Diabetes prevention &/or treatment – Focus on the gut and nutrition? Role and benefits of biomarker discovery and validation.

There is the potential to significantly improve health by minor modifications to our diets in the form of biotics which could be bought relatively cheaply from your local grocery store and improve diabetic health. [1-3] Although diabetes covers two very different diseases (Type-1 and Type-2), they both have a common clinical endpoint: a reliance on insulin injections to control blood glucose concentration levels within a healthy range. Indeed, while the causes of the two diseases are quite dissimilar, both have a common point of intersection at the gut and the immune system. Hence, nutritional interventions such as probiotics could lead to a new generation of therapies that play a pivotal role in fighting diseases like diabetes.

Type 1 & 2 overlapping biology

Focus on the gut?

The consequences of a beneficial (“symbiotic”) vs. a dysfunctional (‘dysbiotic’) microbiota on human health has started to emerge over the last decade [2]. It is clear that there is an association between an altered microbiota and the expression of several diseases from autism to diabetes – though whether that change in the microbiota is also causative of disease remains to be determined.

Symbiosis – the mutually beneficial outcome of two organisms co-existing together – is well-known in biology. For example, lichen is a stable symbiotic association between a fungus and algae/cyanobacteria – each providing their unique contribution to the energy and metabolic needs of both organisms. Apparently something similarly beneficial occurs in humans – in this case between ourselves and the gut bacteria acting as our co-hosts (Do the bacteria host us or do we host our symbiotic partners who outnumber us at least 10:1 on a cell count?).

Given the vast ‘second genome’ that exists within our gastro-intestinal (GI) tract and the role that it plays in many human metabolic conditions, the microbiome has become a focus for clinical research and for probiotic companies alike, presenting opportunities for advancing diagnostics and development of tailored therapeutics [3]. Opinion is divided as to whether daily doses of symbiotic bacteria (“probiotics”) can impact the vast cohort of bacteria already resident in the gut or whether efficacy might be better achieved via functional foods (‘prebiotics’) which preferentially promote the colonization of the commensal bacteria. The ‘synbiotic camp’ hedge their bets with a combination of probiotic bacteria and prebiotic functional foods in one product.

Translational systems biology

Diabetes – when metabolism met immunology

At its simplest level, diabetes manifests itself as the inability to produce sufficient insulin by the pancreas and of the body to ineffectively use what insulin is produced to control blood glucose concentrations via tissues such as the liver, muscle and fat [11]. Given that nutrients are absorbed from the gut, our bacterial brethren who inhabit our intestines may be both responsible for – and a route to reverse – the metabolic disorders such as diabetes and obesity that we see today.

Specifically, in Type-1 (“juvenile”) diabetics, the host immune system is over-activated and which results in the destruction of the beta-cells of the pancreas — the source of insulin. So for these patients, the same network of cells and proteins which prevent many infections is misprogrammed to attack the host (“self-intolerance”) because the immune system cannot immunologically distinguish between (“tolerate”) itself compared to invading pathogens.

In Type-2 diabetes (“adult diabetes”) the immune response is slower, more pervasive and chronic – manifesting itself by making the insulin that is produced less effective in muscle, liver and adipose tissues (“insulin resistance”) so that that the pancreas has to work harder to make more insulin in compensation. Eventually, the beta-cells of the pancreas fail and the organ produces no insulin at all.

In both cases, a dysfunctional (“unbalanced”) immune system plays a direct (Type-1) or contributory (Type-2) role to the pathology of the disease [4]. These slowly developing modifications to the host immune system and the balance of pro- vs. anti-inflammatory factors [5] brings us back to the part played by microbes in our gut.

Role of the microbiome in diabetes

There is mounting evidence that gut microbiota modulate our inflammatory tone and which in turn affects peripheral pathologies, such as insulin resistance.  What is the connection and scientific evidence for such a claim — and is the effect of an unbalanced microbiome reversible?

