Abstract
Epidemiological data reveal an association between obesity and inflammatory bowel disease (IBD). Furthermore, animal models demonstrate that maternal high-fat diet (HFD) and maternal obesity increase susceptibility to IBD in offspring. Here we report that excess calorie intake by neonatal mice, as a consequence of maternal HFD, forced feeding of neonates or low litter competition, leads to an increase during weaning in intestinal permeability, expression of pro-inflammatory cytokines and hydrogen sulfide production by the microbiota. These intestinal changes engage in mutual positive feedback that imprints increased susceptibility to colitis in adults. The pathological imprinting is prevented by the neutralization of IFN-γ and TNF-α or the production of hydrogen sulfide, or by normalization of intestinal permeability during weaning. We propose that excess calorie intake by neonates leads to multiple causally linked perturbations in the intestine that imprint the individual with long-term susceptibility to IBD.
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Data Availability
The data that support the plots within this paper and other findings of this study are available from the corresponding authors upon reasonable request.
Change history
12 November 2019
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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Acknowledgements
We thank all the members of the Microenvironment & Immunity Unit, as well as from the Stroma, Inflammation & Tissue Repair Unit, for support and discussion. We also thank the members of Gnotobiology Platform of the Institut Pasteur for technical support with germfree mice. Z.A.N. was supported by Pasteur–Roux Postdoctoral Fellowships from the Institut Pasteur. This work was supported by Institut Pasteur and INSERM, the Association François Aupetit, the Fondation pour la Recherche Medicale, Janssen Horizon, and an Innovator award from the Kenneth Rainin Foundation.
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Z.A.N. and G.E. planned the project and the experiments; Z.A.N., S.D., E.L., B.P. and M.B. performed the experiments; Z.A.N. and P.C. analysed the data; M.B. provided germ-free resources; Z.A.N. and G.E. wrote the manuscript, acquired the funding and conceived the project.
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Extended data
Extended Data Fig. 1 Excess calorie early in life increased colitis severity in adult mice.
(a,d,g,h,m,n,o) Mice exposed to a HFD early in life were weaned to NC. (b,e,i,j,p,q) Mice fed NC were supplemented or not with coconut oil between 2 to 4 weeks of age. (c,f,k,l,r,s) The number of mice fed NC was reduced at day 3 post-birth to 3 pups (SL) or maintained to 7 pups per litter as NL. Colitis induced at adult age. (a-c) Weight of total body, epididymal fat, retroperitoneal fat and liver in 4-week-old mice or (d-f) before DSS induction in adulthood. (g,i,k) Percentage of survival, (h,j,l) disease-activity index, (m) colonic length before DSS exposure, (n,p,r) myeloperoxidase and intestinal permeability levels and (o,q,s) colonic transcript profile after colitis induction. For a (n=30/group; litters=11), b (n=8/group; litters=5), c (n=8/group; litters/group=5), d (n=26/group; litters/group=9), e (n=10/group; litters=6), f (n=10; NL: 4 litters; SL: litters=6). NC (m (n=10; litters=4), g (n=8; litters=5), h (n=9; litters=6), n-o (n=15; litters=7)); HFD early in life (m (n=8; litters=4), g (n=15; litters=8), h (n=8; litters=6), n-o (n=14; litters=5)); HFD at adult age (m (n=8; litters=3), g (n=13; litters=7), h (n=10; litters=6), n-o (n=11; litters=5)); Vehicle (i (n=9; litters=9), j (n=8; litters=6), p (n=5; litters=4), e (n=8; litters=6)); Coconut oil (i (n=19; litters=9), j (n=9; litters=6), p (n=5; litters=4), e (n=8; litters=6)); NL (k,l (n=8; litters=5), r (n=4-6; litters=4), s (n=8; litters=4)); SL (k (n=14; litters=8), l,s (n=8; litters=5), r (n=4-8; litters=4-5)); No colitis (n-o (n=10; litters=7), p,r (n=4; litters=4), q (n=5; litters=5), s (n=5; litters=4)). For g,i,k Log-rank test (g ***P=0.0009, i *P=0.04; k *P=0.03). For a-f,h,j,l-s post hoc Tukey-adjusted tests following significant (P<0.05, after correction) Analyses of Deviance (mixed-effect models), all ****P<0.0001; b **P=0.001; c *P=0.03; j (***P=0.0005; *P=0.04); n (MPO **P=0.003; ***P=0.0002; Permeability **P=0.009); p (MPO ***P=0.0003, ***P=0.0002; Permeability *P=0.02, **P=0.004); q (Il1b ***P=0.0001; Il4 *P=0.01; Il5 **P=0.002); r (MPO **P=0.003; Permeability *P=0.01); s (Ifng ***P=0.002; Il4 *P=0.04; Il5 **P=0.002; **P=0.003). Data were pooled from at least two independent experiments. Each dot represents 1 offspring mouse. Dots of same color and symbol represent mouse from same litter. Data are shown as mean±s.e.m.
