An Ifnar1 allele impairs the colonization of gut bacteria and promotes tuberculosis

Abstract Both host genetics and gut microbiome have important effects on human health, yet how host genetics regulates gut bacteria and further determines disease susceptibility remains unclear. Here, we find that gut microbiome pattern of active tuberculosis (TB) patients is characterized by a reduction of core species found across healthy controls, particularly Akkermansia muciniphila (A. muciniphila). Oral treatments of A. muciniphila or palmitoleic acid, an A. muciniphila-derived metabolite, strongly inhibit TB infection through epigenetically inhibiting TNF-α. We use three independent cohorts comprising 6512 individuals and identify that single-nucleotide polymorphism rs2257167 “G” allele of type I interferon (IFN-I) receptor 1 (Ifnar1) contributes to stronger IFN-I signaling, impaired colonization and abundance of A. muciniphila, reduced production of palmitoleic acid, higher TNF-α, and much severer TB disease in humans and transgenic mice. Thus, host genetics are critical in modulating structure and functions of gut microbiome and gut microbial metabolites, which further determines disease susceptibility.

Download Full-text

The Role of Gut Microbiome in Psoriasis: Oral Administration of Staphylococcus aureus and Streptococcus danieliae Exacerbates Skin Inflammation of Imiquimod-Induced Psoriasis-Like Dermatitis

International Journal of Molecular Sciences ◽

10.3390/ijms21093303 ◽

2020 ◽

Vol 21 (9) ◽

pp. 3303 ◽

Cited By ~ 1

Author(s):

Karin Okada ◽

Yoshiaki Matsushima ◽

Kento Mizutani ◽

Keiichi Yamanaka

Keyword(s):

Gut Microbiome ◽

Skin Diseases ◽

Skin Inflammation ◽

Gut Bacteria ◽

Rrna Gene ◽

Skin Microbiome ◽

Inflammatory Skin Diseases ◽

Fecal Microbiome ◽

Tnf Α ◽

Inflammatory Skin

Psoriasis is one of the common chronic inflammatory skin diseases in which inflammatory cytokines such as IL-17 and TNF-α play critical roles. Skin microbiome of psoriasis patients is reported to have elevated Staphylococcus and Streptococcus genus. There are controversial reports about gut microbiome of psoriasis patients, and whether the diversity of bacteria in genus level is decreased or not is still unclear. Moreover, it is not yet known if these gut bacteria would be the cause of the inflammation or the result of the inflammation. We analyzed the gut microbiome of the inflammatory skin model mouse (keratinocyte-specific caspase-1 transgenic (Kcasp1Tg) mouse), by analyzing the 16S rRNA gene. Staphylocuccus aureus and Streptococcus danieliae were abundant in Kcasp1Tg mouse fecal microbiome. These dominant bacteria as well as recessive control bacteria were orally administrated to antibiotic-treated wild type mice, and set up imiquimod-induced psoriasis-like skin inflammation model. The skin inflammation including ear thickness and histopathological findings was analyzed. The exacerbated skin lesions with the elevated levels of TNF-α, IL-17A, IL-17F, and IL-22 were observed in Staphylocuccus aureus and Streptococcus danieliae administrated groups. Our finding suggests that there is affinity between skin inflammation severity and certain gut bacteria leading to a vicious cycle: skin inflammation populates certain gut bacteria which itself worsens the skin inflammation. This is the first report on Staphylocuccus aureus and Streptococcuus danieliae effects in vivo. Not only treating the skin lesion but also treating the gut microbiome could be the future key treatment for inflammatory skin disease such as psoriasis.

Download Full-text

Host and gut microbial tryptophan metabolism and type 2 diabetes: an integrative analysis of host genetics, diet, gut microbiome and circulating metabolites in cohort studies

Gut ◽

10.1136/gutjnl-2021-324053 ◽

2021 ◽

pp. gutjnl-2021-324053

Author(s):

Qibin Qi ◽

Jun Li ◽

Bing Yu ◽

Jee-Young Moon ◽

Jin C Chai ◽

...

