Cobamamide

Metformin has been demonstrated to attenuate hyperglycaemia by modulating the gut microbiota. However, the mechanisms through which the microbiome mediates metformin monotherapy failure (MMF) are unclear. Herein, in a prospective clinical cohort study of newly diagnosed type 2 diabetes mellitus (T2DM) patients treated with metformin monotherapy, metagenomic sequencing of faecal samples revealed that Phocaeicola vulgatus abundance was approximately 12 times higher in nonresponders than in responders. P. vulgatus rapidly hydrolysed taurine-conjugated bile acids, leading to ceramide accumulation and reversing the improvements in glucose intolerance conferred by metformin in high-fat diet-fed mice. Interestingly, C22:0 ceramide bound to mitochondrial fission factor to induce mitochondrial fragmentation and impair hepatic oxidative phosphorylation in P. vulgatus-colonized hyperglycaemic mice, which could be exacerbated by metformin. This work suggests that metformin may be unsuitable for P. vulgatus-rich T2DM patients and that clinicians should be aware of metformin toxicity to mitochondria. Suppressing P. vulgatus growth with cefaclor or improving mitochondrial function using adenosylcobalamin may represent simple, safe, effective therapeutic strategies for addressing MMF.

Supposed ‘spontaneous’ remissions in chronic lymphocytic leukaemia (CLL) are extremely rare. By the most stringent immunophenotypic criteria, there are only seven cases to date of unexplained, immune system effected cures. A historic review of this phenomenon is presented as context for this eighth case of CLL immunophenotypic reversal.

A 59‐year‐old, molecular biologist, stage I CLL, whose diagnosis and recovery were both thoroughly documented, not content to watch and wait, chose to treat himself, after individual tumour susceptibility testing, with evidence based, biological response modifiers, which initially seemed to keep his CLL stable. This included 1 mg of hydroxocobalamin injected i.m. daily. However, after some years his lymphocytosis began slowly to drift upwards. At that point, he was persuaded to change his injection protocol to methylcobalamin, at 50 mg i.m. a day, a dose whose clinical safety is sufficiently well‐established, and a form of cobalamin that the research literature shows has anticancer actions.

This change in cobalamin form and dose proved a critical turning point. Complete disappearance of the lymphocytosis also coincided with a severe infection and an even further temporary increase of the parenteral methylcobalamin dose, both catalytic factors. In the 4th and 5th years following this, the patient's repeated immunophenotyping showed no clonal disease present. A brief review of the field of cobalamin in cancer research and treatment is given, with discussion of the various mechanisms by which cobalamins may impact on cancer/CLL. Historic analysis reveals that cyanocobalamin is generally cancer promotional, whereas hydroxocobalamin, methylcobalamin and adenosylcobalamin are cancer protective and cytotoxic. It is hypothesised that the actions of cobalamin in cancer aetiology and oncogenesis/progression are intertwined with those of nitric oxide, which tumours regulate to dupe the immune system to their presence, by causing a functional cobalamin deficiency in the host.