Gut microbiome-derived phenyl sulfate contributes to albuminuria in diabetic kidney disease

Kikuchi, Kôichi; Saigusa, Daisuke; Kanemitsu, Yoshitomi; Matsumoto, Yotaro; Paxton, Thanai; Suzuki, Naoto; Mise, Kazuyuki; Yamaguchi, Hiroaki; Nakamura, Tomohiro; Asaji, Kei; Mukawa, Chikahisa; Tsukamoto, Hiroki; Sato, Toshihiro; Oikawa, Yoshitsugu; Iwasaki, Tomoyuki; Oe, Yuji; Tsukimi, Tomoya; Fukuda, Noriko; Ho, Hsin Jung; Nanto-Hara, Fumika; Ogura, Jiro; Saito, Ryosuke; Nagao, Shizuko; Ohsaki, Yusuke; Shimada, Satoshi; Suzuki, Takehiro; Toyohara, Takafumi; Mishima, Eikan; Shima, Hisato; Akiyama, Yasutoshi; Akiyama, Yukako; Ichijo, M.; Matsuhashi, Tomohiro; Matsuo, Akihiro; Ogata, Yoshiaki; Yang, Ching Chin; Suzuki, Chitose; Breeggemann, Matthew C.; Heymann, Jürgen; Shimizu, Miho; Ogawa, Susumu; Takahashi, Nobuyuki; Suzuki, Takashi; Owada, Yuji; Kure, Shigeo; Mano, Nariyasu; Soga, Tomoyoshi; Wada, Takashi; Kopp, Jeffrey B.; Fukuda, Shinji; Hozawa, Atsushi; Yamamoto, Masayuki; Ito, Sadayoshi; Wada, Jun; Tomioka, Y.; Abe, Takaaki

doi:10.1038/s41467-019-09735-4

Cited by 225 publications

(211 citation statements)

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“…More than one hundred trillion microbes exist in the intestinal tract, one of the biggest immune organs of the human body [12]. An increasing number of studies have revealed that the gut-kidney axis may contribute to the pathogenesis of numerous diseases [4,5]. However, only one pilot study with a relatively small number of samples has reported the dysregulation of the gut microbiome in IgAN patients [6].…”

Section: Discussionmentioning

confidence: 99%

“…Recently, modi cations of the gut microbiota have been recognized as a risk factor for several kidney diseases, including diabetic nephropathy, chronic kidney diseases, cardiovascular disease, in ammatory bowel disease, obesity, and several cancers [3][4][5]. Although a previous study has reported that the gut microbial community in IgAN patients is substantially changed when compared to healthy controls [6], the precise differences and the relationship between the microbes and severity of IgAN clinical manifestations are poorly understood.…”

Section: Introductionmentioning

confidence: 99%

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Modifications of abundances of some bacteria are associated with the severity of IgA nephropathy in Chinese population

Zhong

Tan

et al. 2020

Preprint

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Abstract Background Immunoglobulin A nephropathy (IgAN) is a common autoimmune glomerular disease, the classic manifestations of which are hematuria and proteinuria. The pathogenesis of IgAN has been associated with dysregulated intestinal mucosal immunity. However, whether gut microbial modifications play a part in IgAN remains unclear. Methods Blood and fecal samples were collected from 52 IgAN patients and 25 healthy controls (HCs). The gut microbiome was analyzed by 16S ribosomal RNA (rRNA) gene sequencing, followed by analyses of gut microbiota composition. Furthermore, the levels of galactose-deficient IgA1 (Gd-IgA1), soluble cluster of differentiation 14 (sCD14), lipopolysaccharide binding protein (LBP), intercellular adhesion molecule-1 (ICAM-1), and C-reactive protein (CRP) was quantified by enzyme-linked immunosorbent assay (ELISA). Results Substantial differences in gut microbiota were found between IgAN patients and HCs (P < 0.05). The abundance of pathogenic bacteria (Bacteroides and Escherichia-Shigella) was significantly higher in IgAN patients than in HCs, while that of beneficial strains (Bifidobacterium and Blautia spp.) was lower. Higher proportions of Escherichia-Shigella and lower proportions of Bifidobacterium spp. were observed in IgAN patients with a high urine RBC count (≥ 10/HP) and proteinuria (≥ 1 g/24 h) levers. Spearman’s correlation analysis was used to assess the association between gut microbiota and biomarkers in IgAN patients. The results showed that the genus Prevotella 7 was negatively correlated with Gd-IgA1, LBP, sCD14, and ICAM-1, while Bifidobacterium spp. presented a significant inverse relationship with LBP and Gd-IgA1. Additionally, Escherichia-Shigella was negatively correlated with Prevotella 7. Conclusions In IgAN patients, gut modifications were characterized by an increase in the numbers of pathogenic bacteria and a reduction in the levers of beneficial bacteria. Our results suggest that disturbance of the intestinal microflora might play a critical part in the severity of IgAN, and may be a potential therapeutic target.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Modifications of abundances of some bacteria are associated with the severity of IgA nephropathy in Chinese population

Zhong

Tan

et al. 2020

Preprint

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“…; Kikuchi et al . ). Phenylacetate, a microbial product of phenylalanine, has been reported to trigger steatosis (infiltration of liver cells with fat) in mice and primary cultures of human hepatocytes (Hoyles et al .…”

