Do Prevotella copri and Blastocystis promote euglycaemia?

The PREDICT 1 study reported that long-term dietary patterns were associated with serum cardiometabolic markers and faecal microbiota.1Asnicar F Berry SE Valdes AM et al.Microbiome connections with host metabolism and habitual diet from 1,098 deeply phenotyped individuals.Nat Med. 2021; 27: 321-332Crossref PubMed Scopus (143) Google Scholar This study corroborated our view that faecal microbiota reflect lifestyle factors such as diet, exercise, medicine intake, and other factors.2Janket S-J Ackerson LK Diamandis EP Gut microbiotas and immune checkpoint inhibitor therapy response: a causal or coincidental relationship?.Clin Chem Lab Med. 2019; 58: 18-24Crossref PubMed Scopus (10) Google Scholar The long-term intake of healthy plant-based foods was associated with improved cardiometabolic markers. This finding is consistent with our previous report3Liu S Serdula M Janket SJ et al.A prospective study of fruit and vegetable intake and the risk of type 2 diabetes in women.Diabetes Care. 2004; 27: 2993-2996Crossref PubMed Scopus (159) Google Scholar that fruit and vegetable intake is predictive of risk of diabetes. It is not surprising that plant-based foods were associated with improved metabolic profile and gut microbiota because the foods humans eat are substrates for gut microbiota. Although the association between the intervention and the outcome in a trial can be interpreted as causal, the association of the primary and secondary outcomes (namely blood metabolic markers and faecal microbiota) is not. As we previously stated, due to its anatomical location, microbiota assessed in faeces cannot be assumed to be the cause of specific human biological processes without the assumption that microbiota found in faeces are the same microbiota as are in the gut.4Janket SJ Conte HA Diamandis EP Inappropriate extrapolations abound in fecal microbiota research.Clin Chem Lab Med. 2021; 59: e307-e308Crossref PubMed Scopus (1) Google Scholar This assumption, however, has been proven to be false.4Janket SJ Conte HA Diamandis EP Inappropriate extrapolations abound in fecal microbiota research.Clin Chem Lab Med. 2021; 59: e307-e308Crossref PubMed Scopus (1) Google Scholar Nevertheless, Asnicar and colleagues1Asnicar F Berry SE Valdes AM et al.Microbiome connections with host metabolism and habitual diet from 1,098 deeply phenotyped individuals.Nat Med. 2021; 27: 321-332Crossref PubMed Scopus (143) Google Scholar stated that simultaneous presence of Prevotella copri and Blastocystis seemed to promote healthier metabolic function.1Asnicar F Berry SE Valdes AM et al.Microbiome connections with host metabolism and habitual diet from 1,098 deeply phenotyped individuals.Nat Med. 2021; 27: 321-332Crossref PubMed Scopus (143) Google Scholar This suggestion is ill conceived and quite dangerous because numerous studies have reported that P copri can be proinflammatory. P copri has been identified in chronic inflammatory conditions such as HIV, rheumatoid arthritis, heart failure, and carboplatin-induced mucositis.1Asnicar F Berry SE Valdes AM et al.Microbiome connections with host metabolism and habitual diet from 1,098 deeply phenotyped individuals.Nat Med. 2021; 27: 321-332Crossref PubMed Scopus (143) Google Scholar Kovatcheva-Datchary and colleagues reported that a high-fibre diet resulted in euglycaemia and increased faecal P copri.5Kovatcheva-Datchary P Nilsson A Akrami R et al.Dietary fiber-induced improvement in glucose metabolism is associated with increased abundance of Prevotella.Cell Metab. 2015; 22: 971-982Summary Full Text Full Text PDF PubMed Scopus (762) Google Scholar They also reported that P copri have a role in euglycaemia. However, a study in humans reported that P copri was associated with deleterious glucose metabolism using the serum metabolome.6Pedersen HK Gudmundsdottir V Nielsen HB et al.Human gut microbes impact host serum metabolome and insulin sensitivity.Nature. 2016; 535: 376-381Crossref PubMed Scopus (969) Google Scholar The serum metabolome of insulin-resistant individuals is characterised by increased levels of branched-chain amino acids (BCAAs). P copri was identified as one of the main species driving the association between BCAAs and insulin resistance.6Pedersen HK Gudmundsdottir V Nielsen HB et al.Human gut microbes impact host serum metabolome and insulin sensitivity.Nature. 