FLEXiGUT: Rationale for exposomics associations with chronic low-grade gut inflammation

Gut microbiota-mediated inflammation promotes obesity-associated low-grade inflammation, which represents a hallmark of metabolic syndrome. To investigate if lifestyle-induced weight loss (WL) may modulate the gut microbiome composition and its interaction with the host on a functional level, we analyzed the fecal metaproteome of 33 individuals with metabolic syndrome in a longitudinal study before and after lifestyle-induced WL in a well-defined cohort. The 6-month WL intervention resulted in reduced BMI (−13.7%), improved insulin sensitivity (HOMA-IR, −46.1%), and reduced levels of circulating hsCRP (−39.9%), indicating metabolic syndrome reversal. The metaprotein spectra revealed a decrease of human proteins associated with gut inflammation. Taxonomic analysis revealed only minor changes in the bacterial composition with an increase of the families Desulfovibrionaceae, Leptospiraceae, Syntrophomonadaceae, Thermotogaceae and Verrucomicrobiaceae. Yet we detected an increased abundance of microbial metaprotein spectra that suggest an enhanced hydrolysis of complex carbohydrates. Hence, lifestyle-induced WL was associated with reduced gut inflammation and functional changes of human and microbial enzymes for carbohydrate hydrolysis while the taxonomic composition of the gut microbiome remained almost stable. The metaproteomics workflow has proven to be a suitable method for monitoring inflammatory changes in the fecal metaproteome.

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Obesity in Humans Is Characterized by Gut Inflammation as Shown by Pro-Inflammatory Intestinal Macrophage Accumulation

Frontiers in Immunology ◽

10.3389/fimmu.2021.668654 ◽

2021 ◽

Vol 12 ◽

Author(s):

Theresa V. Rohm ◽

Regula Fuchs ◽

Rahel L. Müller ◽

Lena Keller ◽

Zora Baumann ◽

...

Keyword(s):

Risk Factors ◽

Cardiovascular Risk ◽

Cardiovascular Risk Factors ◽

Vegetable Intake ◽

Cardiovascular Complications ◽

Processed Meat ◽

Low Grade ◽

Blood Monocytes ◽

Unhealthy Lifestyle ◽

Gut Inflammation

Chronic low-grade inflammation is a hallmark of obesity and associated with cardiovascular complications. However, it remains unclear where this inflammation starts. As the gut is constantly exposed to food, gut microbiota, and metabolites, we hypothesized that mucosal immunity triggers an innate inflammatory response in obesity. We characterized five distinct macrophage subpopulations (P1-P5) along the gastrointestinal tract and blood monocyte subpopulations (classical, non-classical, intermediate), which replenish intestinal macrophages, in non-obese (BMI<27kg/m2) and obese individuals (BMI>32kg/m2). To elucidate factors that potentially trigger gut inflammation, we correlated these subpopulations with cardiovascular risk factors and lifestyle behaviors. In obese individuals, we found higher pro-inflammatory macrophages in the stomach, duodenum, and colon. Intermediate blood monocytes were also increased in obesity, suggesting enhanced recruitment to the gut. We identified unhealthy lifestyle habits as potential triggers of gut and systemic inflammation (i.e., low vegetable intake, high processed meat consumption, sedentary lifestyle). Cardiovascular risk factors other than body weight did not affect the innate immune response. Thus, obesity in humans is characterized by gut inflammation as shown by accumulation of pro-inflammatory intestinal macrophages, potentially via recruited blood monocytes. Understanding gut innate immunity in human obesity might open up new targets for immune-modulatory treatments in metabolic disease.

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Age-dependent involvement of gut mast cells and histamine in post-stroke inflammation

10.21203/rs.2.21718/v1 ◽

2020 ◽

Author(s):

Maria Pilar Blasco ◽

Anjali Chauhan ◽

Pedram Honarpisheh ◽

Hilda Ahnstedt ◽

John d’Aigle ◽

...