Extended Data Fig. 2 Excessive calorie intake early in life induces gut dysfunctionality that does not persist later in life.
(a,d,g,j) Mice were fed NC or a HFD early in life, and some were exposed to antibiotics (ABX). (b,e,h,k) Mice fed NC supplemented with coconut oil or vehicle for 2 to 4 weeks after birth. (c,f,i,l) Mice were overfed by reducing litter size (SL) or not (NL). (a,d) Colonic mRNA expression measured at (a-c) 4 weeks or (d-f) 20 weeks of age. (g-i) Levels of lipocalin 2 and (j-l) intestinal permeability measured before colitis induction in adult mice. For a (NC (n=7; litters=5), HFD (n=9; litters=5); NC+ABX (n=6; litters=5); HFD+ABX (n=7; litters=5)); d (NC (n=9; litters=5), HFD (n=9; litters=5), NC+ABX (n=10; litters=4), HFD+ABX (n=10; litters=4)); g,j (n=8/group; litters/group=4). For Vehicle (b (n=7; litters=5), e (n=7; litters=4), h (n=8; litters=6), k (n=6; litters=4)); Coconut oil (b (n=10; litters=6), e (n=7; litters=4), h (n=8; litters=5), k (n=6; litters=4)); Vehicle+ABX (b (n=9; litters=5), e (n=7; litters=4), h (n=8; 6 litters), k (n=6; litters=4)); Coconut oil+ABX (b (n=10; litters=6), e (n=7; litters=4), h (n=8; 5 litters), k (n=6; litters=4)). For NL (c (n=10-14; litters=5-7), d (n=6; litters=3), i (n=8; litters=3), l (n=10; litters=4)); SL (c (n=9-14; litters=5-7), d (n=6; litters=3), i (n=8; litters=4), l (n=10; litters=6)); NL+ABX (c (n=10-14; litters=5-7), d (n=6; litters=3), i (n=8; litters=3), l (n=10; litters=5)); SL+ABX (c (n=9-13; litters=5-8), d (n=6; litters=3), i (n=8; litters=4), l (n=10; litters=6)). (a,g) Post hoc Tukey-adjusted tests following significant (P<0.05, after correction) Analyses of Deviance (mixed-effect models), all ****P<0.0001; a (Il6 ***P=0.0002, ***P=0.0003; Il33 ***P=0.0009; Reg3b **P=0.005; Reg3g *P=0.01; Tff3 ***P=0.0006, *P=0.01; Fcgbp ***P=0.0001; Muc2 **P=0.0018, **P=0.0025); b (Il6 *P=0.011, *P=0.015; Il22 **P=0.0018, *P=0.036; Tff3 ***P=0.0005; Muc2 **P=0.002); c (Reg3b *P=0.025, **P=0.005; Muc4 **P=0.006). ns = not significant. Data were pooled from two independent experiments. Each dot represents 1 offspring mouse. Dots of same color and symbol represent mouse from same litter. Data are shown as mean±s.e.m.
Extended Data Fig. 3 Excessive calorie intake increases body weight through a microbiota-dependent mechanism.
