A key genetic factor for fucosyllactose utilization affects infant gut microbiota development

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Abstract

Recent studies have demonstrated that gut microbiota development influences infants' health and subsequent host physiology. However, the factors shaping the development of the microbiota remain poorly understood, and the mechanisms through which these factors affect gut metabolite profiles have not been extensively investigated. Here we analyse gut microbiota development of 27 infants during the first month of life. We find three distinct clusters that transition towards Bifidobacteriaceae-dominant microbiota. We observe considerable differences in human milk oligosaccharide utilization among infant bifidobacteria. Colonization of fucosyllactose (FL)-utilizing bifidobacteria is associated with altered metabolite profiles and microbiota compositions, which have been previously shown to affect infant health. Genome analysis of infants' bifidobacteria reveals an ABC transporter as a key genetic factor for FL utilization. Thus, the ability of bifidobacteria to utilize FL and the presence of FL in breast milk may affect the development of the gut microbiota in infants, and might ultimately have therapeutic implications.

Abstract

The factors shaping the development of infants' gut microbiota are poorly understood. Here, the authors show that alterations in gut microbiota development in infants are associated with the presence of bifidobacteria having a gene for utilisation of human milk oligosaccharides.

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Short-chain fatty acids and ketones directly regulate sympathetic nervous system via G protein-coupled receptor 41 (GPR41).

Ikuo Kimura, Daisuke Inoue, Takeshi Maeda … (2011)

The maintenance of energy homeostasis is essential for life, and its dysregulation leads to a variety of metabolic disorders. Under a fed condition, mammals use glucose as the main metabolic fuel, and short-chain fatty acids (SCFAs) produced by the colonic bacterial fermentation of dietary fiber also contribute a significant proportion of daily energy requirement. Under ketogenic conditions such as starvation and diabetes, ketone bodies produced in the liver from fatty acids are used as the main energy sources. To balance energy intake, dietary excess and starvation trigger an increase or a decrease in energy expenditure, respectively, by regulating the activity of the sympathetic nervous system (SNS). The regulation of metabolic homeostasis by glucose is well recognized; however, the roles of SCFAs and ketone bodies in maintaining energy balance remain unclear. Here, we show that SCFAs and ketone bodies directly regulate SNS activity via GPR41, a Gi/o protein-coupled receptor for SCFAs, at the level of the sympathetic ganglion. GPR41 was most abundantly expressed in sympathetic ganglia in mouse and humans. SCFA propionate promoted sympathetic outflow via GPR41. On the other hand, a ketone body, β-hydroxybutyrate, produced during starvation or diabetes, suppressed SNS activity by antagonizing GPR41. Pharmacological and siRNA experiments indicated that GPR41-mediated activation of sympathetic neurons involves Gβγ-PLCβ-MAPK signaling. Sympathetic regulation by SCFAs and ketone bodies correlated well with their respective effects on energy consumption. These findings establish that SCFAs and ketone bodies directly regulate GPR41-mediated SNS activity and thereby control body energy expenditure in maintaining metabolic homeostasis.

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The genome sequence of Bifidobacterium longum subsp. infantis reveals adaptations for milk utilization within the infant microbiome.

D. A. Sela, J. Chapman, A Adeuya … (2008)

Following birth, the breast-fed infant gastrointestinal tract is rapidly colonized by a microbial consortium often dominated by bifidobacteria. Accordingly, the complete genome sequence of Bifidobacterium longum subsp. infantis ATCC15697 reflects a competitive nutrient-utilization strategy targeting milk-borne molecules which lack a nutritive value to the neonate. Several chromosomal loci reflect potential adaptation to the infant host including a 43 kbp cluster encoding catabolic genes, extracellular solute binding proteins and permeases predicted to be active on milk oligosaccharides. An examination of in vivo metabolism has detected the hallmarks of milk oligosaccharide utilization via the central fermentative pathway using metabolomic and proteomic approaches. Finally, conservation of gene clusters in multiple isolates corroborates the genomic mechanism underlying milk utilization for this infant-associated phylotype.