Keyword(s):

Ischemic Stroke ◽

Mast Cells ◽

Receptor Expression ◽

Mast Cell Activation ◽

Low Grade ◽

Gut Inflammation ◽

Aged Mice ◽

Post Stroke ◽

Age Related ◽

The Brain

Abstract Background Risk of stroke-related morbidity and mortality increases significantly with age. Aging is associated with chronic, low-grade inflammation, which is thought to contribute to the poorer outcomes after stroke seen in the elderly. Histamine (HA) is a major molecular mediator of inflammation and mast cells residing in the gut are a primary source of histamine. Methods Stroke was induced in male C57BL/6J mice at 3 months (young) and 20 months (aged) of age. Role of histamine after stroke was examined using young (Yg) and aged (Ag) mice, mice underwent MCAO surgery and were euthanized at 6h, 24h and 7 days post-ischemia; sham mice received the same surgery but no MCAO. In this work, we evaluated whether worsened outcomes after experimental stroke in aged mice was associated with age-related changes in mast cells, histamine levels, and histamine receptor expression in the gut, brain, and plasma. Results We found increased numbers of mast cells in the gut and the brain with aging. Using the middle cerebral artery occlusion (MCAO) model of ischemic stroke, we demonstrate that stroke leads to increased numbers of mast cells and histamine receptors in the gut. These gut-centric changes are associated with elevated levels of HA and other pro-inflammatory cytokines including IL-6, G-CSF, TNF-α, and IFN-γ in the peripheral circulation. Our data also shows that post-stroke gut inflammation led to a significant reduction of mucin-producing goblet cells and a loss of gut barrier integrity. Lastly, gut inflammation after stroke is associated with changes in the composition of the gut microbiota as early as 24 hours post-stroke. Conclusion An important theme emerging from our results is that acute inflammatory events following ischemic insults in the brain persist longer in the aged mice when compared to younger animals. Taken together, our findings implicate mast cell activation and histamine signaling as a part of peripheral inflammatory response after ischemic stroke, which are profound in aged animals. Interfering with histamine signaling orally might provide translational value to improve stroke outcome.

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Age-dependent involvement of gut mast cells and histamine in post-stroke inflammation

10.21203/rs.2.21718/v3 ◽

2020 ◽

Author(s):

Maria Pilar Blasco ◽

Anjali Chauhan ◽

Pedram Honarpisheh ◽

Hilda Ahnstedt ◽

John d’Aigle ◽

...

Keyword(s):

Ischemic Stroke ◽

Mast Cells ◽

Receptor Expression ◽

Mast Cell Activation ◽

Low Grade ◽

Gut Inflammation ◽

Aged Mice ◽

Post Stroke ◽

Age Related ◽

The Brain

Abstract Background Risk of stroke-related morbidity and mortality increases significantly with age. Aging is associated with chronic, low-grade inflammation, which is thought to contribute to the poorer outcomes after stroke seen in the elderly. Histamine (HA) is a major molecular mediator of inflammation and mast cells residing in the gut are a primary source of histamine. Methods Stroke was induced in male C57BL/6J mice at 3 months (young) and 20 months (aged) of age. Role of histamine after stroke was examined using young (Yg) and aged (Ag) mice, mice underwent MCAO surgery and were euthanized at 6h, 24h and 7 days post-ischemia; sham mice received the same surgery but no MCAO. In this work, we evaluated whether worsened outcomes after experimental stroke in aged mice was associated with age-related changes in mast cells, histamine levels, and histamine receptor expression in the gut, brain, and plasma. Results We found increased numbers of mast cells in the gut and the brain with aging. Using the middle cerebral artery occlusion (MCAO) model of ischemic stroke, we demonstrate that stroke leads to increased numbers of mast cells and histamine receptors in the gut. These gut-centric changes are associated with elevated levels of HA and other pro-inflammatory cytokines including IL-6, G-CSF, TNF-α, and IFN-γ in the peripheral circulation. Our data also shows that post-stroke gut inflammation led to a significant reduction of mucin-producing goblet cells and a loss of gut barrier integrity. Lastly, gut inflammation after stroke is associated with changes in the composition of the gut microbiota as early as 24 hours post-stroke. Conclusion An important theme emerging from our results is that acute inflammatory events following ischemic insults in the brain persist longer in the aged mice when compared to younger animals. Taken together, our findings implicate mast cell activation and histamine signaling as a part of peripheral inflammatory response after ischemic stroke, which are profound in aged animals. Interfering with histamine signaling orally might provide translational value to improve stroke outcome.