Weight of total body (a,e,i), epididymal fat (b,f,j), retroperitoneal fat (c,g,k) and liver (d,h,l) at 4 weeks after birth of mice exposed or not to antibiotics (ABX). Mice were (a-d) fed NC or a HFD early in life, (e-h) supplemented with coconut oil or vehicle during 2 to 4 weeks after birth, (i-l) overfeed by reducing litter size (SL) or not (NL) at neonatal age in SPF or in GF conditions. Post hoc Tukey-adjusted tests following significant (P<0.05, after correction) analyses of deviance (mixed-effect models), all ****P<0.0001; b (***P=0.0004, ***P=0.0001); c (***P=0.0002); d (**P=0.009, ***P=0.0004); h (*P=0.049, ***P=0.0008); k (***P=0.0001, ***P=0.0007); l (*P=0.01, ***P=0.03). For a-d (n=10/group; litters/group=4), e-h (Vehicle (n=6; litters=4), Coconut oil (n=6; litters=4), Vehicle+ABX (n=8, litters=4), Coconut oil+ABX (n=8, litters=4)), i-l (SPF+NL (n=16, litters=6), SPF+SL (n=18, litters=11), GF + NL (n=8, litters=3), GF+SL (n=16, litters=9), ABX+NL (n=8, litters=3), ABX+SL (n=16, litters=9)). Data were pooled from at least two independent experiments. Each dot represents 1 offspring mouse. Dots of same color and symbol represent mouse from same litter. Data are shown as mean±s.e.m.
Extended Data Fig. 4 Prevention of pathological imprinting early in life.
Mice fed NC or a HFD early in life treated (a-f) with anti-IFN-γ and anti-TNF-α (anti-I+T) neutralizing antibodies (mAb) or (g-l) ML-7 versus controls from ages 2 to 4 weeks old, and colitis was induced in adulthood. (a,g) Weight of epididymal fat, retroperitoneal fat, liver and (b,h) colonic mRNA expression measured at 4-week-old. (c,i) Percentage of survival, (d,j) disease activity index, (e,k) levels of myeloperoxidase and intestinal permeability and (f,l) mRNA colonic transcript profile after colitis initiation. (m-p) Adult mice fed NC or HFD during 6- to 9-week-old are simultaneously treated or not with anti-I+T antibodies or with ML-7 vs controls. (m) Body weight, (n) lipocalin 2, (o) gut permeability and (p) colonic mRNA expression measured 9-week-old. For NC+Isotype and NC+Anti-I+TmAb (a (n=8; litters=4), b,e-f (n=6; litters=4), c-d (n=9; litters=6)); HFD+Isotype (a (n=8; litters=5), b (n=6; litters=4), c (n=15; litters=11), d (n=9; litters=7), e-f (n=7; litters=5)); HFD+Anti-I+TmAb (a (n=8; litters=5), b (n=7; litters=4), c-d (n=9; litters=7), c-e (n=6; litters=4)). For NC+Vehicle (g-h (n=8; litters=4), i,j,l (n=8; litters=5), k (n=6; litters=3)); NC+ML-7 (g-h (n=6; litters=4), i,j,l (n=8; litters=5), k (n=5; litters=3)); HFD+Vehicle (g-h (n=8; litters=5), i (n=15; litters=12), j,l (n=10; litters=6), k (n=5; litters=3)); HFD+ML-7 (g (n=10; litters=5), h (n=9; litters=5), i,j,l (n=10; litters=6), k (n=6; litters=3)). No colitis (e-f (n=4; litters=4), k (n=4; litters=3), l (n=8; litters=7)). For c,i Log-rank (Mantel–Cox) test (c (***P=0.0005); i (*P=0.02)). For a,b,d-f,g,h,j-p, Post hoc Tukey-adjusted tests following significant (P<0.05, after correction) Analyses of Deviance (mixed-effect models), all ****P<0.0001; a (**P=0.008, **P=0.008); b (Fcgbp ***P=0.0002; Muc2 ***P=0.0002, **P=0.006; Il22 ***P=0.0008; Il33 **P=0.002); e (MPO ***P=0.0001; Permeability *P=0.01); f (Ifng *P=0.01, ***P=0.0001; Il1b *P=0.01, **P=0.002, ***P=0.0005; Il4 **P=0.002, ***P=0.0005; Il5 *P=0.03, **P=0.001, ***P=0.0003); g (***P=0.0003, ***P=0.0001), h (Reg3b ***P=0.0005; Reg3g *P=0.04, ***P=0.0004; Tff3 *P=0.02; Il33 ***P=0.0008). k (MPO *P=0.017; Permeability *P=0.012, **P=0.001, **P=0.004); l (Ifng *P=0.018, ***P=0.0001; Il1b *P=0.049, ***P=0.0001, ***P=0.0006; Il4 *P=0.023, **P=0.003; Il4 *P=0.039, ***P=0.0002); o (**P=0.001, ***P=0.0004); p (Tnfa ***P=0.0008; Ifng **P=0.005). ns=not significant. Data were pooled from at least two independent experiments. Each dot represents 1 offspring mouse. Dots of same color and symbol represent mouse from same litter. Data are shown as mean±s.e.m.
