol 3 (4) ◽

pp. 243

Author(s):

Alaa Badawi ◽

Eman Sadoun ◽

Mohamed H. Al Thani

Keyword(s):

Public Health ◽

Type 2 Diabetes ◽

Vitamin D ◽

Immune System ◽

Innate Immune System ◽

Population Level ◽

Innate Immune ◽

Low Grade ◽

Low Grade Inflammation

The incidence of type 2 diabetes mellitus (T2DM) is increasing worldwide. To reduce the disease risk and burden at the population level, preventative strategies should be developed with minimal cost and effort and with no side-effects. Low-grade inflammation resulting from imbalances in the innate immune system has been associated with an array of chronic disorders that predispose to the later development of T2DM (e.g., obesity, metabolic syndrome, and insulin resistance). As a result, inflammation may contribute to the pathogenesis of T2DM. Therefore, attenuation of this inflammatory response via modulating the innate immune system could lead to improved insulin sensitivity and delayed disease onset. Dietary supplementation with vitamin D may represent a novel strategy toward the prevention and control of T2DM at the population level due to its anti-inflammatory and antioxidant properties. This review examines current knowledge linking T2DM to chronic low-grade inflammation and the role of vitamin D in modulating this relationship. The concept that vitamin D, via attenuating inflammation, could be employed as a novel preventive measure for T2DM is evaluated in the context of its relevance to health care and public health practices.

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Aging and serum MCP-1 are associated with gut microbiome composition in a murine model

PeerJ ◽

10.7717/peerj.1854 ◽

2016 ◽

Vol 4 ◽

pp. e1854 ◽

Cited By ~ 47

Author(s):

Melissa N. Conley ◽

Carmen P. Wong ◽

Kyle M. Duyck ◽

Norman Hord ◽

Emily Ho ◽

...

Keyword(s):

Immune System ◽

Murine Model ◽

Gut Microbiome ◽

Inflammatory Marker ◽

Low Grade ◽

Host Immune System ◽

Cancer Type ◽

Microbiome Composition ◽

Aged Mice ◽

Age Related

Introduction.Age is the primary risk factor for major human chronic diseases, including cardiovascular disorders, cancer, type 2 diabetes, and neurodegenerative diseases. Chronic, low-grade, systemic inflammation is associated with aging and the progression of immunosenescence. Immunosenescence may play an important role in the development of age-related chronic disease and the widely observed phenomenon of increased production of inflammatory mediators that accompany this process, referred to as “inflammaging.” While it has been demonstrated that the gut microbiome and immune system interact, the relationship between the gut microbiome and age remains to be clearly defined, particularly in the context of inflammation. The aim of our study was to clarify the associations between age, the gut microbiome, and pro-inflammatory marker serum MCP-1 in a C57BL/6 murine model.Results.We used 16S rRNA gene sequencing to profile the composition of fecal microbiota associated with young and aged mice. Our analysis identified an association between microbiome structure and mouse age and revealed specific groups of taxa whose abundances stratify young and aged mice. This includes the Ruminococcaceae, Clostridiaceae, and Enterobacteriaceae. We also profiled pro-inflammatory serum MCP-1 levels of each mouse and found that aged mice exhibited elevated serum MCP-1, a phenotype consistent with inflammaging. Robust correlation tests identified several taxa whose abundance in the microbiome associates with serum MCP-1 status, indicating that they may interact with the mouse immune system. We find that taxonomically similar organisms can exhibit differing, even opposite, patterns of association with the host immune system. We also find that many of the OTUs that associate with serum MCP-1 stratify individuals by age.Discussion.Our results demonstrate that gut microbiome composition is associated with age and the pro-inflammatory marker, serum MCP-1. The correlation between age, relative abundance of specific taxa in the gut microbiome, and serum MCP-1 status in mice indicates that the gut microbiome may play a modulating role in age-related inflammatory processes. These findings warrant further investigation of taxa associated with the inflammaging phenotype and the role of gut microbiome in the health status and immune function of aged individuals.

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