Abstract
Lactate can be produced by many gut bacteria, but in adults its accumulation in the colon is often an indicator of microbiota perturbation. Using continuous culture anaerobic fermentor systems, we found that lactate concentrations remained low in communities of human colonic bacteria maintained at pH 6.5, even when dl-lactate was infused at 10 or 20 mM. In contrast, lower pH (5.5) led to periodic lactate accumulation following lactate infusion in three fecal microbial communities examined. Lactate accumulation was concomitant with greatly reduced butyrate and propionate production and major shifts in microbiota composition, with Bacteroidetes and anaerobic Firmicutes being replaced by Actinobacteria, lactobacilli, and Proteobacteria Pure-culture experiments confirmed that Bacteroides and Firmicutes isolates were susceptible to growth inhibition by relevant concentrations of lactate and acetate, whereas the lactate-producer Bifidobacterium adolescentis was resistant. To investigate system behavior further, we used a mathematical model (microPop) based on 10 microbial functional groups. By incorporating differential growth inhibition, our model reproduced the chaotic behavior of the system, including the potential for lactate infusion both to promote and to rescue the perturbed system. The modeling revealed that system behavior is critically dependent on the proportion of the community able to convert lactate into butyrate or propionate. Communities with low numbers of lactate-utilizing bacteria are inherently less stable and more prone to lactate-induced perturbations. These findings can help us to understand the consequences of interindividual microbiota variation for dietary responses and microbiota changes associated with disease states.IMPORTANCE Lactate is formed by many species of colonic bacteria, and can accumulate to high levels in the colons of inflammatory bowel disease subjects. Conversely, in healthy colons lactate is metabolized by lactate-utilizing species to the short-chain fatty acids butyrate and propionate, which are beneficial for the host. Here, we investigated the impact of continuous lactate infusions (up to 20 mM) at two pH values (6.5 and 5.5) on human colonic microbiota responsiveness and metabolic outputs. At pH 5.5 in particular, lactate tended to accumulate in tandem with decreases in butyrate and propionate and with corresponding changes in microbial composition. Moreover, microbial communities with low numbers of lactate-utilizing bacteria were inherently less stable and therefore more prone to lactate-induced perturbations. These investigations provide clear evidence of the important role these lactate utilizers may play in health maintenance. These should therefore be considered as potential new therapeutic probiotics to combat microbiota perturbations.
Highlights
Lactate can be produced by many gut bacteria, but in adults its accumulation in the colon is often an indicator of microbiota perturbation
Impact of fecal inoculum, pH, and lactate infusions on colonic microbiota present in fermentor vessels. pH-controlled continuous flow fermentor systems, at either pH 5.5 or 6.5, mimicking the approximate pH of the proximal and distal colons, respectively [27], were supplied with culture medium containing 0.74% mixed polysaccharides and 0.2% peptides, and were inoculated with fecal microbiota. Fermentors held at both pHs were continuously infused with either 20 mM (“high”), 10 mM (“medium”), or zero lactate, in order to monitor the overall impact on the microbial community structure
Principal-component analysis (PCA) revealed that, samples clustered by donor (Fig. S1b), the data points derived from samples at pH 5.5 were more widely distributed throughout the plot, indicating that the lower pH had a greater destabilizing impact on the microbiota (Fig. 1a)
Summary
Lactate can be produced by many gut bacteria, but in adults its accumulation in the colon is often an indicator of microbiota perturbation. The pH of the intestinal lumen is largely determined by the concentrations of short-chain acids being produced by the fermentation of dietary fiber [4] This means that the activities of the gut microbiota have the potential to feed back on its behavior and species composition by altering the gut environment. Lactate has been shown to inhibit the growth of some pathogenic bacteria, including Escherichia coli [6], and can reach high concentrations in the gut of healthy infants, reflecting the dominance of L-lactate-producing bifidobacteria [7, 8] It can exert an array of deleterious effects, in particular due to its potential to drive down gut pH as a result of its low pKa, which can lead to changes in the microbiota and to acidosis in the adult colon [9]. Lactate can enhance immune evasion by the fungal pathogen Candida albicans by triggering masking of its cell wall antigens [16]
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