Mounting evidence suggests that the bacteria resident within our GI tract – and the immune response to those bacteria – influence the permeability of the gut mucosa. This idea — which has become to be known as the “leaky gut” hypothesis [4,6] — proposes that a cycle of dysbiosis, dysregulated immune response, and unintended gut permeability leads to the peripheral host immune system being unbalanced towards a pro-inflammatory response [7]. This in turn is suggested to lead to (some of) the imbalances that are thought to be causative of diabetes [8, 9,12-14, 17] and other non-metabolic disorders [10].

Indeed, lipopolysaccharides (LPS) which are derived from some bacteria are very powerful pro-inflammatory modulators of the innate immune response [6], the infiltration of which into the circulation provides one example of a connection between the microbiota and the host immune system – and in turn the potential for peripheral diseases with a chronic inflammatory contribution.

It is difficult to distinguish causative vs. associative factors. Is bacterial dysbiosis a cause of Type-2 diabetes or a reflection of a more pervasive co-associated life-style choice? How can the scientific community objectively assess the value (or otherwise) of pro- and synbiotics in the prevention, amelioration or reversal of metabolic disease? By classical, controlled, interventional clinical trials [16].

Nutraceutical interventions for diabetes?

The UN and the WHO has defined a probiotic specifically as “live microorganisms that, when administered in adequate amounts, confer a health benefit to the host” and indeed, several papers have been published which clarify what is – and is not – a probiotic [15]. A synbiotic on the other hand is a combination of a probiotic as defined above and a nutrient (often a poly-saccharide) which encourages the growth of the probiotic bacteria.

The last decade has seen a major increase in publications within peer-reviewed scientific Journals providing evidence for associative (and potentially causative) connections between microbiota, the introduction of probiotics/synbiotics into the diet, and the outcome of several pathologies from autism to diabetes [2]. Despite this ever-increasing weight of scientific evidence there remains the need for high-quality, leading clinical trials to provide data from which the Regulatory authorities in the USA and Europe can assess the underlying science behind biotic research into specific maladies [19]. Certainly the questionable claims made by some companies – notably on the web – have been a disservice to the more mainstream science that is being undertaken on an objective and rational basis using methods that would feel at home in any biopharmaceutical company, hospital or University [15, 16, 20]. This research seeks data with which to better understand the underlying biology and the consequent therapeutic and commercial potential of probiotic intervention. Indeed, several organizations of academics, clinicians and pro/synbiotic companies have come together to support solid, evidence-based science [21, 22] – which is the only language that Regulators can (and should) objectively respond to.

MIND

Role/ benefits of biomarker discovery and validation

Given the prevalence of type-1 and type-2 diabetes, there is clearly benefit to objectively assess potential therapies and which may also have secondary benefits in obesity and cardiovascular disease.Acknowledging the value that preclinical research has provided to understanding the host-microbiotic relationship, models need to have greater potential for translatability (e.g. immunologically-humanized diabetic mice [18,19]) or preferably undertake interventional (not associative) research in the clinic [16].

The scientific, clinical and Regulatory communities are seeking interventions which are preventative in at-risk populations, mechanistically linked to risk factors via specific biomarkers and pathways and which have a causal impact on the clinical outcomes of disease status.

With individual partners able to undertake research both independently and collaboratively and with economies of scale, we would envisage public- and proprietary data that could result in numerous publications across high-quality peer reviewed Journals – preferably leading to subsequent academic and commercial collaboration between Partners using the data and IP.

Type 1 & 2 overlapping biology 1

A research proposal could integrate four main scientific and clinical themes: (a) the composition of the gut microbiota, (b) the status of the host immune system, (c) functional and multi-dimensional ‘omic biomarkers and (d) the whole-body physiological and clinical outcomes.

A key component of these trials could incorporate an assessment of the physical gut barrier, the breakdown of which (“leaky gut”) may allow bacterial antigens to trigger of a pro-inflammatory immune state — and in turn contribute to the development of the disease(s) [4,6,8].