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Bacterial colonization factors control specificity and stability of the gut microbiota

S Lee, Gregory Donaldson, Zbigniew Mikulski … (2013)

Mammals harbor a complex gut microbiome, comprised of bacteria that confer immunologic, metabolic and neurologic benefits 1 . Despite advances in sequence-based microbial profiling and myriad studies defining microbiome composition during health and disease, little is known about the molecular processes employed by symbiotic bacteria to stably colonize the gastrointestinal (GI) tract. We sought to define how mammals assemble and maintain the Bacteroides, one of the most numerically prominent genera of the human microbiome. While the gut normally contains hundreds of bacterial species 2,3 , we surprisingly find that germ-free mice mono-associated with a single Bacteroides are resistant to colonization by the same, but not different, species. To identify bacterial mechanisms for species-specific saturable colonization, we devised an in vivo genetic screen and discovered a unique class of Polysaccharide Utilization Loci (PUL) that are conserved among intestinal Bacteroides. We named this genetic locus the commensal colonization factors (ccf). Deletion of the ccf genes in the model symbiont, Bacteroides fragilis, results in colonization defects in mice and reduced horizontal transmission. The ccf genes of B. fragilis are up-regulated during gut colonization, preferentially at the colonic surface. When we visualize microbial biogeography within the colon, B. fragilis penetrates the colonic mucus and resides deep within crypt channels, while ccf mutants are defective in crypt association. Remarkably, the CCF system is required for B. fragilis colonization following microbiome disruption with Citrobacter rodentium infection or antibiotic treatment, suggesting the niche within colonic crypts represents a reservoir for bacteria to maintain long-term colonization. These findings reveal that intestinal Bacteroides have evolved species-specific physical interactions with the host that mediate stable and resilient gut colonization, and the CCF system represents a novel molecular mechanism for symbiosis.

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Author and article information

Journal

Journal ID (nlm-ta): Nat Commun

Journal ID (iso-abbrev): Nat Commun

Title: Nature Communications

Publisher: Nature Publishing Group

ISSN (Electronic): 2041-1723

Publication date (Electronic): 24 June 2016

Publication date Collection: 2016

Volume: 7

Electronic Location Identifier: 11939

Affiliations

[1 ]Yakult Central Institute , 5-11 Izumi, Kunitachi-shi, Tokyo 186-8650, Japan

[2 ]Department of Biological Information, Tokyo Institute of Technology , 2-12-1 Ookayama, Meguro-ku, Tokyo 152-8550, Japan

[3 ]Teikyo University School of Medicine , 2-11-1 Kaga, Itabashi-Ku, Tokyo 117-8605, Japan

[4 ]Earth-Life Science Institute, Tokyo Institute of Technology , 2-12-1 Ookayama, Meguro-ku, Tokyo 152-8550, Japan

[5 ]National Institute of Genetics, Center for Information Biology , Yata 1111, Mishima, Shizuoka 411-8540, Japan

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[a ] takahiro-matsuki@ 123456yakult.co.jp

[*]

These authors contributed equally to this work

[†]

These authors jointly supervised this work

Author information

Takahiro Matsuki http://orcid.org/0000-0001-7777-1602

Ken Kurokawa http://orcid.org/0000-0001-8662-9958

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Publisher Item ID: ncomms11939

DOI: 10.1038/ncomms11939

PMC ID: 4931012

PubMed ID: 27340092

SO-VID: e62c2b89-ee4a-4035-a0ea-a84a623aca4a

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A key genetic factor for fucosyllactose utilization affects infant gut microbiota development

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Role of Microbes in Soil Fertility and Human Health

Most cited references 25

Short-chain fatty acids and ketones directly regulate sympathetic nervous system via G protein-coupled receptor 41 (GPR41).

The genome sequence of Bifidobacterium longum subsp. infantis reveals adaptations for milk utilization within the infant microbiome.

Bacterial colonization factors control specificity and stability of the gut microbiota

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