Members of the gut microbiome belonging to phylum Proteobacteria are typically considered to be undesirable, and are associated with infectious diarrhea, elevated inflammation, increased permeability of the gut wall and the production of harmful metabolites . Here, we describe a correlation between increasing levels of Parasutterella (phylum Proteobacteria), a core member of the gut microbiota , and decreasing levels of LDL, an important risk factor for cardiovascular disease. Notably, the linear correlation between increases in Parasutterella and decreases in LDL facilitates integration into gut microbiome testing platforms, such that interventions (such as prebiotic or probiotic supplementation) that increase Parasutterella will be predicted to similarly reduce LDL levels in a proportional manner. While the effect of RPS on LDL cholesterol was modest (Fig. 5B; mean change − 0.33 mmol/L in Responders) compared to cholesterol lowering medications , RPS supplementation may help reduce LDL levels in combination with other therapies. The evaluation of Parasutterella levels in the gut microbiome to predict a person’s response to RPS is consistent with a personalized approach to medicine and speaks to growing appreciation for the role that differences in gut microbiome composition play in shaping human health.
Parasutterella is an anaerobic, asaccharolytic Gram-negative, non-spore-forming coccobacillus, that was originally described based on a strain isolated from a fecal sample from a healthy Japanese male . Deep sea water (DSW) is one of several dietary supplements that tend to increase Parasutterella levels   . Using a diet-induced hamster model of hypercholesterolemia, Lin and colleagues demonstrated that DSW also led to significant reductions in triglycerides, LDL, and total cholesterol, although Bacteroidetes was the only bacterial population significantly correlated with serum cholesterol and LDL in response to the high cholesterol diet . Increases in Parasutterella in response to GOS supplementation in mice were associated with significant reductions in triglycerides but not LDL levels . Parasutterella levels were inversely correlated with fat consumption but not total energy intake in obese people .
Introduction of Parasutterella into normal mice led to reductions in cecal levels of cholic acid, taurocholic acid, taurodeoxycholic acid, 7-ketodeoxycholic acid (or isomers), and glycolithocholic acid . Additionally, there were concomitant increases in taurine, and changes in bile acid metabolism that were consistent with bacteria-mediated deconjugation of primary bile acids . Furthermore, the same study demonstrated changes in farnesoid X receptor (FXR)-dependent gene expression, including increases in Cyp7a1, suggesting enhanced bile acid synthesis . Mushroom polysaccharide supplementation of a high fat diet led to similar changes in gene expression, along with increases in Parasutterella that were correlated with reductions in serum lipids . While total cholesterol levels were decreased, although not significantly, by the introduction of Parasutterella, LDL levels were not measured , suggesting that the mechanisms documented in mice could be acting similarly in humans consuming RPS, specifically those with above-threshold levels of Parasutterella. Furthermore, although stable colonization of Parasutterella in the gastrointestinal tract occurred rapidly in mice , it is possible that the mean changes in bile acid abundance, FXR-dependent gene expression, and the effects on cholesterol are driven by mice in which higher levels of Parasutterella engrafted to the gut microbiome, consistent with the data presented here for humans.
Despite potatoes having been identified as dietary sources of asparagine and aspartic acid , our analysis reveals that all amino acids, except for a trace amount of tryptophan, are absent in RPS. Thus, it is unclear from our data how RPS supports the growth of Parasutterella. It is intriguing to note that Parasutterella was identified as part of a co-abundance response group that increased in response to chemically modified resistant starches (Type 4) in people . This suggests that resistant starch may generally support the growth of Parasutterella, through cross-feeding or some other indirect mechanism(s). Indirect growth via complex ecological interactions could explain why RPS consumption stimulated growth of Parasutterella in some people and not others. Furthermore, Fig. 2 demonstrates that there are a number of microbial shifts within the gut microbiome that occur in humans consuming RPS (e.g. Bifidobacteria, Staphylococcus, and Clostridium increase while Faecalbacterium and Blautia decrease). This suggests there may be a “co-abundance” type response in humans related to RPS consumption. This supports Marchesi and others’ statement : “However, as we learn more about the ecology of the gut microbiota it is becoming clear that the prebiotic concept has tapped into the underlying fabric of the gut microbiota as a primarily saccharolytic and fermentative microbes community evolved to work in partnership with its host’s digestive system to derive energy and carbon from complex plant polysaccharides which would otherwise be lost in faeces.”
Limitations of our study include the large dose (30 g/day), the relatively small study population, and the use of age brackets within that population. Furthermore, statistical analysis of Parasutterella levels was hampered by the low relative abundance of this genus (mean levels < 0.4%). Future studies examining the response of Parasutterella to lower doses of RPS in a larger, general population are warranted