Keyword(s):

Type 2 Diabetes ◽

Gut Microbiome ◽

Probiotic Bacterium ◽

Gut Bacteria ◽

Dietary Factors ◽

Milk Intake ◽

Tryptophan Metabolism ◽

Host Genetics ◽

Tryptophan Metabolites

ObjectiveTryptophan can be catabolised to various metabolites through host kynurenine and microbial indole pathways. We aimed to examine relationships of host and microbial tryptophan metabolites with incident type 2 diabetes (T2D), host genetics, diet and gut microbiota.MethodWe analysed associations between circulating levels of 11 tryptophan metabolites and incident T2D in 9180 participants of diverse racial/ethnic backgrounds from five cohorts. We examined host genome-wide variants, dietary intake and gut microbiome associated with these metabolites.ResultsTryptophan, four kynurenine-pathway metabolites (kynurenine, kynurenate, xanthurenate and quinolinate) and indolelactate were positively associated with T2D risk, while indolepropionate was inversely associated with T2D risk. We identified multiple host genetic variants, dietary factors, gut bacteria and their potential interplay associated with these T2D-relaetd metabolites. Intakes of fibre-rich foods, but not protein/tryptophan-rich foods, were the dietary factors most strongly associated with tryptophan metabolites. The fibre-indolepropionate association was partially explained by indolepropionate-associated gut bacteria, mostly fibre-using Firmicutes. We identified a novel association between a host functional LCT variant (determining lactase persistence) and serum indolepropionate, which might be related to a host gene-diet interaction on gut Bifidobacterium, a probiotic bacterium significantly associated with indolepropionate independent of other fibre-related bacteria. Higher milk intake was associated with higher levels of gut Bifidobacterium and serum indolepropionate only among genetically lactase non-persistent individuals.ConclusionHigher milk intake among lactase non-persistent individuals, and higher fibre intake were associated with a favourable profile of circulating tryptophan metabolites for T2D, potentially through the host–microbial cross-talk shifting tryptophan metabolism toward gut microbial indolepropionate production.

Download Full-text

A phase I trial to assess the biologic effect of CBM588 (Clostridium butyricum) in combination with nivolumab plus ipilimumab (nivo/ipi) in patients with metastatic renal cell carcinoma (mRCC).

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.6_suppl.tps764 ◽

2020 ◽

Vol 38 (6_suppl) ◽

pp. TPS764-TPS764 ◽

Cited By ~ 1

Author(s):

Paulo Gustavo Bergerot ◽

Nazli Dizman ◽

Nora Ruel ◽

Paul Henry Frankel ◽

Joann Hsu ◽

...

Keyword(s):

Phase I ◽

Gut Microbiome ◽

Phase I Trial ◽

Standard Dose ◽

Dose Schedule ◽

Gut Bacteria ◽

Clostridium Butyricum ◽

Type I ◽

Poor Risk ◽

Biologic Effect

TPS764 Background: The combination of the immune checkpoint inhibitors (ICIs) nivo/ipi is standard of care for pts with intermediate/poor-risk clear cell RCC. Although data are encouraging, less than 50% of pts will exhibit partial or complete response with nivo/ipi, and approximately 20% of pts will progress through this regimen. Studies have shown that response to ICIs may be modulated by the gut microbiome (Routy et al Science 2018), and that certain gut bacteria (e.g., Bifidobacterium spp) may predispose pts to response (Caitano et al ASCO GU 2017). CBM588 is a strain of Clostridium butyricum, a Gram-positive bacillus which produces short-chain fatty acids. It promotes the growth of commensal gut bacteria like Bifidobacterium, Lactobacillus and Bacteroides spp, and has been shown to enhance Th1 cells and IL-10 production with immunomodulatory effects. Here, we present the study design of an ongoing phase I trial to assess the biologic effect of CBM588 in combination with nivo/ipi in pts with mRCC. Methods: This is a single institution phase I trial. Pts will be randomized to one of two treatment arms. The experimental arm will receive the standard dose/schedule for nivo/ipi (3 mg/kg / 1 mg/kg Q3w for 12w, followed by nivo alone Q4w) plus CBM588 (60 mg PO 3x/d). The control arm will receive nivo/ipi at standard dose/schedule. Key eligibility criteria include intermediate/poor-risk mRCC, no concurrent antibiotic therapy and no prior systemic treatment. The primary objective is to determine the biologic effect of CBM588 + nivo/ipi in the modulation of the gut microbiome, measured by the change in Bifidobacterium spp and Shannon index (a measure of microbiome diversity). Secondary objectives include clinical efficacy (progression free survival by RECIST 1.1) and assessment of systemic immune-modulation effects through the analysis of circulating Tregs, MDSCs, and circulating cytokines/chemokines. Stool samples and serum correlatives will be collected on weeks 1 and 13 of treatment. A two-group t-test with a one-sided type I error of 0.05 will be used to assess the study primary endpoints. Clinical trial information: NCT03829111.

