Could the gut microbiome help manage diabetes?

Diabetes remains one of the most prevalent and costliest disorders, despite a wide palette of available treatments.

Leading diabetes players continue to churn out more convenient versions of their drugs, grappling for share in a highly competitive, price-pressured market.  Novo Nordisk recently invested in a short-cut route-to-market for its oral GLP-1 agonist, semaglutide, buying a priority review voucher from another company that may allow it to launch three months earlier.

GLP-1 agonists, like Novo’s own once-daily injectable, Victoza, have proven effective among many thousands of patients. They can help delay patients’ move onto insulin, and are much easier to use.

But the growth in diabetes prevalence means that new approaches are needed. Drugs are effective when they’re taken properly, but most often, they aren’t. Technology is helping – “intelligent” insulin pens, connected glucose monitors and apps to encourage healthy behavior and medication adherence are proliferating. The diabetes challenge has also drawn in behavioural psychologists and urban planners.

The gut microbiome may be the next frontier in battling diabetes. Research is uncovering a key role for the gut flora in many diseases, not just gastro-intestinal conditions but also cancers, auto-immune, endocrine and even central nervous system disorders. Gut bacteria are now understood to communicate with the brain and influence behavior – including, in some cases, by generating neurotransmitters like serotonin, gamma-aminobutyric acid (GABA) or dopamine.

An imbalance in the gut microbiome has already been associated with the development of insulin resistance in Type 2 (acquired) diabetes. Shifts in the gut microbiota can alter host metabolism – shifting it toward greater energy-harvesting and fat-deposition, for instance, or, potentially, driving appetite even when energy stores are replete.

The precise mechanisms and molecules involved, along with causal links, remain to be figured out. But it seems intuitive that gut health will impact diabetes, not least as this is a disease exacerbated by a high-fat diet. If, as is now believed, the gut influences behavior too, then a gut-microbiome-targeted approach could provide an effective solution for the many diabetics who cannot control their condition using existing therapies and tools.

Novo has been working since mid-2018 with Kallyope to uncover novel peptides to treat diabetes and obesity. New York City-based Kallyope is one of a handful of biotech companies seeking new therapeutic approaches through harnessing the “gut-brain axis” – the multiple two-way communication channels (neuronal, endocrine and humoral) between head and stomach.

The effort is still in discovery. But if drugs or nutritional supplements could be found that modulate both physiology (blood sugar regulation, energy homeostasis, insulin resistance) and psychology (appetite, willpower), this could prove a very useful addition to the diabetes toolbox.  

TargEDys in France already markets an appetite-regulating probiotic, ProbioSatys. Available over-the-counter, it allegedly promotes a feeling of fullness by providing a protein, ClpB, which mimics a satiety hormone called alpha-MSH. ClpB is produced naturally by certain types of gut bacteria. Its action is two-pronged – it enters the blood stream to act directly on the central nervous system, but also stimulates intestinal endocrine cells to produce more alpha-MSH. ProbioSatys is designed to enhance those natural regulatory pathways.

A trial is underway among 236 overweight people, to assess the supplement’s impact on weight, as well as its tolerability and safety, over a 12-week period versus placebo. The estimated completion date is August 2019, according to clinicaltrials.gov.

Cervical cancer screening comes to your mobile phone

Effective screening programs have helped reduce cervical cancer-linked mortality by over 50% in the last forty years. But thousands of women still die each year from the disease, including many in developing countries with little or no access to screening and early diagnosis.

New technologies and artificial intelligence-based software are now making cervical cancer screening and detection easier and cheaper, and opening it up to non-specialists – including, potentially, the patients themselves.

Scientists at Duke University in Durham, North Carolina, have developed a pocket-sized colposcope – a small camera – which can be used to generate clear images of the cervix without the use of a speculum. The device, which is far smaller and cheaper than a conventional colposcope, can be inserted as easily as a tampon, by the woman herself or a non-specialist health provider. It has FDA clearance and has been tested in eight countries and over 1000 women, across the US, Peru and some African nations.

If it gains traction, the device would enable community clinics and relatively unskilled providers to detect and potentially treat cervical cancer much earlier – at the screening stage, when the traditional pap smear happens. (Colposcopy is the more involved procedure that follows a positive smear test.)

The Duke researchers are also working on algorithms that could help non-specialists detect abnormalities in the images generated by the device, and even on ways to treat early stage, pre-invasive cancer. These include an ethanol-based gel that could target and destroy cancerous lesions, scalpel-free.

Israel-based Mobile ODT is pursuing a similar goal. Its ‘smart’ colposcope, which generates advanced images of the cervix on a mobile phone, is already used in 29 countries including the US. And it has recently been enhanced with an artificial-intelligence based algorithm trained to detect abnormalities in the images. A study among 212 patients in South Korea suggests that the algorithm may be better at detecting pre-cancerous or cancerous lesions than trained humans using pap cytology. And it can do so much faster – in one minute, while the patient is still present, rather than in days.

That study was only a pilot. But the potential of artificial intelligence in medical imaging more generally is already proven, making it likely that cervical screening and early detection will continue to become more widely available.

More treatments are on the way for metastatic or recurrent cervical cancer, which remains the biggest unmet need. But there are bumps in the road: FDA in January 2019 placed a partial hold on Advaxis’ Phase III study of therapeutic cancer vaccine Axal, following a trial re-design. Two earlier trials, including combination studies, were forcibly halted due to patient deaths. Axal is a strain of listeria bacteria programmed to generate cancer-targeting T cells.

Regeneron/Sanofi’s checkpoint inhibitor Libtayo (cemiplimab), meanwhile, has shown early promise both as monotherapy and in combination with radiotherapy in early clinical trials of patients with advanced or recurrent cancer; a larger Phase III is underway. Checkpoint inhibitors like Libtayo have thus far not proven very effective in first-line cervical cancer, where platinum-based therapies and Avastin dominate.