Mucin-derived O-glycans supplemented to diet mitigate diverse microbiota perturbations

K M Pruss,B Choudhury,L Bode,J L Sonnenburg,S A Smits,D Dahan,P C Kashyap,A M Southwick,E D Sonnenburg,A Marcobal,S K Higginbottom,J A Ferreyra

doi:10.1038/s41396-020-00798-6

K M Pruss, B Choudhury + Show 10 more

Open Access

https://doi.org/10.1038/s41396-020-00798-6

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Abstract

Microbiota-accessible carbohydrates (MACs) are powerful modulators of microbiota composition and function. These substrates are often derived from diet, such as complex polysaccharides from plants or human milk oligosaccharides (HMOs) during breastfeeding. Host-derived mucus glycans on gut-secreted mucin proteins serve as a continuous endogenous source of MACs for resident microbes; here we investigate the potential role of purified, orally administered mucus glycans in maintaining a healthy microbial community. In this study, we liberated and purified O-linked glycans from porcine gastric mucin and assessed their efficacy in shaping the recovery of a perturbed microbiota in a mouse model. We found that porcine mucin glycans (PMGs) and HMOs enrich for taxonomically similar resident microbes. We demonstrate that PMGs aid recovery of the microbiota after antibiotic treatment, suppress Clostridium difficile abundance, delay the onset of diet-induced obesity, and increase the relative abundance of resident Akkermansia muciniphila. In silico analysis revealed that genes associated with mucus utilization are abundant and diverse in prevalent gut commensals and rare in enteric pathogens, consistent with these glycan-degrading capabilities being selected for during host development and throughout the evolution of the host–microbe relationship. Importantly, we identify mucus glycans as a novel class of prebiotic compounds that can be used to mitigate perturbations to the microbiota and provide benefits to host physiology.

Highlights

We and others have previously reported the ability of both Bacteroides and Bifidobacterium to utilize select human milk oligosaccharides (HMOs) in vitro [5, 28]; as such, we wished to determine whether complex HMOs isolated from human donors favored Bifidobacterium or Bacteroides within the context of the gut environment. 6-week-old GF mice were bi-colonized with two HMO-utilizing taxa common to the infant gut: Bacteroides thetaiotaomicron (Bt) and B. infantis
Mice were fed a Microbiota-accessible carbohydrates (MACs)-deficient (MD) diet supplemented with HMOs (1% in water, chosen to approximate the mass of HMOs consumed by human newborns, adjusted for body weight, see Methods) for 1 week
After 1 week, HMO supplementation resulted in an expansion in the population of B. infantis relative to Bt compared to mice on regular water (24.3 ± 3.12% versus 2.5 ± 1.45% on day 7; P < 0.001, n = 4 mice) (Fig. 1b)

Summary

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Residues of the mucin protein, while HMOs are built upon a lactose core structure universally present at the reducing end of these glycans [6]. Extensive research has focused on the potential prebiotic role of HMOs. HMOs are indigestible by humans and are degraded throughout the gastrointestinal tract of breast-fed infants [21], becoming the primary microbiotaaccessible carbohydrates available in the newborn diet. We use both gnotobiotic and humanized mice to establish that the gut microbiota efficiently consumes HMOs. we demonstrate that a complex mix of glycans isolated from porcine mucin recreates some of the effect of HMOs on the gut microbiota and mitigates the negative effects of various community perturbations including antibiotic treatment, pathogen invasion, and a high-fat diet (HFD)

Results

Discussion

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