Introduction
Small intestinal bacterial overgrowth (SIBO) is a gastrointestinal condition where there is an excess of bacteria in the small intestine. It is not easy to diagnose and therefore tends to go underdiagnosed. It is estimated that between 10 and 15% of the population has SIBO in developing countries and this number increases for certain populations and with specific diseases such as diabetes and IBS (Roszkowska et al., 2024). Symptoms of SIBO are largely nonspecific, but generally include diarrhea or constipation, belching, bloating and abdominal pain. One of the most common risk factors for SIBO is intestinal dysmotility (Rao & Bhagatwala, 2019).
One condition that seems to have an intimate connection to SIBO is diabetes (Rao & Bhagatwala, 2019). In 2021, 11.6% of the U.S. population had diabetes and 38% of the U.S. population had prediabetes (Center for Disease Control, 2024). This accounts for almost 50% of the population. Currently, 48% of people over the age of 65 are diabetic (Center for Disease Control, 2024) and there is expected to be a 700% increase in type 2 diabetes in young people by 2060 (Center for Disease Control, 2022). Diabetes diagnosis rates are rapidly increasing, with no foreseeable decline. Parcha et al. (2022) conducted a cross-sectional survey of data from 2007-2010 and discovered that 4 out of 10 young individuals had insulin resistance. Furthermore, the gut microbiota is known to play a significant role in insulin sensitivity and insulin resistance (Semo et al., 2024). Given this, there is a unique microbial relationship between SIBO and diabetes.
There are numerous dietary and supplement interventions for managing both SIBO and diabetes. These interventions can also significantly influence the levels of Akkermansia muciniphila (A. muciniphila), which itself plays a crucial role in the intersection of SIBO and diabetes. In the human intestinal microbiota, A. muciniphila is one of the most abundant single species ranging from .5 to 5% (Jian, 2023). Depending on the intervention, the impact on A. muciniphila can be either highly beneficial or detrimental. The purpose of this review is to investigate the bi-directional connection between SIBO and diabetes and to discuss the potential role of adequate commensal A. muciniphila as an adjunct intervention for those patients with both.
Review and Discussion
It is important to set the stage with the introduction of A. muciniphila with some general information as to how it fits into this unique setting. A. muciniphila is found in about 80% of the population and is an anaerobic bacterium found in the gastrointestinal tract. It is known to significantly affect the intestinal mucosal lining and barrier (Augustyn et al., 2019), it has been shown to positively affect insulin resistance and inflammation, and it assists with metabolism regulation (Si et al., 2022). Metabolism regulation comes from the fact that it has been shown to reduce gut permeability (Si et al., 2022). Lastly, concentrations of A. muciniphila are inversely correlated with conditions such as obesity and diabetes (Tilg & Moschen, 2014) as well as oxidative stress (Mruk-Mazurkiewicz et al., 2024). It is important to note that some of the risk factors for both diabetes and SIBO are fueled by oxidative stress and inflammation, which can lead to dysmotility (Malik et al., 2018). It is also important to first understand the bi-directional association between SIBO and diabetes in order to understand how A. muciniphila could potentially play a role in positively assisting both these conditions.
One thing to note is the difference between commensal A. muciniphila and the probiotic A. muciniphila. While supplementing with A. muciniphila can provide the transient benefit of the probiotic, it may not necessarily affect the commensal population. Han et al. (2021) note that probiotics encounter resistance from commensal bacteria as the probiotics work their way through the gut after oral administration. While the benefits of probiotics are numerous, they often are met with such colonization resistance and are excreted out in feces. Colonization resistance is an important function of the microbial community to resist foreign invaders. Regardless of the approach to either supplement, increase native A. muciniphila, or both, it is important to understand the current population of A. muciniphila to not increase it (or decrease it) to the point where negative effects begin.
Diabetes and Risk for SIBO
Feng and Li (2022) set out to investigate the prevalence of SIBO among diabetic patients by conducting a systematic review of existing literature. Fourteen studies met the inclusion criteria for consideration. Among these, nine were cohort studies and five were cross-sectional studies, no further specificity was made about the types of studies. Upon completion of all analyses, they concluded that the prevalence of SIBO in diabetic patients was 29% (95% CI 20-39%). Additionally, the risk of developing SIBO in diabetics was found to be 2.91-fold higher (no statistics given). Notably, no significant difference was observed between type 1 and type 2 diabetics. The discussed mechanisms of action were decreased motility due to autonomic neuropathy (common in diabetics occurring throughout the whole intestinal tract resulting in hypomobility) as well as through inflammatory cytokines and oxidative stress. A flipside association was also noted in that SIBO-positive patients also were shown to have decreased insulin production potentially due to the activation of inflammatory pathways. The conclusion drawn from this study is that diabetes may increase risk for the development of SIBO.