Extended Data Fig. 5 Exposure to SCFAs in mice fed HFD early in life reduced the severity of colitis in adulthood by mechanism dependent on RORγt-expressing Tregs.
(a-i) Mice were exposed to NC or to a HFD early in life and treated with SCFAs or vehicle controls during 2 to 4 weeks of age. (m-q) Foxp3Cre × Rorc(gt)Fl mice and littermate control were fed HFD early in life and exposed to SCFAs or vehicle during weaning. (a,m) Weight of total body, (b) epididymal fat, (c) retroperitoneal fat, (d) and liver, (e,n) level of intestinal permeability, and (f,g) colonic mRNA expression measured post-weaning. (h,p) Colonic length, (i) intestinal permeability, (j) level of myeloperoxidase, (k) lipocalin-2, (l,q) colonic transcript profile and (o) loss of body weight measured after initiation of colitis at 9-10 weeks of age. For NC+Vehicle (a-g (n=6); h-l (n=7); litters=4); HFD+Vehicle (a-g (n=10; litters=6), h-l (n=7; litters=4)); NC+SCAFs (a-g (n=5), h-l (n=6); litters=4); HFD+SCFAs (a-g (n=10; litters=6), h-l (n=6; litters=4)); Littermate+Vehicle (m-n (n=6; litters=6), o (n=5; litters=5), p-q (n=8; litters=8)); Littermate+SCFAs (m-n (n=10; litters=7), o (n=10; litters=6), p-q (n=6; litters=6)); Foxp3CreRORyt+Vehicle (m-n (n=6; litters=6), o (n=5; litters=5), p-q (n=9; litters=8)); Foxp3CreRORyt+SCFAs (m-n (n=6; litters=6), o (n=6; litters=5), p-q (n=5; litters=5)); No colitis (n=5; litters=5). Post hoc Tukey-adjusted tests following significant (P<0.05, after correction) Analyses of Deviance (mixed-effect models), all ****P<0.0001; a (***P=0.0006); b (***P=0.0004, *P=0.012); c (**P=0.003); d (*P=0.04, *P=0.02); f (Il12 ***P=0.0002; Mylk ***P=0.0004; Tjp1 **P=0.004; Tjp2 ***P=0.0003); g (Reg3g ***P=0.0005; Reg3b ***P=0.0004; Tff3 **P=0.004; Fcgbp **P=0.006; Muc2 *P=0.02, **P=0.008; Il6 *P=0.03; Il33 **P=0.007); h (**P=0.002, **P=0.008); i (*P=0.02, **P=0.007, ***P=0.0003); j (**P=0.005, **P=0.003); k (*P=0.04, ***P=0.0006); l (Tnfa **P=0.004, **P=0.005; Ifng ***P=0.0003; Il1b **P=0.003, **P=0.008; Il4 **P=0.008, **P=0.004; Il5 **P=0.003, **P=0.007; Il13 **P=0.006, **P=0.008); m (***P=0.0003); o (*P=0.01, ***P=0.0008); p (***P=0.0003, ***P=0.0009); q (**P=0.007); ns = not significant. Data were pooled from at least two independent experiments. Each dot represents 1 offspring mouse. Dots of same color and symbol represent mouse from same litter. Data are shown as mean±s.e.m.