With a view to causation (vs. association), an assessment could be made of the potential for one or more pro/synbiotics to rebalance dysbiosis and potentially to ameliorate the clinical state [9]. A comprehensive set of biomarkers collected across all the major ‘omic and targeted analytical platforms could then analyzed to assess whether intervention leads to reversal in the proposed mechanistic pathways resulting in improved disease outcomes.

Biomarker Types

There may be benefit in undertaking both preventative and treatment studies in diabetic mice, treatment studies in clinically diagnosed diabetics (~ 1 yr. intervention period) and, if operationally and clinically practical, also preventative studies in pre-diabetics.

Deliverables would be numerous publications in high-quality peer reviewed Journals and subsequent academic and commercial collaboration between Partners using the data and IP arising from the research.

A detailed proposal is being drafted and available upon request

Some questions we’re currently receiving stakeholder feedback on:

  • Are there relevant interventions which you/ colleagues may have an interest in profiling in diabetes?
  • Is it reasonable to expect (pro)biotics to ameliorate the severity of a risk factor over ~ 6-9 mo. intervention and/or to slow the progression of disease? If not, what is reasonable?
  • Would you prioritize undertaking (or funding) research in type-1 or type-2 diabetes?
  • What are some ways you could/ may want to be involved?
  • Are there any individuals you know whom you think may be relevant/ interested in being involved?

Please share comments below.

CLICK TO SEE REFERENCES
[1] Petschow. B et al. (2013) Ann. N.Y. Acad. Sci. 1306: 1-17

[2] Thomas, L. et al, (2014) British Journal of Nutrition 112(S1): S1-S18

[3] Gerritsen, J et al. (2011) Genes Nutr. 6:209-240

[4] Vaarala, O et al (2008) Diabetes 57: 2555-2562

[5] Calcinaro, F et al (2005) Diabetologia 48: 1565-1575

[6] Cani, P et al (2007) Diabetes 56: 1761 – 1772

[7] Atkinson, M and Chervonsky, A (2012) Diabetologia 55: 2868-2877

[8] O’Flaherty, S. (2010) Gut Microbes. 1(5): 293–300

[9] Gomes et al. (2014) Nutrition Journal 13:60

[10] Hsiao, E. Y., (2014) Harvard Review of Psychiatry, 22(2), 104-111

[11] Kwon H and Pessin JE (2013 Front. Endocrinol. 4:71.

[12] Regnell, S and Lernmark, A (2013) Diabet. Med. 30(2): 155-160

[13] Larsen, N. et al (2010) PLoS ONE 5(2): e9085 doi:10.1371/journal.pone.0009085

[14] De Goffau et al (2013) Diabetes. 62(4):1238-44

[15] Hill, C et al (2014) Nature Reviews: Gastroenterology & Hepatology 11:506-514

[16] Vehik, K et al (2013) Diabetes Metab. Res. Rev. 29(7): 557-567

[17] Vaarala, O. (2013) Rev. Diabet. Stud. (2012) 9:251-259

[18] Brehm, M et al. (2012) Cold Spring Harb. Perspect. Med. 2:a007757

[19] Ito, R et al, (2012) Cellular and Molecular Immunology 9: 208-214 12

[20] Global Alliance for Prebiotics (GAP) http://www.gap-probiotics.org/wp-content/uploads/2013/02/GAP-position-paper-15.02.2013.pdf

[21] GAP: http://www.gap-probiotics.org/

[22] ISAPP: http://www.isapp.net/

Keith Moore

Keith Moore Ph.D. is founder of Moore BioAnalysis, a company supporting the development of emerging life sciences companies and of the continued growth of established institutions, both in the USA and Europe. With 20 years of experience leading and developing discovery biology departments in major international pharmaceutical companies and CROs, Moore BioAnalysis brings a practical and pragmatic approach to advancing client’s ideas with a combination of scientific and business acumen.

Moore BioAnalysis provides a flexible and cost-effective solution to meet the needs of a wide variety of clients. We are currently working with Medbiomarkers to advance the biology, clinical understanding and commercial potential of modulating the host microbiome using rigorous science.