Microbes in the human gut (collectively known as the gut microbiome) provide many functions that are important for human health. A notable example is that some gut bacteria are able to ferment non-digestible carbohydrates in our diet, e.g. dietary fibers, to produce short-chain fatty acids (SCFAs). These SCFAs nourish our gut epithelial cells, reduce inflammation, and play a role in appetite control. Deficiency of SCFAs has been associated with many diseases including type 2 diabetes. Many gut bacteria have the genes (and therefore the capacity) to produce SCFAs from carbohydrate fermentation. However, we know little about how these bacteria, as individual strains and as a group, actually respond to an increased supply of carbohydrates. This is key to improve clinical efficacy of dietary fiber interventions to help treat or prevent type 2 diabetes.
A recently published study in Science investigated the effects of a high fiber intervention on blood glucose and metabolic health in patients with type 2 diabetes. Dr. Liping Zhao and colleagues randomized patients to treatment or control group. The control group received standard patient education and dietary recommendations; the intervention group was provided with a diet similar to the controls, plus a large amount of dietary fibers with diverse structures and properties. Throughout the 12-week treatment, the intervention group experienced more significant and faster improvement in blood glucose control, greater weight loss, and better lipid profile compared to the controls. Importantly, the study showed that these beneficial effects of the high fiber diet were directly contributed by changes in the gut microbiota. Researchers further identified a small group of bacterial strains that were likely to be the key drivers of patients’ clinical improvements: these bacteria all possess the ability to produce SCFAs, and by taking advantage of the increased dietary fibers, they out-competed the others and became dominant members of the gut microbial community. Their activity increased the production of butyrate and acetate (two major beneficial sub-types of SCFAs) that benefited the human host: 1) by promoting the secretion of gut hormones and subsequently increasing insulin production that led to improved blood glucose control; and 2) by maintaining a mildly acidic gut environment which is unfavorable for known detrimental bacteria. Overall, when members of this group of bacteria reached greater abundance and diversity, the patients had lower acetylated hemoglobin levels which indicated better blood glucose regulation.
The identification of this group of bacterial strains selectively promoted by dietary fibers not only make them attractive therapeutic targets, but also implies broader implications for a new nutritional approach to manage type 2 diabetes. In addition to the conventional focus on body weight and carbohydrate counting, this study showed that a dietary program that targets the beneficial gut bacteria is a clinically effective “gut-specific” way to improve insulin secretion and therefore alleviates type 2 diabetes. This work also prompts a new interpretation of the relationship between gut microbiota, human health and diseases – rather than being pathogenic, the gut microbiota may cause diseases due to the loss/deficiency of beneficial function(s). This would then call for a “health-centric” approach that focuses on restoring and/or maintaining a healthy gut microbiota which is able to provide all the beneficial functions that are required to keep its human host healthy.
Q&A
What did you study?
We conducted a randomized, controlled clinical trial in patients with type 2 diabetes (T2D). We randomized patients to join treatment group or control group. Compared to those in control group, patients in treatment group received a very large amount of diversely-structured dietary fibers while the total energy and macronutrients intake remained the same between the two groups. Both group had the same drug acarbose as the medication for blood glucose control.
We investigated whether adding large amount of dietary fibers with diverse physicochemical structures would benefit T2D patients. And we aimed to unveil the chains of causation from infusion of dietary fibers to improved disease endpoints with molecular and genomic tools.
What are your major findings?
1)We conducted two trials: the first is a mechanistic trial (GUT2D), in which participants in the treatment group (n=27) experienced greater HbA1c reduction and achieved a low level of fasting blood glucose within a shorter period of time compared to the control group (n=16). Patients in the treatment group also lost more weight than the control group. By design the only difference between the treatment and control groups was the dietary fiber supplementation in the former, thus we can attribute better clinical outcomes in treatment group to the large amount of diversely-structured dietary fibers added to the diet.
The second is an independent efficacy trial (QIDONG) in which 71 patients finished the three-month trial with WTP dietary intervention. This trial was used to validate the efficacy the high fiber intervention and confirm the findings on the role of the guild of positive responders to high fiber intervention for Type 2 diabetes alleviation.
2) Dietary fibers can be fermented by some gut bacteria as energy source and release short-chain fatty acids (SCFAs) including acetic and butyric acids to benefit human hosts. We expected that this large amount of diversely-structured dietary fibers would alter the composition of the gut microbiota of T2D patients and therefore benefit the human hosts (“gut microbiota” refers to the ecological community of all microorganisms living in one’s gut). To confirm our hypothesis, we transplanted the pre-intervention and post-intervention gut microbiota from the same patient to germ-free mice. We found that baseline microbiotas of patients impaired blood glucose control of the recipient mice while post-intervention microbiotas induced significantly improved metabolic health of the recipient mice.