Extended Data Fig. 6 The expression of bacterial dsrA, H2S levels and impact of 5-ASA on colitis susceptibility.
(a-b) The expression of bacterial dsrA coding for the dissimulatory sulfite reductase (a) by weeks and (b) at 4 weeks after birth in mice grown in reduced litters (SL=Small Litter) or normal litters (NL). For NL (a (n=10; litters=4), b (n=34; litters=15)); SL (a (n=7; litters=5), b (n=34; litters=20)). (c-f) Faecal H2S levels (c) from mice grown in NL (n=34; litters=15) and SL (n=43; litters=25), (d) from mice gavaged with coconut oil (n=16; litters=10) or Vehicle (n=8; litters=6), or in the colon of (e) mice fed NC (n=12; litters=5) or HFD early in life (HFDn; n=12; litters=5), or (f) mice grown in NL (n=21; litters=9) or SL (n=21; litters=12). (g) The expression of dsrA at 12-week-old from mice fed HFD between 6- to 12-week-old (n=23; litters=15) or NC (n=23; litters=10). (h-j) Fecal H2S levels (h) measured at 12-week-old mice that fed HFD in adulthood (n=15; litters=7) or NC (n=12; litters=5), (i) measured at 4-week-old mice that fed HFDn and treated with antibiotics (n=10; litters=4) or not (n=10; litters=5), and (j) mice grown in SL and treated or not with antibiotics (n=19/group; litters/group=13). (k-q) Mice fed NC or HFD early in life treated during weaning with 5-ASA or controls. (k) Weight of epididymal fat, retroperitoneal fat and liver, (l) colonic mRNA expression at 4-week-old. (m) Percentage of survival, (n) disease activity index, (o) levels of gut permeability, (p) myeloperoxidase and (q) colonic mRNA expression after colitis initiation in adulthood. HFD and HFD+5-ASA (k (n=11), l (n=12), litters=6); NC+5-ASA (k (n=6; litters=4), l (n=8; litters=6)). HFD (i (n=15; litters=12), j-l (n=7; litters=4)); HFD+5-ASA (i (n=15; litters=12), j-l (n=7; litters=4)); No colitis (e-f (n=4), k-l (n=6), litters=4). For m (*P=0.03) Log-rank test; a-l;n-q, Post hoc Tukey-adjusted tests following significant (P<0.05, after correction) Analyses of Deviance (mixed-effect models), all ****P<0.0001; d (**P=0.002); l (Reg3b **P=0.009; Reg3g *P=0.02; Il33 **P=0.003); o (***P=0.0001); q (Il4 **P=0.001, Il5 ***P=0.0001). Data were pooled from at least two independent experiments. Each dot represents 1 offspring mouse. Dots of same color and symbol represent mouse from same litter. Data are shown as mean±s.e.m.
Extended Data Fig. 7 Pathological imprinting through H2S and microbial immunogens early in life.