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Age-dependent involvement of gut mast cells and histamine in post-stroke inflammation

10.21203/rs.2.21718/v2 ◽

2020 ◽

Author(s):

Maria Pilar Blasco ◽

Anjali Chauhan ◽

Pedram Honarpisheh ◽

Hilda Ahnstedt ◽

John d’Aigle ◽

...

Keyword(s):

Ischemic Stroke ◽

Mast Cells ◽

Receptor Expression ◽

Mast Cell Activation ◽

Low Grade ◽

Gut Inflammation ◽

Aged Mice ◽

Post Stroke ◽

Age Related ◽

The Brain

Abstract Background Risk of stroke-related morbidity and mortality increases significantly with age. Aging is associated with chronic, low-grade inflammation, which is thought to contribute to the poorer outcomes after stroke seen in the elderly. Histamine (HA) is a major molecular mediator of inflammation and mast cells residing in the gut are a primary source of histamine. Methods Stroke was induced in male C57BL/6J mice at 3 months (young) and 20 months (aged) of age. Role of histamine after stroke was examined using young (Yg) and aged (Ag) mice, mice underwent MCAO surgery and were euthanized at 6h, 24h and 7 days post-ischemia; sham mice received the same surgery but no MCAO. In this work, we evaluated whether worsened outcomes after experimental stroke in aged mice was associated with age-related changes in mast cells, histamine levels, and histamine receptor expression in the gut, brain, and plasma. Results We found increased numbers of mast cells in the gut and the brain with aging. Using the middle cerebral artery occlusion (MCAO) model of ischemic stroke, we demonstrate that stroke leads to increased numbers of mast cells and histamine receptors in the gut. These gut-centric changes are associated with elevated levels of HA and other pro-inflammatory cytokines including IL-6, G-CSF, TNF-α, and IFN-γ in the peripheral circulation. Our data also shows that post-stroke gut inflammation led to a significant reduction of mucin-producing goblet cells and a loss of gut barrier integrity. Lastly, gut inflammation after stroke is associated with changes in the composition of the gut microbiota as early as 24 hours post-stroke. Conclusion An important theme emerging from our results is that acute inflammatory events following ischemic insults in the brain persist longer in the aged mice when compared to younger animals. Taken together, our findings implicate mast cell activation and histamine signaling as a part of peripheral inflammatory response after ischemic stroke, which are profound in aged animals. Interfering with histamine signaling orally might provide translational value to improve stroke outcome.

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Novel Models for Chronic Intestinal Inflammation in Chickens: Intestinal Inflammation Pattern and Biomarkers

Frontiers in Immunology ◽

10.3389/fimmu.2021.676628 ◽

2021 ◽

Vol 12 ◽

Author(s):

Gabriela C. Dal Pont ◽

Bruna L. Belote ◽

Annah Lee ◽

Cristiano Bortoluzzi ◽

Cinthia Eyng ◽

...

Keyword(s):

