Nature - 2019.08.29

reSeArCH Letter

22 patients with a range of E. faecium densities and found lantibiotic
gene abundance inversely correlated with the relative abundance of

E. faecium (Spearman correlation coefficient = −0.43, P = 2.08 ×  10 −^10 )
(Fig. 4a). Samples with high lantibiotic abundance (Lanhigh > 85th

percentile) consistently had low abundance of E. faecium (<10% 16S

relative abundance), and were detected in half of patients (Extended

Data Fig. 10). In Lanhigh and Lanlow settings, 25% and 21%, respec-

tively, had high microbiota diversity (inverse Simpson index ≥  8 )

Lantibiotic gene abundance (log 2 (RPKM))

Relative

E. faecium

abundance (% 16S)

32.35 0

0 0

52.52 15.13

a

0

25

50

75

100

−5.0 −2.5 0.0 2.5 5.0

0

25

50

75

100

01020

0

25

50

75

100

01020

37.62 0.50

40.59 21.29 75.00 25.00

Relative

E. faecium

abundance (% 16S)

D diversity (inverse Simpson index) D diversity (inverse Simpson index)

b Low lantibiotic abundance**** High lantibiotic abundance

012510

103

104

105

106

107

108

109

1010

1011

(^1012) ****
Inverse Simpson = 2.7 ± 0.6
012510

Inverse Simpson = 4.35 ± 0.15
012510
LOD
*
Inverse Simpson = 5.35 ± 0.12
[VRE] (CFU g
–1 faeces)
c
Time (days after VRE administration)
Lanhigh
Lanlow
Fig. 4 | Enrichment of lantibiotic genes correlates with reduced
E. faecium in patient faecal samples. a, b, Longitudinally collected
faecal samples (n =  238 biologically independent samples) from
22 patients undergoing allogeneic haematopoietic cell transplantation
were shotgun sequenced. a, The relative abundance of E. faecium
determined by 16S rRNA was plotted against lantibiotic gene abundance
(Spearman correlation coefficient = −0.43, P = 2.08 ×  10 −^10 ). b, Samples
were then stratified by abundance of the lantibiotic, and the relative
abundance of E. faecium was plotted against microbiota α diversity. The
percentage of sample distribution is shown in each quadrant. c, Faecal
microbiota transplants were performed on germ-free mice using diversity-
matched microbiomes containing either high or low lantibiotic gene
abundance. One week after FMT administration, mice were orally gavaged
with VRE and colonization was monitored by quantifying VRE from
faecal samples. VRE (ATCC 700221) was used for experiments in c. Low
lantibiotic abundance ≤  2 2.5^ < high lantibiotic abundance (RPKM); low
E. faecium abundance ≤  10 < high E. faecium abundance (% relative 16S);
low α diversity ≤  8 < high α diversity (inverse Simpson index). P < 0.05,
****P < 0.0001, two-tailed Mann–Whitney U-test.
a b
MSK6MSK7MSK9MSK10MSK1
1
MSK13MSK19MSK8MSK14MSK15MSK16MSK17MSK18MSK20MSK21
1 2 3 4 5 6 7 8 9
10
Total
Lantibiotic sequence
c
R. faecis (MSK.20.87)
R. faecis (MSK.10.13)
R. faecis (MSK.13.33)
Culture broth alone
[VRE] (CFU ml–1)

• LOD VRE inoculum
  102 103 104 105 106 107 108 109 1010
  102 103 104 105 106 107 108 109
  B. wexlerae (MSK.6.27)
  B. wexlerae(MSK.6.16)
  B. wexlerae (MSK.6.25)
  B. glucerasea (MSK.6.32)
  B. wexlerae (MSK.6.26)
  B. schinkii (MSK.14.32)
  B. schinkii (MSK.15.25)
  B. luti (MSK.18.38)
  B. luti (MSK.16.79)
  B. luti (MSK.9.19)
  B. luti (MSK.15.26)
  B. luti (MSK.15.19)
  B. glucerasea (MSK.6.6)
  B. luti (MSK.13.38)
  B. luti (MSK.13.24)
  B. hansenii (MSK.15.43)
  B. producta (BPSCSK)
  B. producta (BPcontrol)
  B. producta (MSK.4.13)
  B. producta (MSK.4.17)
  B. producta (MSK.4.14)
  B. obeum (MSK.13.53)
  B. obeum (MSK.14.21)
  B. obeum (MSK.13.37)
  B. glucerasea (MSK.21.93)
  B. luti (MSK.14.58)
  B. faecis (MSK.14.13)
  B. faecis (MSK.17.74)
  B. luti (MSK.18.71)
  B. luti (MSK.21.50)
  B. luti (MSK.20.76)
  B. luti (MSK.20.44)
  Culture broth alone
  [VRE] (CFU ml–1)


• 
  

  LOD VRE inoculum
  Lantibiotic genes absent
  Lantibiotic genes present
  Lantibiotic genes absent
  Lantibiotic genes present
  Fig. 3 | Lantibiotic genes are present in human microbiomes of healthy
  individuals and gut resident, lantibiotic-producing species inhibit
  VRE. a, Microbiota-derived Blautia species were whole-genome
  sequenced, assembled, annotated and mined for lantibiotic precursor
  sequences. VRE was inoculated in conditioned media from 39 strains
  (n = 4 biologically independent samples from four independent
  experiments) and monitored for growth. b, Lantibiotic detection from
  shotgun sequencing of human faecal samples (n = 15 faecal samples).
  c, In total 421 commensal biobank isolates were whole-genome sequenced,
  assembled, annotated and mined for lantibiotic precursor sequences
  to identify a strain of R. faecis that encoded a homologous lantibiotic.
  VRE was inoculated in conditioned media from three strains of R. faecis
  cultures (n = 4 biologically independent samples from four independent
  experiments) with or without detected lantibiotic genes, and VRE growth
  was monitored 8 h after inoculation. VRE (ATCC 700221) was used in
  experiments in a and c. *P = 0.0286, two-tailed Mann–Whitney U-test for
  comparisons with negative control. Data are mean ± s.d. (a, c).
  668 | NAtUre | VOL 572 | 29 AUGUSt 2019