(a-g) Germ-free mice grown in SL are exposed to sodium hydrogen sulfide (NaHS) and/or heat-killed microbiota (M), or to vehicle during 2- to 4-week-old. Weight of (a) epididymal fat, (b) retroperitoneal fat, (c) liver and colonic mRNA expression for (d) cytokines and (e) mucins and antimicrobial peptides measured at 4-week-old. (f) Disease activity index and (g) colonic transcript profile after colitis induction in adulthood. (h-n) Adult germ-free mice grown in SL are exposed to NaHS and/or M, or to vehicle during 8- to 10-week-old. (h) Body weight, (i) colonic mRNA expression and (j) gut permeability measured at 10-week-old. (k) Loss of body weight, (l) disease activity index and (m) colonic length after colitis induction at 12 week-old. (n-r) Germ-free mice grown in SL are exposed to NaHS and M, and treated with ML-7, or with anti-IFNγ and anti-TNFα (anti-IT) antibodies (mAb) or with vehicle, during 2- to 4-week-old. (n) epididymal fat, (o) retroperitoneal fat and (p) liver at 4-week-old. (q) Diseases activity index and (r) colonic transcript profile after colitis induction in adulthood. For SL+Vehicle (a-c,k-m (n=6; litters=5), d-e (n=7; litters=6), f (n=9; litters=6), g (n=4; litters=4), h-j (n=5; litters=5)); SL+NaHS (a-c,d-e (n=6; litters=5), f (n=7; litters=4), g (n=6; litters=4)); SL+M (a-c (n=7; litters=6), d-e,g (n=6; litters=5), f (n=8; litters=4)); SL+M+NaHS (a-c (n=7; litters=6), d-e,g (n=6; litters=5), f (n=6; litters=4), k-m (n=5; litters=5), n-r (n=6; litters=6)); SL+M+NaHS adult (h (n=8; litters=7), i-j (n=4; litters=4), k-m (n=5; litters=5)); SL (n-r (n=6; litters=5)); SL+M+NaHS+ML-7 (n-r (n=7; litters=7)); SL+M+NaHS+anti-IT (n-r (n=7; litters=7)); No colitis group (g (n=6), m (n=4), r (n=5), litters=4); Post hoc Tukey-adjusted tests following significant (P<0.05, after correction) Analyses of Deviance (mixed-effect models), all ****P<0.0001; a (**P=0.009); b (**P=0.006); c (**P=0.005); d (Il6 ***P=0.0004); Il22 **P=0.002, ***P=0.0005); f (*P=0.01, ***P=0.0002); g (Ifng **P=0.009, Il1b *P=0.02, Il4 *P=0.03, Il5 **P=0.007); k (**P=0.002, ***P=0.0004); l (**P=0.003); m (***P=0.0005); q (**P=0.005). ns=not significant. Data were pooled from at least two independent experiments. Each dot represents 1 offspring mouse. Each color represent mouse from same litter. Data are shown as mean±s.e.m.
Extended Data Fig. 8 Effect of hydrogen sulfide early in life on colitis susceptibility.
Weight of (a) total body, (b) epididymal fat, (c) retroperitoneal fat, (d) liver, (e) intestinal permeability and (f) colonic expression of mRNA for cytokines and MLCK and epithelial tight junction proteins at 4 weeks of age in germfree mice grown in small litter (SL) and exposed to slow release of H2S (GYY4137) and/or heat-killed microbiota (M), or to vehicle control during 2 to 4 weeks of age. (g) Percentage of body loss, (h) disease activity index, (i) colonic length and (j) colonic transcript profile after colitis induction in adult germfree mice exposed to a slow-release H2S donor (GYY4137) and/or heat-killed microbiota (M) or to vehicle control, and grown in SL, during 2 to 4 weeks of age. Post hoc Tukey-adjusted tests following significant (P<0.05, after correction) Analyses of Deviance (mixed-effect models), all ****P<0.0001; d (***P=0.0005); f (Il6 *P=0.02; Il22 *P=0.03; Tjp1 *P=0.04; Tjp2 **P=0.004); g (*P=0.03, ***P=0.0005); h (*P=0.04); i (***P=0.0005); j (***P=0.0008). ns= not significant. For SL+Vehicle (a-e (n=8; litters=7), f (n=7; litters=6), g-j (n=6; litters=6)); SL+GYY4137 (a-e (n=8; litters=6), f (n=5; litters=4), g-j (n=6; litters=6)); SL+M (a-e (n=8; litters=7), f (n=6; litters=5), g-j (n=6; litters=6)); SL+M+GYY4137 (a-e (n=10; litters=9), f (n=8; litters=7), g-j (n=8; litters=8)); No colitis (g-j (n=7; litters=7)). Data were pooled from at least two independent experiments. Each dot represents 1 offspring mouse. Dots of same color and symbol represent mouse from same litter. Data are shown as mean±s.e.m.
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Al Nabhani, Z., Dulauroy, S., Lécuyer, E. et al. Excess calorie intake early in life increases susceptibility to colitis in adulthood. Nat Metab 1, 1101–1109 (2019). https://doi.org/10.1038/s42255-019-0129-5
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DOI: https://doi.org/10.1038/s42255-019-0129-5
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