Type 2 Diabetes
While SIBO has been associated with type 2 diabetes in general, Yan et al. (2020) note that the particular association with beta cell function had not been studied. They conducted a retrospective observational study on 104 type 2 diabetic patients. SIBO breath tests and glucose tolerance tests were performed, and the participants were separated into the study group (SIBO-positive) and the control group (SIBO-negative). Glucose and insulin were measured at the 0, 30, 60, 120 and 180 marks. There was no statistical significance in glucose except at the 120-minute mark. SIBO-positive patients had statistically significant higher 120-minute mark blood glucose, higher HbA1c, higher insulin resistance and lower insulin at every measurement point. What they also determined was that SIBO-positive, 0-minute glucose, and BMI had a strong correlation with insulin secretion early in the cycle as well as total insulin secretion. Two things of particular interest from previous studies were that the serum endotoxin levels in SIBO-positive patients was higher and that insulin secretion was reduced due to activation of inflammatory pathways. This led the authors to deduce the possible association between increased inflammation and decreased insulin production in the SIBO-positive patients, but that further studies were needed to determine the exact mechanisms. Type 1 diabetics were excluded from this study.
Malik et al. (2020) conducted an observational study involving 300 patients with type 2 diabetes and 200 controls, aiming to examine inflammatory and oxidative stress markers and compare these markers between SIBO-positive and SIBO-negative participants. SIBO breath tests were administered and 5 ml of blood was collected for analysis. Several observations were made. First, the incidence of SIBO in patients with type 2 diabetes (14.4%) was significantly higher than in the SIBO-negative control group (0.5%). They also presented with delayed gut motility. Additionally, inflammatory markers (specifically IL-6, TNF-alpha and IL-10) were significantly elevated in this subset of patients (P <= .05). Oxidative stress was significantly higher in the SIBO-positive group as shown by lipid peroxidation, catalase and superoxide dismutase. The study concluded that oxidative stress and inflammation is at risk of being higher in type 2 diabetic patients due to SIBO.
Yan et al. (2020) and Malik et al. (2020) both discuss inflammation. What has been shown is a bi-directional association between inflammation caused by both SIBO and diabetes and its relationship to the development of the other condition.
Type 1 Diabetes
Adamska et al. (2016) conducted a study to determine the prevalence of SIBO among type 1 diabetes patients. The study included 148 type 1 diabetic patients and a control group of 41 healthy volunteers. Study participants fasted for 8 hours and then drank 20g of lactulose in 200ml of water. Following this was a hydrogen breath test where SIBO was diagnosed if the fasting levels were 20 ppm or higher or if a peak of 12 ppm occurred within 60 minutes. The findings revealed a lower incidence of SIBO in type 1 diabetic patients compared to the control group. Specifically, 37.8% of the study group had SIBO, while 73% of the healthy volunteers were found to have SIBO (P = 0.006). A noted limitation of the study was the lack of nutritional information collected from the participants. However, the authors mentioned that such data can be subjective in their opinion and may not necessarily constitute a significant limitation. They acknowledge the potential role of nutrition as to why the diabetic group was lower in SIBO occurrence, but do not have data to support this yet.
Malik et al. (2018) set out to study the interconnectedness of SIBO, gut motility, oxidative stress and inflammation in type 1 diabetics. This was a separate group of participants than in the previously discussed study by Malik et al. (2020). They had 75 type 1 diabetics in the study group and 75 healthy volunteers for the control group. Orocecal transit time, SIBO, pro-inflammatory and anti-inflammatory cytokines, and antioxidant defense status were all measured. Oxidative stress (LPO) and inflammatory cytokines (IL-6 and IL-10) were much higher in the study group. LPO (measured in mmol/min/g Hb) was 5.01 in the study group and 3.97 in the control group. Inflammatory cytokines were measured in pg/mL. IL-6 was 10.04 in the study group and 6.3 in the control group, TNF-alpha was 24.2 in the study group and 11.3 in the control group, and IL-10 was 33.4 in the study group and 7.6 in the control group. There was a significant delay in orocecal transit time in the study group and SIBO occurrence was also significantly higher in the study group. Finally, the orocecal transit time was even more delayed in the SIBO-positive patients in the study group as compared to the SIBO-negative patients. It was interesting to note that in the SIBO-positive subgroup, uncontrolled HbA1c was noted in 64% of them versus only 20% in the SIBO-negative subgroup. The conclusion of the study is that there is an association between oxidative stress, inflammation, orocecal transit time and SIBO in type 1 diabetic patients.
The findings of Malik et al. (2018) and Adamska et al. (2016) seem to contradict one another which supports the need for further investigation. One notable difference is that Malik et al. (2018) used a glucose medium whereas Adamska et al. (2016) used lactulose. Glucose is considered more specific and lactulose tends to have a second peak when it reaches the colon. Additionally, lactose can have a higher false positive than glucose because of the fact that it is not directly absorbed by the small intestines (Tansel & Levinthal, 2023). Malik et al. (2018) performed a much more in-depth study as well.