Download Full-text

The HOXD8 locus (2q31) is linked to type I diabetes. Interaction with chromosome 6 and 11 disease susceptibility genes

Diabetes ◽

10.2337/diabetes.44.1.132 ◽

1995 ◽

Vol 44 (1) ◽

pp. 132-136 ◽

Cited By ~ 19

Author(s):

D. Owerbach ◽

K. H. Gabbay

Keyword(s):

Disease Susceptibility ◽

Type I Diabetes ◽

Susceptibility Genes ◽

Type I ◽

Chromosome 6

Download Full-text

Study a level of TNF-α and INF-Ƴ in patients with Type I and II Diabetes Mellitus in Diayla governorate

Diyala Journal for Pure Science ◽

10.24237/djps.1303.250b ◽

2017 ◽

Vol 13 (3) ◽

pp. 196-207

Author(s):

Mohammed Abdul-Daim Saleh ◽

◽

Shahrazad Ahmed Khalaf

Keyword(s):

Diabetes Mellitus ◽

Type I ◽

Tnf Α

Download Full-text

Genetic Determinants of Neurobehavioral Responses to Caffeine Administration during Sleep Deprivation: A Randomized, Cross Over Study (NCT03859882)

Genes ◽

10.3390/genes12040555 ◽

2021 ◽

Vol 12 (4) ◽

pp. 555

Author(s):

Mégane Erblang ◽

Fabien Sauvet ◽

Catherine Drogou ◽

Michaël Quiquempoix ◽

Pascal Van Beers ◽

...

Keyword(s):

Sleep Deprivation ◽

Nucleotide Polymorphisms ◽

Genetic Determinants ◽

Placebo Condition ◽

Double Blind ◽

Single Nucleotide ◽

Psychomotor Vigilance Test ◽

Tnf Α ◽

And Performance ◽

Psychomotor Vigilance

This study investigated whether four single nucleotide polymorphisms (SNPs) moderated caffeine effects on vigilance and performance in a double-blind and crossover total sleep deprivation (TSD) protocol in 37 subjects. In caffeine (2 × 2.5 mg/kg/24 h) or placebo-controlled condition, subjects performed a psychomotor vigilance test (PVT) and reported sleepiness every six hours (Karolinska sleepiness scale (KSS)) during TSD. EEG was also analyzed during the 09:15 PVT. Carriers of the TNF-α SNP A allele appear to be more sensitive than homozygote G/G genotype to an attenuating effect of caffeine on PVT lapses during sleep deprivation only because they seem more degraded, but they do not perform better as a result. The A allele carriers of COMT were also more degraded and sensitive to caffeine than G/G genotype after 20 h of sleep deprivation, but not after 26 and 32 h. Regarding PVT reaction time, ADORA2A influences the TSD effect but not caffeine, and PER3 modulates only the caffeine effect. Higher EEG theta activity related to sleep deprivation was observed in mutated TNF-α, PER3, and COMT carriers, in the placebo condition particularly. In conclusion, there are genetic influences on neurobehavioral impairments related to TSD that appear to be attenuated by caffeine administration. (NCT03859882).

