We present a novel methodology to construct a Boolean dynamic model from time series metagenomic information and integrate this modeling with genome-scale metabolic network reconstructions to identify metabolic underpinnings for microbial interactions. We apply this in the context of a critical health issue: clindamycin antibiotic treatment and opportunistic Clostridium difficile infection. Our model recapitulates known dynamics of clindamycin antibiotic treatment and C. difficile infection and predicts therapeutic probiotic interventions to suppress C. difficile infection. Genome-scale metabolic network reconstructions reveal metabolic differences between community members and are used to explore the role of metabolism in the observed microbial interactions. In vitro experimental data validate a key result of our computational model, that B. intestinihominis can in fact slow C. difficile growth. Bird Shannyn birdgirl@arcticmail.com University of Nebraska-Lincoln 2016-12-23T21:22:20Z 2017-04-10T16:11:19Z

Genus: Coprobacillus

Family: Erysipelotrichaceae

 2017-02-01T12:07:30Z

Family: Enterobacteriaceae

Order: Enterobacterales

Klebsiella species and Escherichia coli (E. coli) are part of the Enterobacteriaceae family and are commonly found in the gut microbiome.

 2016-12-29T20:09:24Z

Genus: Enterococcus

Family: Enterococcaceae

Opportunistic Pathogen

 2017-01-30T09:46:02Z

Genus: Blautia

Family: Lachnospiraceae

Blautia are common gut bacteria and aid in the digestion of complex carbohydrates.

 2017-01-30T09:51:58Z

Refers to microorganisms that are not in the ten most abundant genera in the gut microbiome.

 2016-12-29T20:06:43Z

Family: Lachnospiraceae

Order: Clostridiales

Lachnospiraceae is an common member of the human gut microbiota that degrades complex polysaccharides to short-chain fatty acids.

 2016-12-29T20:06:43Z

Class: Mollicutes

Phylum: Tenericutes

Experiment data on mice gut bacteria indicates that Mollicutes is an abundant member of the gut microbiome.

 2016-12-29T20:09:24Z

Genus: Akkermansia

Family: Akkermansiaceae

Gram-negative bacteria

Akkermansia is one of the most abundant members of the human gut microbiota.

 2016-12-29T19:53:41Z

Genus : Barnesiella

Family: Porphyromonadaceae

Gram-negative bacteria

Barnesiella is usually only found at relatively ow levels in the gut.

 2016-12-29T19:53:41Z

Genus: Clostridium

Family: Clostridiaceae

Spore-forming, gram-positive bacillus

Opportunistic pathogen

 2017-01-25T11:01:49Z

An antibiotic that is known to be effective against some gram-positive and anaerobic bacteria. The summarized mechanism of action is that it is effective by blocking peptide formation via direct binding to sites on ribosomes, which inhibits cell growth.

 2016-12-29T20:06:43Z

Family: Lachnospiraceae

Order: Clostridiales

Lachnospiraceae is an common member of the human gut microbiota that degrades complex polysaccharides to short-chain fatty acids.

 2016-12-29T20:06:43Z

Enterobacteriaceae activates itself.

Enterobacteriaceae activates itself.

 S_1 1

Blautia, Clostridium_difficile, Enterobacteriaceae, and Mollicutes are positive regulators of Enterococcus. Coprobacillus is a non-dominant inhibitor of Enterococcus.

Best-fit extension was used to determine that Clostridium_difficile positively regulates Enterococcus.

Best-fit extension was used to determine that Enterobacteriaceae positively regulates Enterococcus.

Best-fit extension was used to determine that Blautia positively regulates Enterococcus.

Best-fit extension was used to determine that Coprobacillus negatively regulates Enterococcus.

Best-fit extension was used to determine that Mollicutes positively regulates Enterococcus.

