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Human Milk Oligosaccharide Utilization in Intestinal Bifidobacteria Is Governed by Global Transcriptional Regulator NagR.
mSystems. 2022 Oct 26; 7(5):e0034322.M

Abstract

Bifidobacterium longum subsp. infantis is a prevalent beneficial bacterium that colonizes the human neonatal gut and is uniquely adapted to efficiently use human milk oligosaccharides (HMOs) as a carbon and energy source. Multiple studies have focused on characterizing the elements of HMO utilization machinery in B. longum subsp. infantis; however, the regulatory mechanisms governing the expression of these catabolic pathways remain poorly understood. A bioinformatic regulon reconstruction approach used in this study implicated NagR, a transcription factor from the ROK family, as a negative global regulator of gene clusters encoding lacto-N-biose/galacto-N-biose (LNB/GNB), lacto-N-tetraose (LNT), and lacto-N-neotetraose (LNnT) utilization pathways in B. longum subsp. infantis. This conjecture was corroborated by transcriptome profiling upon nagR genetic inactivation and experimental assessment of binding of recombinant NagR to predicted DNA operators. The latter approach also implicated N-acetylglucosamine (GlcNAc), a universal intermediate of LNT and LNnT catabolism, and its phosphorylated derivatives as plausible NagR transcriptional effectors. Reconstruction of NagR regulons in various Bifidobacterium lineages revealed multiple potential regulon expansion events, suggesting evolution from a local regulator of GlcNAc catabolism in ancestral bifidobacteria to a global regulator controlling the utilization of mixtures of GlcNAc-containing host glycans in B. longum subsp. infantis and Bifidobacterium bifidum. IMPORTANCE The predominance of bifidobacteria in the gut of breastfed infants is attributed to the ability of these bacteria to metabolize human milk oligosaccharides (HMOs). Thus, individual HMOs such as lacto-N-tetraose (LNT) and lacto-N-neotetraose (LNnT) are considered promising prebiotics that would stimulate the growth of bifidobacteria and confer multiple health benefits to preterm and malnourished children suffering from impaired (stunted) gut microbiota development. However, the rational selection of HMO-based prebiotics is hampered by the incomplete knowledge of regulatory mechanisms governing HMO utilization in target bifidobacteria. This study describes NagR-mediated transcriptional regulation of LNT and LNnT utilization in Bifidobacterium longum subsp. infantis. The elucidated regulatory network appears optimally adapted to simultaneous utilization of multiple HMOs, providing a rationale to add HMO mixtures (rather than individual components) to infant formulas. The study also provides insights into the evolutionary trajectories of complex regulatory networks controlling carbohydrate metabolism in bifidobacteria.

Authors+Show Affiliations

Infectious and Inflammatory Diseases Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA.Graduate School of Biostudies, Kyoto University, Kyoto, Japan.Graduate School of Biostudies, Kyoto University, Kyoto, Japan.Graduate School of Biostudies, Kyoto University, Kyoto, Japan.Graduate School of Biostudies, Kyoto University, Kyoto, Japan.Infectious and Inflammatory Diseases Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA.Infectious and Inflammatory Diseases Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