Section: Diet‐derived Microbial Metabolites In Health and Diseasementioning

confidence: 97%

“…Apart from SCFAs, these proteolytic degradation products have in general been considered to be deleterious for the host (Nyangale et al 2012). For example, phenolicand indolic acid-derived host-microbial co-metabolites, such as p-cresol sulphate, phenol sulphate, phenylacetylglutamine and indoxyl sulphate, have been associated with kidney diseases (Shafi et al 2015;Devlin et al 2016;Kikuchi et al 2019). Phenylacetate, a microbial product of phenylalanine, has been reported to trigger steatosis (infiltration of liver cells with fat) in mice and primary cultures of human hepatocytes (Hoyles et al 2018).…”

Section: Microbial Proteolytic Degradation Productsmentioning

confidence: 99%

Diet‐derived microbial metabolites in health and disease

Roager

Dragsted

2019

Nutrition Bulletin

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The gut microbiota helps us digest food and has been associated with both good health and risk of disease. Although compositions of the gut microbiota are highly divergent, the gut microbiota exhibits a high level of functional redundancy making it difficult to reliably link gut microbiome patterns to health and diet across individuals. Thus, there is a need to move beyond profiling of the gut microbial composition to the assessment of gut microbial metabolic activity in order to expand knowledge on the impact of the gut microbiota on health. Metabolomics has already proven its utility in identifying gut‐derived microbial metabolites, which may be mediators of diet‐induced host–microbial crosstalk important for health. These diet‐derived metabolites include, among many others, the short‐chain fatty acids originating from bacterial degradation of dietary fibres and proteins, secondary bile acids derived from primary bile acids, microbial tryptophan catabolites resulting from proteolysis, imidazole propionate produced from histidine and trimethylamine N‐oxide, a host–microbial co‐metabolite of nutrients such as phosphatidylcholine, choline and L‐carnitine, present in high‐fat foods. These co‐metabolites have been associated with beneficial and detrimental effects in the host. However, the vast majority of metabolites measured by untargeted metabolomics in human blood and excreta remain unknown and may include additional microbial molecules of importance for health. Thus, there is great potential, yet to be explored, for identifying additional diet‐derived microbial products that affect the host. Herein, we review key advances, challenges and limitations in our understanding of diet–microbiome interactions and diet‐derived microbial metabolites in relation to human health and discuss how metabolomics may shed light on inter‐individual differences in dietary responses.

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“…Importantly, the levels of these colon-derived metabolites were substantially higher in the patients with ESKD than in individuals with normal kidney function, and the majority were not effectively removed by conventional hemodialysis. Abe and colleagues (36) have raised specific interest in phenyl sulfate, a tyrosine metabolite derived from gut microbes, as a potential causal factor in diabetic kidney disease. In patients with diabetes, they found that phenyl sulfate levels correlate with albuminuria, and, further, that phenyl sulfate administration and inhibition of the bacterial enzyme responsible for its synthesis induce and ameliorate albuminuria in mice, respectively.…”

Section: Metabolomics and The Contribution Of The Gut Microbiome To Umentioning

confidence: 99%

Proteomics and Metabolomics in Kidney Disease, including Insights into Etiology, Treatment, and Prevention

Dubin¹,

Rhee²

2019

CJASN

127

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In this review of the application of proteomics and metabolomics to kidney disease research, we review key concepts, highlight illustrative examples, and outline future directions. The proteome and metabolome reflect the influence of environmental exposures in addition to genetic coding. Circulating levels of proteins and metabolites are dynamic and modifiable, and thus amenable to therapeutic targeting. Design and analytic considerations in proteomics and metabolomics studies should be tailored to the investigator's goals. For the identification of clinical biomarkers, adjustment for all potential confounding variables, particularly GFR, and strict significance thresholds are warranted. However, this approach has the potential to obscure biologic signals and can be overly conservative given the high degree of intercorrelation within the proteome and metabolome. Mass spectrometry, often coupled to up-front chromatographic separation techniques, is a major workhorse in both proteomics and metabolomics. High-throughput antibody-and aptamer-based proteomic platforms have emerged as additional, powerful approaches to assay the proteome. As the breadth of coverage for these methodologies continues to expand, machine learning tools and pathway analyses can help select the molecules of greatest interest and categorize them in distinct biologic themes. Studies to date have already made a substantial effect, for example elucidating target antigens in membranous nephropathy, identifying a signature of urinary peptides that adds prognostic information to urinary albumin in CKD, implicating circulating inflammatory proteins as potential mediators of diabetic nephropathy, demonstrating the key role of the microbiome in the uremic milieu, and highlighting kidney bioenergetics as a modifiable factor in AKI. Additional studies are required to replicate and expand on these findings in independent cohorts. Further, more work is needed to understand the longitudinal trajectory of select protein and metabolite markers, perform transomics analyses within merged datasets, and incorporate more kidney tissue-based investigation.

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Gut microbiome-derived phenyl sulfate contributes to albuminuria in diabetic kidney disease

Cited by 225 publications

References 71 publications

Modifications of abundances of some bacteria are associated with the severity of IgA nephropathy in Chinese population

Modifications of abundances of some bacteria are associated with the severity of IgA nephropathy in Chinese population

Diet‐derived microbial metabolites in health and disease

Proteomics and Metabolomics in Kidney Disease, including Insights into Etiology, Treatment, and Prevention

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