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9. Human gut-associated Bifidobacterium species salvage exogenous indole, a uremic toxin precursor, to synthesize indole-3-lactic acid via tryptophan

Author

Cheng Chung Yong, Takuma Sakurai, Hiroki Kaneko, Ayako Horigome, Eri Mitsuyama, Aruto Nakajima, Toshihiko Katoh, Mikiyasu Sakanaka, Takaaki Abe, Jin-Zhong Xiao, Miyuki Tanaka, Toshitaka Odamaki, and Takane Katayama

Subjects
Indole, indole-3-lactic acid, tryptophan, Bifidobacterium, trpB, aldh, Diseases of the digestive system. Gastroenterology, RC799-869
Abstract

ABSTRACTIndole in the gut is formed from dietary tryptophan by a bacterial tryptophan-indole lyase. Indole not only triggers biofilm formation and antibiotic resistance in gut microbes but also contributes to the progression of kidney dysfunction after absorption by the intestine and sulfation in the liver. As tryptophan is an essential amino acid for humans, these events seem inevitable. Despite this, we show in a proof-of-concept study that exogenous indole can be converted to an immunomodulatory tryptophan metabolite, indole-3-lactic acid (ILA), by a previously unknown microbial metabolic pathway that involves tryptophan synthase β subunit and aromatic lactate dehydrogenase. Selected bifidobacterial strains converted exogenous indole to ILA via tryptophan (Trp), which was demonstrated by incubating the bacterial cells in the presence of (2-13C)-labeled indole and l-serine. Disruption of the responsible genes variedly affected the efficiency of indole bioconversion to Trp and ILA, depending on the strains. Database searches against 11,943 bacterial genomes representing 960 human-associated species revealed that the co-occurrence of tryptophan synthase β subunit and aromatic lactate dehydrogenase is a specific feature of human gut-associated Bifidobacterium species, thus unveiling a new facet of bifidobacteria as probiotics. Indole, which has been assumed to be an end-product of tryptophan metabolism, may thus act as a precursor for the synthesis of a host-interacting metabolite with possible beneficial activities in the complex gut microbial ecosystem.

Published
2024
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36. Epigenetic dysregulation of eukaryotic initiation factor 3 subunit E (eIF3E) by lysine methyltransferase REIIBP confers a pro-inflammatory phenotype in t(4;14) myeloma

Author

Phyllis S.Y. Chong, Jing Yuan Chooi, Sze Lynn Julia Lim, Tae-Hoon Chung, Reinhard Brunmeir, Aaron Chung Yong Leow, Sabrina Hui Min Toh, Kalpnaa Balan, Muhamad Irfan Bin Azaman, Zhengwei Wu, Nagavidya Subramaniam, Leah A Vardy, and Wee-Joo Chng

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

REIIBP is a lysine methyltransferase aberrantly expressed through alternative promoter usage of NSD2 locus in t(4;14)-translocated multiple myeloma (MM). Clinically, t(4;14) translocation is an adverse prognostic factor found in approximately 15% of MM patients. The contribution of REIIBP relative to other NSD2 isoforms as a dependency gene in t(4;14)-translocated MM remains to be evaluated. Here, we demonstrated that despite homology with NSD2, REIIBP displayed distinct substrate specificity by preferentially catalyzing H3K4me3 and H3K27me3, with little activity on H3K36me2. Furthermore, REIIBP was regulated through microRNA by EZH2 in a Dicer-dependent manner, exemplifying a role of REIIBP in SET-mediated H3K27me3. Chromatin immunoprecipitation sequencing revealed chromatin remodeling characterized by changes in genome-wide and loci-specific occupancy of these opposing histone marks, allowing a bidirectional regulation of its target genes. Transcriptomics indicated that REIIBP induced a pro-inflammatory gene signature through upregulation of TLR7, which in turn led to B-cell receptor-independent activation of BTK and driving NFkB-mediated production of cytokines such as IL-6. Activation of this pathway is targetable using Ibrutinib and partially mitigated bortezomib resistance in a REIIBP xenograft model. Mechanistically, REIIBP upregulated TLR7 through eIF3E, and this relied on eIF3E RNA-binding function instead of its canonical protein synthesis activity, as demonstrated by direct binding to the 3’UTR of TLR7 mRNA. Altogether, we provided a rationale that co-existence of different NSD2 isoforms induced diversified oncogenic programs that should be considered in the strategies for t(4;14)-targeted therapy.

Published
2023
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49. A Multicenter, Randomized, Open-Label Study to Compare the Efficacy and Safety of Tacrolimus and Corticosteroids in Combination With or Without Mycophenolate Mofetil in Liver Transplantation Recipients Infected With Hepatitis B Virus

Author

Park, Jeong-Ik, Song, Gi-Won, Ryu, Je Ho, Choi, Sang-Tae, Choi, Nam-Gyu, Jung, Bo-Hyun, Chu, Chong Woo, Kim, Keon-Kuk, Jung, Dong-Hwan, Ha, Tae-Yong, Moon, Deok-Bog, Yang, Kwangho, Shin, Min-Ho, Chung, Yong-Kyu, Hwang, Shin, Yoon, Young-In, and Lee, Sung-Gyu

Published
2023
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