36094076

Citation

Arzamasov, Aleksandr A., et al. "Human Milk Oligosaccharide Utilization in Intestinal Bifidobacteria Is Governed By Global Transcriptional Regulator NagR." MSystems, vol. 7, no. 5, 2022, pp. e0034322.
Arzamasov AA, Nakajima A, Sakanaka M, et al. Human Milk Oligosaccharide Utilization in Intestinal Bifidobacteria Is Governed by Global Transcriptional Regulator NagR. mSystems. 2022;7(5):e0034322.
Arzamasov, A. A., Nakajima, A., Sakanaka, M., Ojima, M. N., Katayama, T., Rodionov, D. A., & Osterman, A. L. (2022). Human Milk Oligosaccharide Utilization in Intestinal Bifidobacteria Is Governed by Global Transcriptional Regulator NagR. MSystems, 7(5), e0034322. https://doi.org/10.1128/msystems.00343-22
Arzamasov AA, et al. Human Milk Oligosaccharide Utilization in Intestinal Bifidobacteria Is Governed By Global Transcriptional Regulator NagR. mSystems. 2022 Oct 26;7(5):e0034322. PubMed PMID: 36094076.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Human Milk Oligosaccharide Utilization in Intestinal Bifidobacteria Is Governed by Global Transcriptional Regulator NagR. AU - Arzamasov,Aleksandr A, AU - Nakajima,Aruto, AU - Sakanaka,Mikiyasu, AU - Ojima,Miriam N, AU - Katayama,Takane, AU - Rodionov,Dmitry A, AU - Osterman,Andrei L, Y1 - 2022/09/12/ PY - 2022/9/13/pubmed PY - 2022/9/13/medline PY - 2022/9/12/entrez KW - HMO KW - bifidobacteria KW - carbohydrate metabolism KW - comparative genomics KW - evolution KW - prebiotics KW - regulon KW - transcription factor SP - e0034322 EP - e0034322 JF - mSystems JO - mSystems VL - 7 IS - 5 N2 - Bifidobacterium longum subsp. infantis is a prevalent beneficial bacterium that colonizes the human neonatal gut and is uniquely adapted to efficiently use human milk oligosaccharides (HMOs) as a carbon and energy source. Multiple studies have focused on characterizing the elements of HMO utilization machinery in B. longum subsp. infantis; however, the regulatory mechanisms governing the expression of these catabolic pathways remain poorly understood. A bioinformatic regulon reconstruction approach used in this study implicated NagR, a transcription factor from the ROK family, as a negative global regulator of gene clusters encoding lacto-N-biose/galacto-N-biose (LNB/GNB), lacto-N-tetraose (LNT), and lacto-N-neotetraose (LNnT) utilization pathways in B. longum subsp. infantis. This conjecture was corroborated by transcriptome profiling upon nagR genetic inactivation and experimental assessment of binding of recombinant NagR to predicted DNA operators. The latter approach also implicated N-acetylglucosamine (GlcNAc), a universal intermediate of LNT and LNnT catabolism, and its phosphorylated derivatives as plausible NagR transcriptional effectors. Reconstruction of NagR regulons in various Bifidobacterium lineages revealed multiple potential regulon expansion events, suggesting evolution from a local regulator of GlcNAc catabolism in ancestral bifidobacteria to a global regulator controlling the utilization of mixtures of GlcNAc-containing host glycans in B. longum subsp. infantis and Bifidobacterium bifidum. IMPORTANCE The predominance of bifidobacteria in the gut of breastfed infants is attributed to the ability of these bacteria to metabolize human milk oligosaccharides (HMOs). Thus, individual HMOs such as lacto-N-tetraose (LNT) and lacto-N-neotetraose (LNnT) are considered promising prebiotics that would stimulate the growth of bifidobacteria and confer multiple health benefits to preterm and malnourished children suffering from impaired (stunted) gut microbiota development. However, the rational selection of HMO-based prebiotics is hampered by the incomplete knowledge of regulatory mechanisms governing HMO utilization in target bifidobacteria. This study describes NagR-mediated transcriptional regulation of LNT and LNnT utilization in Bifidobacterium longum subsp. infantis. The elucidated regulatory network appears optimally adapted to simultaneous utilization of multiple HMOs, providing a rationale to add HMO mixtures (rather than individual components) to infant formulas. The study also provides insights into the evolutionary trajectories of complex regulatory networks controlling carbohydrate metabolism in bifidobacteria. SN - 2379-5077 UR - https://www.unboundmedicine.com/medline/citation/36094076/Human_Milk_Oligosaccharide_Utilization_in_Intestinal_Bifidobacteria_Is_Governed_by_Global_Transcriptional_Regulator_NagR_ DB - PRIME DP - Unbound Medicine ER -