Intestinal Inflammation ◽

Negative Impact ◽

Low Grade ◽

Lipocalin 2 ◽

Gut Health ◽

Chemical Induction ◽

Spatial And Temporal Patterns ◽

Gut Inflammation ◽

Chronic Intestinal Inflammation

For poultry producers, chronic low-grade intestinal inflammation has a negative impact on productivity by impairing nutrient absorption and allocation of nutrients for growth. Understanding the triggers of chronic intestinal inflammation and developing a non-invasive measurement is crucial to managing gut health in poultry. In this study, we developed two novel models of low-grade chronic intestinal inflammation in broiler chickens: a chemical model using dextran sodium sulfate (DSS) and a dietary model using a high non-starch polysaccharide diet (NSP). Further, we evaluated the potential of several proteins as biomarkers of gut inflammation. For these experiments, the chemical induction of inflammation consisted of two 5-day cycles of oral gavage of either 0.25mg DSS/ml or 0.35mg DSS/ml; whereas the NSP diet (30% rice bran) was fed throughout the experiment. At four times (14, 22, 28 and 36-d post-hatch), necropsies were performed to collect intestinal samples for histology, and feces and serum for biomarkers quantification. Neither DSS nor NSP treatments affected feed intake or livability. NSP-fed birds exhibited intestinal inflammation through 14-d, which stabilized by 36-d. On the other hand, the cyclic DSS-treatment produced inflammation throughout the entire experimental period. Histological examination of the intestine revealed that the inflammation induced by both models exhibited similar spatial and temporal patterns with the duodenum and jejunum affected early (at 14-d) whereas the ileum was compromised by 28-d. Calprotectin (CALP) was the only serum protein found to be increased due to inflammation. However, fecal CALP and Lipocalin-2 (LCN-2) concentrations were significantly greater in the induced inflammation groups at 28-d. This experiment demonstrated for the first time, two in vivo models of chronic gut inflammation in chickens, a DSS and a nutritional NSP protocols. Based on these models we observed that intestinal inflammation begins in the upper segments of small intestine and moved to the lower region over time. In the searching for a fecal biomarker for intestinal inflammation, LCN-2 showed promising results. More importantly, calprotectin has a great potential as a novel biomarker for poultry measured both in serum and feces.

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Direct Observation of Crystalline Ordering In Naturally Graphitized Carbon Produced by Low Grade Metamorphism

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100078377 ◽

1977 ◽

Vol 35 ◽

pp. 162-163

Author(s):

Thomas R. McKee ◽

Peter R. Buseck

Keyword(s):

Crystallite Size ◽

Sedimentary Rocks ◽

Carbonaceous Material ◽

Low Grade ◽

X Ray ◽

Graphitized Carbon ◽

Transmission Electron ◽

Heat Treated ◽

Commercial Carbon ◽

Metamorphic Zone

Sediments commonly contain organic material which appears as refractory carbonaceous material in metamorphosed sedimentary rocks. Grew and others have shown that relative carbon content, crystallite size, X-ray crystallinity and development of well-ordered graphite crystal structure of the carbonaceous material increases with increasing metamorphic grade. The graphitization process is irreversible and appears to be continous from the amorphous to the completely graphitized stage. The most dramatic chemical and crystallographic changes take place within the chlorite metamorphic zone.The detailed X-ray investigation of crystallite size and crystalline ordering is complex and can best be investigated by other means such as high resolution transmission electron microscopy (HRTEM). The natural graphitization series is similar to that for heat-treated commercial carbon blacks, which have been successfully studied by HRTEM (Ban and others).

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Scanning Electron Microscope Study of Bacteria on Mineral Surfaces

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100090634 ◽

1976 ◽

Vol 34 ◽

pp. 130-131

Author(s):

V.K. Berry

Keyword(s):

Oxidation Reaction ◽

Electron Microscope Study ◽

Elemental Sulfur ◽

Thiobacillus Ferrooxidans ◽

Physical Contact ◽

Metal Sulfides ◽

Low Grade ◽

Mineral Surfaces ◽

Mineral Surface ◽

Scanning Electron Microscope Study

There are two strains of bacteria viz. Thiobacillus thiooxidansand Thiobacillus ferrooxidanswidely mentioned to play an important role in the leaching process of low-grade ores. Another strain used in this study is a thermophile and is designated Caldariella .These microorganisms are acidophilic chemosynthetic aerobic autotrophs and are capable of oxidizing many metal sulfides and elemental sulfur to sulfates and Fe2+ to Fe3+. The necessity of physical contact or attachment by bacteria to mineral surfaces during oxidation reaction has not been fairly established so far. Temple and Koehler reported that during oxidation of marcasite T. thiooxidanswere found concentrated on mineral surface. Schaeffer, et al. demonstrated that physical contact or attachment is essential for oxidation of sulfur.