 S_1 1 S_9 1 S_6 1 S_3 1 S_9 1 S_1 1 S_3 1 S_10 1 S_6 1

Blautia activates itself when Coprobacillus is inactive. Coprobacillus activates Blautia when Blautia is inactive. Enterococcus also activates Blautia.

Best-fit extension was used to determine that Blautia regulates its own activity.

Best-fit extension was used to determine that Coprobacillus regulates Blautia.

Best-fit extension was used to determine that Enterococcus positively regulates Blautia.

 S_2 1 S_3 1 S_10 1 S_3 1 S_3 1 S_10 1

Other, Lachnospiraceae_other, and Lachnospiraceae are activators of Other. Clindamycin is a negative regulator of Other which expresses dominance over Other, Lachnospiraceae_other, and Lachnospiraceae.

Best-fit extension was used to determine that Lachnospiraceae positively regulates Other.

Best-fit extension was used to determine that Other activates itself.

Best-fit extension was used to determine that Clindamycin negatively regulates Other.

Best-fit extension was used to determine that Lachnospiraceae_other positively regulates Other.

 S_5 1 S_11 1 S_4 1 S_11 1 S_12 1 S_11 1

Other, Lachnospiraceae_other, and Lachnospiraceae activate Lachnospiraceae. Clindamycin is a negative regulator of Lachnospiraceae which expresses dominance over Other, Lachnospiraceae_other, and Lachnospiraceae.

Best-fit extension was used to determine that Lachnospiraceae positively regulates itself.

Best-fit extension was used to determine that Other positively regulates Lachnospiraceae.

Lachnosporaceae populations drop drastically after antibiotic treatment, including treatment with Clindamycin.

Best-fit extension was used to determine that Lachnospiraceae_other positively regulates Lachnospiraceae.

 S_4 1 S_11 1 S_5 1 S_11 1 S_12 1 S_11 1

Mollicutes activates itself.

Mollicutes activates itself.

 S_6 1

Akkermansia is activated by Coprobacillus.

Coprobacillus is inferred to positively regulate Akkermansia through an unknown mechanism.

 S_10 1

Other, Lachnospiraceae_other, and Lachnospiraceae activate Barnesiella. Clindamycin is a negative regulator of Barnesiella which expresses dominance over Lachnospiraceae, Lachnospiraceae_other, and Other.

Best-fit extension was used to determine that Lachnospiraceae positively regulates Barnesiella through an unknown mechanism.

Best-fit extension was used to determine that Other positively regulates Barnesiella through an unknown mechanism.

A day after a single dose of Clindamycin resulted in a significant loss of Barnesiella populations.

Best-fit extension was used to determine that Lachnospiraceae_other positively regulates Barnesiella.

 S_5 1 S_11 1 S_12 1 S_11 1 S_4 1 S_11 1

Clostridium_difficile activates itself. Barnesiella is a negative regulator of Clostricium_difficile which also expresses dominance over it.

Clostridium_difficile activates itself.

Clostridium_difficile grows slower when co-cultured with B. intestinihominis. The mechanism behind this decreased growth when when exposed to B. intestinihominis is unknown, but indicates that Barnesiella negatively regulates Clostridium_difficile proliferation.

 S_9 1 S_8 1

Clindamycin activates itself.

Clindamycin activates itself.

 S_11 1

Other, Lachnospiraceae_other, and Lachnospiraceae are activators of Lachnospiraceae_other. Clindamycin is a negative regulator of Lachnospiraceae_other which expresses dominance over Other, Lachnospiraceae_other, and Lachnospiraceae.

Best-fit extension was used to determine that Lachnospiraceae positively regulates Lachnospiraceae_other.

Best-fit extension was used to determine that Other positively regulates Lachnospiraceae_other.

Lachnosporaceae populations drop drastically after antibiotic treatment, including treatment with Clindamycin.

Best-fit extension was used to determine that Lachnospiraceae_other positively regulates itself.

 S_5 1 S_11 1 S_4 1 S_11 1 S_12 1 S_11 1