Download Full-text

MicroRNA-513b-5p targets COL1A1 and COL1A2 associated with the formation and rupture of intracranial aneurysm

Scientific Reports ◽

10.1038/s41598-021-94116-5 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Zheng Zheng ◽

Yan Chen ◽

Yinzhou Wang ◽

Yongkun Li ◽

Qiong Cheng

Keyword(s):

Cell Death ◽

Intracranial Aneurysm ◽

Luciferase Reporter Assay ◽

Luciferase Reporter ◽

Control Group ◽

Type I ◽

Mrna Levels ◽

Reporter Assay ◽

Over Expression ◽

Tnf Α

AbstractCollagen-type I alpha 1 chain (COL1A1) and COL1A2 are abnormally expressed in intracranial aneurysm (IA), but their mechanism of action remains unclear. This study was performed to investigate the mechanism of COL1A1 and COL1A2 affecting the occurrence and rupture of IA. Quantitative real-time polymerase chain reaction was used to measure the expression of hsa-miR-513b-5p, COL1A1, COL1A2, TNF-α, IL-6, MMP2, MMP3, MMP9 and TIMP4 in patients with ruptured IA (RA) (n = 100), patients with un-ruptured IA (UA) (n = 100), and controls (n = 100). Then, human vascular smooth muscle cells (HASMCs) were cultured, and dual luciferase reporter assay was performed to analyse the targeting relationship between miR-513b-5p and COL1A1 or COL1A2. The effects of the miR-513b-5p mimic and inhibitor on the proliferation, apoptosis, and death of HASMC and the RIP1-RIP3-MLKL and matrix metalloproteinase pathways were also explored. The effect of silencing and over-expression of COL1A1 and COL1A2 on the role of miR-513b-5p were also evaluated. Finally, the effects of TNF-α on miR-513b-5p targeting COL1A1 and COL1A2 were tested. Compared with those in the control group, the serum mRNA levels of miR-513b-5p, IL-6 and TIMP4 were significantly decreased in the RA and UA groups, but COL1A1, COL1A2, TNF-α, IL-1β, MMP2, MMP3 and MMP9 were significantly increased (p < 0.05). Compared with those in the UA group, the expression of COL1A1, COL1A2, TNF-α, IL-1β and MMP9 was significantly up-regulated in the RA group (p < 0.05). Results from the luciferase reporter assay showed that COL1A1 and COL1A were the direct targets of miR-513b-5p. Further studies demonstrated that miR-513b-5p targeted COL1A1/2 to regulate the RIP1-RIP3-MLKL and MMP pathways, thereby enhancing cell death and apoptosis. Over-expression of COL1A1 or COL1A2, rather than silencing COL1A1/2, could improve the inhibitory effect of miR-513b-5p on cell activity by regulating the RIP1-RIP3-MLKL and MMP pathways. Furthermore, over-expression of miR-513b-5p and/or silencing COL1A1/2 inhibited the TNF-α-induced cell proliferation and enhanced the TNF-α-induced cell death and apoptosis. The mechanism may be related to the inhibition of collagen I and TIMP4 expression and promotion of the expression of RIP1, p-RIP1, p-RIP3, p-MLKL, MMP2 and MMP9. MiR-513b-5p targeted the inhibition of COL1A1/2 expression and affected HASMC viability and extracellular mechanism remodelling by regulating the RIP1-RIP3-MLKL and MMP pathways. This process might be involved in the formation and rupture of IA.