Akkermansia Muciniphila and the Role of Diet
Common SIBO diets include the low FODMaP diet, Bi-Phasic diet, Specific Carbohydrate Diet, Paleo diet and Keto diet (Lapine, 2021). FODMaP stands for fermentable oligosaccharides, disaccharides, monosaccharides, and polyols. These diets are also inherently lower carbohydrate diets, some more than others. The low-carb diet itself is a popular eating pattern for diabetics according to the American Diabetes Association (n.d.). Given the popularity of these low carb interventions, it is important to note that many low carbohydrate diets are traditionally higher in fat (Oh et al., 2023). Mruk-Mazurkiewicz et al. (2024) studied mice on a high fat diet for 16 weeks. He showed this way of eating increased inflammation, induced hyperinsulinemia, induced hypoglycemia and decreased A. muciniphila. In a contrasting study, Tilg and Moschen (2014) report A. muciniphila concentrations in rats on a high fat diet which reduce butyrate, were higher than in the control (and hence increased inflammation), suggesting potentially conflicting information. It is therefore important to consider the balance of carbohydrates with fat in these lower carbohydrate diets.
Since fiber is a carbohydrate, lower carbohydrate diets can also mean lower fiber content or (minimally) more restricted fiber options, both of which can affect the commensal population and concentration of A. muciniphila. Yue et al. (2022) explain that when there is minimal dietary fiber in a diet, A. muciniphila increases thus resulting in destruction of the mucin layer. They also note that dietary supplementation can also increase A. muciniphila. While this might seem contradictory, they explain that this is most likely due to a cross-feeding between butyrate-producing bacteria and A. muciniphila. Therefore, promoting short chain fatty acid production in the colon by adding dietary fiber can result in more mucin being produced and more food for A. muciniphila.
When looking at the FODMaP diet, its effectiveness at alleviating SIBO symptoms stems from the fact that it limits fermentable carbohydrates. They are resistant to digestion and are a popular food for gut microbes, especially those that produce methane and hydrogen. While not a treatment option, this diet can help alleviate symptoms. However, the low FODMap diet is also known to drastically reduce A. muciniphila (Zhou, 2017). In fact, including oligofructose in one’s diet restored levels of A. muciniphila and, therefore, metabolic function (Tilg & Moschen, 2014). More generally, FODMaPs, resistant starch and polyphenols can increase the abundance of A. muciniphila (Mruk-Mazurkiewicz et al., 2024).
Putting it All Together
While it would appear to be a bi-directional relationship between SIBO and diabetes, the focus is generally on SIBO prevalence in diabetics. As can be seen, this is often due to things like inflammation, higher blood glucose, higher insulin and oxidative stress. As discussed, A. muciniphila is inversely associated with diabetes (Tilg & Moschen, 2014) and oxidative stress (Mruk-Mazurkiewicz et al., 2024), both of which can cause dysmotility (Malik et al., 2018). Dysmotility, along with inflammation, are risk factors for SIBO (Achufusi et al., 2020). One pathway for inflammation is through increased gut permeability (Das & Ganesh, 2023). A. muciniphila has been shown to decrease pro-inflammatory factors, increase anti-inflammatory factors and increase tight junctions, thereby decreasing gut permeability (Li et al., 2023).
Supplementing A. muciniphila was shown to not only restore mucus thickness in the intestinal lining, but also a reduction in serum lipopolysaccharides (LPS) (Zhou, 2017). LPS are produced by gram-negative bacteria and are known to trigger chronic inflammation (Candelli et al., 2021). Attempts at modifying existing numbers of A. muciniphila, however, should be evaluated on a case-by-case basis. This is because while A. muciniphila has been shown to positively affect conditions such as diabetes, an overabundance has been seen in cases of Parkinson’s disease and multiple sclerosis (Chiantera et al., 2023). There are many things that can naturally increase A. muciniphila, namely, some flavonoids, polyphenols, saccharides and Traditional Chinese Medicine (Li et al., 2023). What is interesting to note is that Metformin, a common treatment for type 2 diabetes, increases A. muciniphila as well (Zhou, 2017). The exact mechanism is not readily discussed in literature and warrants more detailed study. While not a treatment option on its own, A. muciniphila shows promise in addressing some of the overlapping stress and dysfunction.
Conclusion
The intricate connection between SIBO and diabetes underscores the significant role of gut microbiota, particularly A. muciniphila, in managing and considering these conditions. The inverse relationship between A. muciniphila levels and conditions such as obesity, diabetes, and oxidative stress highlights its potential as a therapeutic interest. The literature reviewed demonstrates that A. muciniphila can positively influence insulin resistance, inflammation, and gut permeability, all of which are critical factors in both SIBO and diabetes.
Furthermore, the bidirectional relationship between SIBO and diabetes emphasizes the need for a holistic approach to treatment. Managing oxidative stress and inflammation is crucial, as these factors not only contribute to the development of both conditions but also exacerbate their symptoms. The role of A. muciniphila in reducing inflammation and improving gut health presents a promising avenue for future research and interventions. While dietary interventions and A. muciniphila considerations show potential, individual patient assessments are necessary.
Recommendation
It is recommended that more detailed studies be conducted, tailored to motility, oxidative stress, inflammation and the role of A. muciniphila in patients presenting with both SIBO and diabetes. These future studies should also investigate whether A. muciniphila intervention or manipulation could decrease the cases of SIBO in diabetes as well as the cases of diabetes in SIBO patients. There are unique attributes to both but also a lot of overlap and consideration to be able to effectively manage both.
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