Effect of water flow and chemical environment on microbiota growth and composition in the human colon

Abstract

The human gut harbors a dynamic microbial community whose composition bears great importance for the health of the host. Here, we investigate how colonic physiology impacts bacterial growth, which ultimately dictates microbiota composition. Combining measurements of bacterial physiology with analysis of published data on human physiology into a quantitative, comprehensive modeling framework, we show how water flow in the colon, in concert with other physiological factors, determine the abundances of the major bacterial phyla. Mechanistically, our model shows that local pH values in the lumen, which differentially affect the growth of different bacteria, drive changes in microbiota composition. It identifies key factors influencing the delicate regulation of colonic pH, including epithelial water absorption, nutrient inflow, and luminal buffering capacity, and generates testable predictions on their effects. Our findings show that a predictive and mechanistic understanding of microbial ecology in the gut is possible. Such predictive understanding is needed for the rational design of intervention strategies to actively control the microbiota. T he human gut microbiota is composed of trillions of bacterial cells (1-4) from several hundred species (1-3, 5, 6). Over the last two decades, a multitude of studies have shown a strong impact of human health status on the composition of this microbiota, and in turn a strong effect of microbiota composition on host physiology has also been confirmed (7-9). Various intervention strategies are being investigated to modify the microbiota composition via prebiotics and probiotics (10). Despite this importance for human health, little is known about how the microbiota composition is shaped by the interplay between human and bacterial physiology in the gut.In this study, we present a physiological model that quantitatively describes this host-microbiota interplay. Our model is based on a hydrodynamic perspective, which posits that bacterial densities reached in the colon result from a dynamic balance between bacterial growth, flow through the colon, and peristaltic mixing (11). To build the present model, we extensively analyzed literature data on human gut physiology to obtain quantitative estimates for a range of relevant host parameters. We further characterized the rates of bacterial growth, carbohydrate consumption, and fermentation product excretion for representatives of the two dominant bacteria phyla, Bacteroidetes and Firmicutes, that typically make up more than 90% of the bacterial cells observed in the gut (6).Combining these aspects of human and bacterial physiology into a coarse-grained mathematical model allowed us to study bacterial growth dynamics in the human gut. Without resorting to ad hoc fitting parameters, model results are in quantitative agreement with available data on key observables of human gut physiology. We find that changes in pH values in the colon that are due to the secretion of acidic fermentation products and shaped by human physiology (such a...

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“…growth minus death) must be exactly balanced by the clearance of each species due to flow. Generally speaking, the growth rate of a species will be determined by the concentrations of nutrients that it can use and of substances that inhibit its metabolism, as well as environmental variables such as pH and osmolality . Recently, microbiota growth rates have been estimated, using snapshot metagenomics approaches, to range from between one and ten replications per day, with a differential rate depending on the phyla .…”

“…(i) Mucus‐resident bacteria sticking to the colon walls are often referred to as important for replenishing the luminal bacterial population. However, a quantitative consideration of their contribution indicates that this is far from sufficient to maintain the luminal microbiota . To make this clearer, to a human‐sized bacterium (scaling up by 2 × 10 6 ‐fold) the ascending colon would be a tube with a 100 km diameter, with the content flowing at around 100 km/hr.…”

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“…The anaerobic environment of the distal colon, due to the removal of water and the abundance of substrate, is the appropriate situation for fermentation. Saccharolytic bacteria, such as Bacteroidetes , ferment the processed monosaccharides within the glycolysis and pentose‐phosphate pathways, to produce SCFAs in addition to the gases CO 2 and H 2 . From the main short‐chain fatty acids, acetate, propionate, and butyrate are present in an estimated ratio of 60:20:20 in the large intestine.…”

“…Saccharolytic bacteria, such as Bacteroidetes, ferment the processed monosaccharides within the glycolysis and pentose-phosphate pathways, to produce SCFAs in addition to the gases CO 2 and H 2 . 23,24 From the main shortchain fatty acids, acetate, propionate, and butyrate are present in an estimated ratio of 60:20:20 in the large intestine. Butyrate is produced by beneficial colonic bacteria and acts as the main source of energy for the colonocytes.…”

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“…For example, Cremer et al . (2017) have developed a mathematical model that provides insight into the microbiota interaction with pH and water flow in the gut. McLoughlin et al .…”