The human gut harbors an enormous number of symbiotic microbes, which is vital for human health. However, interactions within the complex microbiota community and between the microbiota and its host are challenging to elucidate, limiting development in the treatment for a variety of diseases associated with microbiota dysbiosis. Using in silico simulation methods based on flux balance analysis, those interactions can be better investigated. Flux balance analysis uses an annotated genome-scale reconstruction of a metabolic network to determine the distribution of metabolic fluxes that represent the complete metabolism of a bacterium in a certain metabolic environment such as the gut. Simulation of a set of bacterial species in a shared metabolic environment can enable the study of the effect of numerous perturbations, such as dietary changes or addition of a probiotic species in a personalized manner. This review aims to introduce to experimental biologists the possible applications of flux balance analysis in the host-microbiota interaction field and discusses its potential use to improve human health.

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47The human gut harbors an enormous number of symbiotic microbes, which is vital for human 48 health. However, interactions within the complex microbiota community and between the 49 microbiota and its host are challenging to elucidate, limiting development in the treatment 50 for a variety of diseases associated with microbiota dysbiosis. Using In silico simulation 51 methods based on flux balance analysis, those interactions can be better investigated. Flux 52 balance analysis uses an annotated genome-scale reconstruction of a metabolic network to 53 determine the distribution of metabolic fluxes that represent the complete metabolism of a 54 bacterium in a certain metabolic environment such as the gut. Simulation of a set of bacterial 55 species in a shared metabolic environment can enable the study of the effect of numerous 56 perturbations, such as dietary changes or addition of a probiotic species in a personalized 57 manner. This review aims to introduce these applications of flux balance analysis to 58 experimental biologists and discusses its potential use to improve human health. 59 60 Keywords 61 Flux balance analysis, Gut microbiota, Probiotics, Metabolic model, Microbial community 62 63 64 65 66 67 68 69 4 70 Metabolic networks 71 The gut microbiota is the community of microorganisms residing in the gut and include 72 commensal, symbiotic, and pathogenic bacteria. Under normal circumstances, the gut 73 microbiota and the host are in symbiosis [1]. Disruption of the symbiosis is detrimental for 74 host health and can result in disease including gastrointestinal disorders such as inflammatory 75 bowel disease [2], metabolic disorders such as diabetes mellitus [3], and mental disorders such 76 as autism spectrum disorder [4], and major depressive disorder [5]. To understand the 77 symbiosis, the different members of the gut microbiota, and the way they communicate with 78 each other and with the host need to be known. The microbiota communicates via production 79 of metabolites [6]. Therefore, it is key in the field of host-microbe interactions to identify 80 which microbial members are present and what their metabolic output is. However, this does 81 not fully elucidate the dynamic interactions within the microbiota, and between host and the 82 microbiota, since the metabolic output of microorganisms is dependent on their surroundings 83 [7]. Therefore the metabolic output and, in turn, the interactions between host and 84 microbiota is different among individuals [8], making successful treatment of the 85 aforementioned disorders more challenging. Although experimental approaches are crucial to 86 the progress of the microbiota field, they are not able to fully capture the mechanisms, 87 interactions, and behavior due to the huge complexity of the environment in the gut. These 88 limitations have led to the development of a complimentary approach to completely 89 understand the relationship between host and microbe; bacterial metabolic networks [9]. In 90 this approach, bacterial interactions can be v...

The gut microbiota plays a pivotal role in health and disease. The use of probiotics as microbiota- targeted therapies is a promising strategy to improve host health. However, dynamic molecular mechanisms are often not elucidated, especially when targeting the small intestinal microbiota. Here, we show that supplementation of a probiotic formula (Ecologic825) to the adult human small intestinal ileostoma microbiota counteracts the growth of Enterococcaceae, Bacteroidaceae and Enterobacteriaceae and reduces ethanol production, leading to major changes in nutrient utilization and resistance to perturbations. The observed alterations coincided with an initial increase in lactate production and decrease in pH by the probiotics, followed by a sharp increase in the levels of butyrate and propionate. Additionally, increased production of multiple N-acyl amino acids was detected in the stoma samples supplemented with the probiotic formula. Overall, this study shows how network theory can be used to improve the current or identify novel microbiota-targeted therapies. The outcome may help further understand the reported effects of these probiotic formula on the host.