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TEM/AEM characterization of fine-grained clay minerals in very-low-grade rocks: Evaluation of contamination by empa involving celadonite family minerals

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100165938 ◽

1996 ◽

Vol 54 ◽

pp. 694-695

Author(s):

Gejing Li ◽

D. R. Peacor ◽

D. S. Coombs ◽

Y. Kawachi

Keyword(s):

Electron Microscopy ◽

Volcanic Rocks ◽

Analytical Electron Microscopy ◽

Metamorphic Rocks ◽

New Mineral ◽

Chemical Compositions ◽

Low Grade ◽

Fine Grained ◽

Depth Analysis ◽

Mineral Aggregates

Recent advances in transmission electron microscopy (TEM) and analytical electron microscopy (AEM) have led to many new insights into the structural and chemical characteristics of very finegrained, optically homogeneous mineral aggregates in sedimentary and very low-grade metamorphic rocks. Chemical compositions obtained by electron microprobe analysis (EMPA) on such materials have been shown by TEM/AEM to result from beam overlap on contaminant phases on a scale below resolution of EMPA, which in turn can lead to errors in interpretation and determination of formation conditions. Here we present an in-depth analysis of the relation between AEM and EMPA data, which leads also to the definition of new mineral phases, and demonstrate the resolution power of AEM relative to EMPA in investigations of very fine-grained mineral aggregates in sedimentary and very low-grade metamorphic rocks.Celadonite, having end-member composition KMgFe3+Si4O10(OH)2, and with minor substitution of Fe2+ for Mg and Al for Fe3+ on octahedral sites, is a fine-grained mica widespread in volcanic rocks and volcaniclastic sediments which have undergone low-temperature alteration in the oceanic crust and in burial metamorphic sequences.

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Inflammageing in the cardiovascular system: mechanisms, emerging targets, and novel therapeutic strategies

Clinical Science ◽

10.1042/cs20191213 ◽

2020 ◽

Vol 134 (17) ◽

pp. 2243-2262

Author(s):

Danlin Liu ◽

Gavin Richardson ◽

Fehmi M. Benli ◽

Catherine Park ◽

João V. de Souza ◽

...

Keyword(s):

Cardiovascular Diseases ◽

Cardiovascular System ◽

Nlrp3 Inflammasome ◽

Molecular Mechanisms ◽

Molecular Targets ◽

Therapeutic Interventions ◽

Low Grade ◽

Cardiovascular Research ◽

Inflammatory Processes ◽

Ach Receptors

Abstract In the elderly population, pathological inflammation has been associated with ageing-associated diseases. The term ‘inflammageing’, which was used for the first time by Franceschi and co-workers in 2000, is associated with the chronic, low-grade, subclinical inflammatory processes coupled to biological ageing. The source of these inflammatory processes is debated. The senescence-associated secretory phenotype (SASP) has been proposed as the main origin of inflammageing. The SASP is characterised by the release of inflammatory cytokines, elevated activation of the NLRP3 inflammasome, altered regulation of acetylcholine (ACh) nicotinic receptors, and abnormal NAD+ metabolism. Therefore, SASP may be ‘druggable’ by small molecule therapeutics targeting those emerging molecular targets. It has been shown that inflammageing is a hallmark of various cardiovascular diseases, including atherosclerosis, hypertension, and adverse cardiac remodelling. Therefore, the pathomechanism involving SASP activation via the NLRP3 inflammasome; modulation of NLRP3 via α7 nicotinic ACh receptors; and modulation by senolytics targeting other proteins have gained a lot of interest within cardiovascular research and drug development communities. In this review, which offers a unique view from both clinical and preclinical target-based drug discovery perspectives, we have focused on cardiovascular inflammageing and its molecular mechanisms. We have outlined the mechanistic links between inflammageing, SASP, interleukin (IL)-1β, NLRP3 inflammasome, nicotinic ACh receptors, and molecular targets of senolytic drugs in the context of cardiovascular diseases. We have addressed the ‘druggability’ of NLRP3 and nicotinic α7 receptors by small molecules, as these proteins represent novel and exciting targets for therapeutic interventions targeting inflammageing in the cardiovascular system and beyond.

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