2016; 535: 376-381Crossref PubMed Scopus (969) Google Scholar These two incongruous reports suggest that Simpson's paradox might be involved in the association between P copri and glucose metabolism. Simpson's paradox occurs when a third factor confounds the association of interest, generating ostensibly opposing results, as we have previously reported.7Janket SJ Ackerson LK Diamandis E Simpson's paradox in proof-of-concept studies.Nat Med. 2019; 251640Crossref PubMed Scopus (9) Google Scholar In our opinion, these microorganisms proliferate in a specific dietary and lifestyle milieu and, thus, they are likely epiphenomena for a lifestyle. The attention that P copri and Blastocystis received in PREDICT 1 might propel their commercialisation as probiotics, which might cause harm to the public, as we observed in previous attempts of microbial transplantation.8Janket SJ Ackerson LK Diamandis EP Drug-resistant bacteremia after fecal microbiota transplant.N Engl J Med. 2020; 3821960Crossref PubMed Scopus (4) Google Scholar Additional characteristics of these microorganisms are noteworthy. They both have predatory potential and extreme caution must be exercised when dealing with them. Usually, the microbes found in faeces are those that prefer a given diet or were able to survive other microbes' predation (figure). For example, Micavibrio aeruginosavorus are predators of other Gram-negative bacteria. Thus, they were considered to be an alternative to antibiotics. However, exposure to M aeruginosavorus resulted in over-growth of Prevotella.9Shatzkes K Tang C Singleton E et al.Effect of predatory bacteria on the gut bacterial microbiota in rats.Sci Rep. 2017; 743483Crossref PubMed Scopus (31) Google Scholar Regarding Blastocystis, Asnicar and colleagues1Asnicar F Berry SE Valdes AM et al.Microbiome connections with host metabolism and habitual diet from 1,098 deeply phenotyped individuals.Nat Med. 2021; 27: 321-332Crossref PubMed Scopus (143) Google Scholar labelled them as commensals, insinuating their innocuousness. Whether Blastocystis are commensals or pathobionts is still debatable; however, in our opinion, no commensals are truly harmless because under specific conditions they can become pathobionts, or support the proliferation of pathobionts by providing substrates for them.4Janket SJ Conte HA Diamandis EP Inappropriate extrapolations abound in fecal microbiota research.Clin Chem Lab Med. 2021; 59: e307-e308Crossref PubMed Scopus (1) Google Scholar Furthermore, Blastocystis spp are eukaryotic Chromista, more evolved than bacteria, and have sophisticated organelles, making them difficult to eradicate. They can cause treatment failures or fatal diarrhoea, especially in patients who are immunocompromised. Additionally, Blastocystis spp express cysteine proteases that cleave secretory immunoglobulin A and secrete anti-lysozyme and anti-lactoferrin—factors that lead to immune evasion. Moreover, Blastocystis spp have shown predatory actions and can become phagocytic when nutrients and space are scare. The predatory nature of Blastocystis spp contributes to their persistence. For these reasons, in some patients, Blastocystis spp can be invasive, resulting in ulceration of intestinal mucosa and rectal bleeding. A recent article by O'Keeffe and colleagues10O'Keeffe M Barratt A Fabbri A et al.Global media coverage of the benefits and harms of early detection tests.JAMA Intern Med. 2021; 181: 865-867Crossref PubMed Scopus (8) Google Scholar suggested that medical media coverage tends to overplay benefits, downplay harms, and ignore conflicts of interest. There is a need for journals to provide space for healthy debates of such controversial issues. In conclusion, faecal P copri and Blastosystis spp are likely epiphenomena to healthy diets and improved glucose metabolism. Thus, suggesting these microbes are the cause of euglycaemia might be an inappropriate extrapolation of PREDICT 1. Additionally, a diverse gut microbiome contributes to better immunity. However, administering one or two faecal microbiota without the checks and balances of other microbes might introduce risks, resulting in infection, bacteraemia, and intestinal ischaemia. EPD holds an advisory and consultant role with Abbott Diagnostics and Imaware Diagnostics. S-JJ and HAC declare no competing interests. We thank Annie Ren for help designing the figure.