3) We then performed metagenomic sequencing of fecal DNA from all patients collected monthly over the 12-week trial. We identified nearly 5 million microbial genes. We found 422 bacterial genomes (“genome” refers to the complete set of genes present in a bacterium). After taking the treatment diet for 4 weeks, patients had a new gut microbiota. Keeping the new gut microbiota for another 8 weeks, we observed continued reduction of HbA1c and improvement of other clinical parameters. Dietary fibers induced changes of the gut microbiota preceded the alleviation of clinical parameters of the patients, indicating that dietary fiber-induced changes of the gut microbiota play a causative role in alleviating T2D.
4) Bacteria interact with each other and the human host by way of producing various bioactive compounds. We found slight increase of acetic acid and more significant increase of butyric acid in the stool samples of treatment group patients compared to those in control. Acetic acid and butyric acid are known to promote the secretion of a peptide hormone call glucagon-like peptide-1 (GLP-1) by L-cells in the human gut. This hormone can in turn promote secretion of insulin. We also found decrease of two other bacterial metabolites indole and hydrogen sulfite in the stools of treatment group patients. These two metabolites are known to inhibit GLP-1 production. Indeed, we saw increased GLP-1 and insulin secretion among patients of the treatment group. Such data demonstrated how high fiber induced changes of the gut microbiota promoted production of beneficial metabolites and reduced the production of detrimental ones. This molecular cross-talk between bacterial metabolites and human L-cells is very likely the molecular chain of causation that links dietary fiber intake to eventual improved human metabolic health.
5) To identify the key bacteria that play a critical role in this molecular cross-talk, we assembled high quality draft genomes of 141 gut bacteria which are more commonly found in the T2D patients of this study. These 141 bacteria are all identified as SCFA producers because they all carry genes for SCFA production. However, we found that only 15 strains were promoted by the high fiber diet (positive responders), 47 strains were reduced by the diet (negative responders) and the rest 79 did not show changes in their population (non-responders). All 15 positive responders can produce acetic acid and 5 of them can also produce butyric acid. Genomic analysis showed that these 15 positive responders had more genes for utilizing plant fibers, producing more energy and SCFAs from the same amount of fibers and were more tolerant to an acidified gut environment. In contrast, the 47 negative responders had more genes for utilizing animal carbohydrates derived from mucin in the gut, were less efficient to energy production from dietary fibers and has a lower tolerance to an acidified gut environment. Such genetic differences may have contributed to the promotion of positive responders and diminution of negative responders. Among the reduced negative responders are bacteria that can produce indole and hydrogen sulfite. Thus, only a small fraction of the potential SCFA producers can take advantage of increased dietary fiber intake. Not all the bacteria which are genetically capable of fermenting dietary fibers to produce SCFAS can actually take advantage of greater dietary fiber intake.
6) Gut microbiota is an ecosystem. And it is the ecological interactions that determine which strains can become a winner in the race of survival and play a key role to benefit human hosts. These 15 positive responders can be considered as a “guild” in ecological terms, because “they use the same class of environmental resources in a similar way”. They are a collection of very different bacteria, but they work together to explore the newly available resources. They can also be considered as the “foundation species” for a healthy gut microbiota, acting as the foundation of a healthy gut ecosystem just as tall trees are to a closed forest. When these positive responders grow to a high abundance level, they acidify the gut, produce inhibitory compounds and exert more competitive exclusion effect to other competitive bacteria. Restoration of such a group of SCFA producers not only replenish the deficient SCFAs that we need but also maintain a healthy gut ecosystem by creating a gut environment that keeps other pathogenic and detrimental bacteria at bay.
7) When we constructed an Active SCFA Producer Index (ASP-Index) based on total abundance and diversity of these 15 positive responders, we found that this index at baseline and end of the trial were negatively correlated with the primary disease outcome HbA1c at baseline and end of the trial. Such a statistical model was validated with data from a larger independent clinical trial with a similar diet. Interestingly, the ASP-Index reached a plateau after 4 weeks and remained unchanged during the rest of the trial. When we used baseline and one month after ASP-Indexes to correlate with baseline and three-month after HbA1c, we found similar negative correlation. This is an indication that we could predict clinical outcome of the 12-week trial based on what happened in the gut microbiota in the first month.
Why does it matter, and what are the practical implications?
1) This study provides compelling evidence supporting increased intake of dietary fibers may benefit T2D patients.
2) When you are on a new high fiber diet, sequencing your gut microbiome in the first few weeks may help you adjust the diet in a way that best fit the genetic potential of your gut microbiome for utilizing the dietary fibers. This is a new form of personalized diet for T2D patients.
3) If you have lost most or all the members of the guild of positive responders (guild of the foundation species), you may need a microbiota transplantation from a healthy donor whose microbiota profile best benefit you by providing those members missing in your gut. You can then start a personalized dietary intervention to help you recover and maintain your health.
What is the next big question for research?
If we help a patient establish a new gut microbiota with the best possible profile of such guild of positive responders, how much of his/her health can be restored if they keep the new microbiota for long-term? In other words, can we reverse T2D by restoring and keeping a healthy gut microbiota with this group of SCFA producers as targets?
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This research was originally published on ScienceMag.