Insights on the Gut Microbiome, Obesity, and NAFLD: Part II
As outlined in DRG’s Microbiome-Based Therapies 101 blog post, there are several strategies to therapeutically modify the gut microbiota including: probiotics, antibiotics, and fecal transplants. Both obesity and NASH are diseases that are hard to treat and have high unmet need. The absence of effective treatment options may open the door for therapies, such has microbiota modulation, that are at the frontier of human biology understanding. On the other hand, there is high safety thresholds for any therapy targeting diseases this prevalent.
The biggest challenge in attempting to using antibiotics is specificity. We do not yet have the technology to target the destruction of only harmful bacteria, while not destroying the diverse bacteria that are essential to normal gut functionality. Futhermore, there is conflicting evidence of which bacterial classes or phylum are associated with disease states and therefore should be targeted.1 Widespread disruption of microbiota carries the risk of overgrowth of opportunistic microbes, causing conditions more acutely harmful than obesity or NASH. Chronic metabolic diseases such as NASH and obesity, could require long term management of microbiota; current antibiotic therapies are not appropriate for chronic treatment.
Fecal transplantation is an approved procedure for the treatment of C. difficile infection. The concept has progressed to clinical trials in metabolic disorders where transplantation of fecal matter from lean individuals to patients with obesity resulted in a reduction in insulin resistance.2 We will need to wait for stronger evidence of long-term improvement to markers of metabolic health (e.g. change in weight after a year) and much larger trials before we can assess the potential of fecal transplant as a treatment of NASH or obesity.
There are plenty of reasons why fecal transplantation isn’t going to have a big impact on the NASH or obesity treatment landscape, let me stick to the main one; without a clear way to monetize the procedure, no company is ever going to fund clinical trials of the size and duration required to establish fecal transplantation as a viable treatment for NASH or obesity. Pharmaceutical products for obesity need Phase III clinical trials with a patient enrolment of several thousand, and lasting over a year; cardiovascular outcomes trials in metabolic disorders regularly exceed 10,000 patients. Unless some remarkable effects are observed in small, early-Phase clinical trials, I’m not convinced any kind of microbiome transplantation therapy will be able to compete on the grounds of evidence.
Probiotics are specific bacterial strains that can be ingested to promote a beneficial effect. The bacterial strains need to be either resistant to degradation by the digestive system or delivered by something that can protect them, for example, a capsule. Randomized clinical trials in this space are still very limited, but if a strain can be identified that acts to repair the ‘leaky gut’ of a NASH patient, or negatively affect energy derived from the diet in individuals with obesity, it could feasibly be a prescriptible intervention. Administering specific strains seems a lot less risky than transplanting a mixture of microbiota that carries the risk of unwanted infections. Oral ingestion of probiotics in the out-patient setting is clearly hugely favourable over an enema, and a lot more viable as a product.
There is a growing understanding of how obesity and NASH are influenced by the microbiome, and sufficient rationale for clinical studies with microbiome-based interventions. Conflicting literature on how the abundance of different bacterial phyla are associated with NASH/obesity/healthy disease states underscores how challenging developing these interventions will be. Before we start envisioning how the treatment of prevalent metabolic disease might be influenced by microbiome modulation, we need sweeping advances in understanding what bugs needs to be targeted, what happens to overall health if they are targeted, and improvements in the selectivity of the interventions in question.
For further insights on the gut microbiome, obesity, and NAFLD from DRG’s Tim Blackstock, please click here.
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- Bashiardes S, et al. Non-alcoholic fatty liver and the gut microbiota. Mol Metab. 2016 Jun 14;5(9):782-94.
- Vrieze A, et al. Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome. Gastroenterology. 2012;143:913–916.