Download Full-text

Flavonoid-Modifying Capabilities of the Human Gut Microbiome—An In Silico Study

Nutrients ◽

10.3390/nu13082688 ◽

2021 ◽

Vol 13 (8) ◽

pp. 2688

Author(s):

Tobias Goris ◽

Rafael R. C. Cuadrat ◽

Annett Braune

Keyword(s):

Gut Microbiome ◽

Large Scale ◽

Health Impact ◽

Gut Bacteria ◽

Human Gut ◽

Positive Health ◽

Human Gut Microbiome ◽

Nutritional Recommendations ◽

Genes Encoding ◽

A Minor

Flavonoids are a major group of dietary plant polyphenols and have a positive health impact, but their modification and degradation in the human gut is still widely unknown. Due to the rise of metagenome data of the human gut microbiome and the assembly of hundreds of thousands of bacterial metagenome-assembled genomes (MAGs), large-scale screening for potential flavonoid-modifying enzymes of human gut bacteria is now feasible. With sequences of characterized flavonoid-transforming enzymes as queries, the Unified Human Gastrointestinal Protein catalog was analyzed and genes encoding putative flavonoid-modifying enzymes were quantified. The results revealed that flavonoid-modifying enzymes are often encoded in gut bacteria hitherto not considered to modify flavonoids. The enzymes for the physiologically important daidzein-to-equol conversion, well studied in Slackiaisoflavoniconvertens, were encoded only to a minor extent in Slackia MAGs, but were more abundant in Adlercreutzia equolifaciens and an uncharacterized Eggerthellaceae species. In addition, enzymes with a sequence identity of about 35% were encoded in highly abundant MAGs of uncultivated Collinsella species, which suggests a hitherto uncharacterized daidzein-to-equol potential in these bacteria. Of all potential flavonoid modification steps, O-deglycosylation (including derhamnosylation) was by far the most abundant in this analysis. In contrast, enzymes putatively involved in C-deglycosylation were detected less often in human gut bacteria and mainly found in Agathobacter faecis (formerly Roseburia faecis). Homologs to phloretin hydrolase, flavanonol/flavanone-cleaving reductase and flavone reductase were of intermediate abundance (several hundred MAGs) and mainly prevalent in Flavonifractor plautii. This first comprehensive insight into the black box of flavonoid modification in the human gut highlights many hitherto overlooked and uncultured bacterial genera and species as potential key organisms in flavonoid modification. This could lead to a significant contribution to future biochemical-microbiological investigations on gut bacterial flavonoid transformation. In addition, our results are important for individual nutritional recommendations and for biotechnological applications that rely on novel enzymes catalyzing potentially useful flavonoid modification reactions.

Download Full-text

Linkage Disequilibrium in Domestic Sheep

Genetics ◽

10.1093/genetics/160.3.1113 ◽

2002 ◽

Vol 160 (3) ◽

pp. 1113-1122

Author(s):

A F McRae ◽

J C McEwan ◽

K G Dodds ◽

T Wilson ◽

A M Crawford ◽

...

Keyword(s):

Linkage Disequilibrium ◽

Type I Error ◽

Statistical Significance ◽

Domestic Sheep ◽

Type I ◽

Single Nucleotide ◽

Microsatellite Genotype ◽

Marker Distance ◽

The Relationship ◽

Two Populations

Abstract The last decade has seen a dramatic increase in the number of livestock QTL mapping studies. The next challenge awaiting livestock geneticists is to determine the actual genes responsible for variation of economically important traits. With the advent of high density single nucleotide polymorphism (SNP) maps, it may be possible to fine map genes by exploiting linkage disequilibrium between genes of interest and adjacent markers. However, the extent of linkage disequilibrium (LD) is generally unknown for livestock populations. In this article microsatellite genotype data are used to assess the extent of LD in two populations of domestic sheep. High levels of LD were found to extend for tens of centimorgans and declined as a function of marker distance. However, LD was also frequently observed between unlinked markers. The prospects for LD mapping in livestock appear encouraging provided that type I error can be minimized. Properties of the multiallelic LD coefficient D′ were also explored. D′ was found to be significantly related to marker heterozygosity, although the relationship did not appear to unduly influence the overall conclusions. Of potentially greater concern was the observation that D′ may be skewed when rare alleles are present. It is recommended that the statistical significance of LD is used in conjunction with coefficients such as D′ to determine the true extent of LD.

Download Full-text