Indolepropionic acid (IPA) is a gut microbiota produced tryptophan metabolite that exhibits beneficial effects on alzheimer’s disease, protect the intestinal barrier, and also is an anti-oxidative and anti-inflammatory metabolite (1)^[1]. The effects of other diet and gut derived metabolites, such as SCFAs and BCAAs have been extensively explored however, the beneficial effect of IPA in metabolic diseases have been a recent addition (2)^[2]. WResearchers have shown previously that serum IPA concentrations were associated with higher dietary fiber intake and in turn protected against the development of T2D (3)^[3]. A higher dietary fiber intake has constantly been shown to protect from lifestyle-related disorders (4)^[4]. IPA is produced exclusively by gut microbiota, however it is quiet likely that these effects are modifiable and might be regulated by genetic variants. IPA has also been shown to as an hepatoprotective metabolite in one of our the previous studies, adding on to a holistic beneficial effect of IPA in humans (5)^[5]. In the pForesent narrative review on IPA and T2D and fatty liver disease, weresearchers will extend ourthe analyses on the available IPA data that weresearchers have published earlier to explore the putative interactions between IPA and well-known genetic variants (TCF7L2, FTO, and PPARG) that were associated with the risk of T2D in DPS study participants.

2. Diet, Gut Microbiota, and IPA

Abundance and diversity of gut microbiota are linked in complex ways to obesity, T2D, NAFLD, metabolic syndrome, inflammatory bowel disease, cardiovascular disease, and neurological disorders (6)^[6]. In addition to endogenous metabolism, it has been shown that certain gut bacteria can synthesize IPA from tryptophan via the indole pathway (7)^[7]. Clostridium (Cl.) sporogenes and Cl. botulinum but also Peptostreptococcus anaerobius and three strains of Cl. calaveris may also synthesize IPA (8)^[8].

The synthesis and conversion of IPA in humans have been summarized in the figure above. IPA via the blood circulation can gain excess to multiple organs either via passive diffusion or with the help of amino acid transporters and can induce multiple beneficial effects.

3. IPA, T2D, & NAFLD

The mechanistic effect of IPA on glucose metabolism has not yet been studied in detail and the studies that have identified IPA and the risk of development of T2D have been combined. in the present review. In this narrative review, we Researchers further explored if T2D-specific genetic variants (TCF7L2 rs7903146 and rs12255372; FTO rs9939609 and PPARG rs1801282) from the same DPS population modified this association. A total of 522 individuals with IGT were originally randomly allocated into either a lifestyle intervention or control group for a mean four-year intervention (active study) period. DI₃₀ is the estimate for beta cell function or peripheral insulin sensitivity, as validated before. Mathematically, DI₃₀ = Matsuda insulin sensitivity index × ratio of total insulin area under the curve (AUC) and total glucose AUC during 0–30 min of the oral glucose tolerance test. After data normalization, analysis of variance models adjusted for study group, age, sex, and BMI were used to study the associations of IPA with long-term follow-up insulin secretion (DI₃₀), fasting, and postprandial glucose or insulin additionally considering the effect of TCF7L2, FTO or PPARG genotypes (categorical variable; dominant model). For testing correlations, wresearchers applied Pearson’s correlation test and the value of p-value < 0.05 was considered significant. In models adjusted for age, sex, BMI, and study group, persons in the lowest third for serum IPA concentration have lower averaged DI during the 7-year FU compared with those in the second and third categories. This association did not change by TCF7L2 variants rs7903146 and rs12255372, which are known to be associated with insulin secretion, which was also the case in the DPS population. Another variant associated with the development of T2D in the DPS, PPARG rs1801282 may be associated with improvements in insulin sensitivity. When this variant was included in the model, the association of IPA with DI₃₀ was not lost. Also, the interaction of variant rs1801282 with IPA was not significant.

We observed a significant trend for the interaction of IPA with

Researchers observed a significant trend for the interaction of IPA with

FTO

variant rs9939609 (

p = 0.05). In individuals with the minor allele A, we found that those in the lowest IPA tertile had lower averaged IPA concentrations as compared with the second (

= 0.05). In individuals with the minor allele A, researchers found that those in the lowest IPA tertile had lower averaged IPA concentrations as compared with the second (

p

-value = 0.003) and third (

p

-value = 0.018) tertiles for DI

₃₀

. 

Gut-liver axis is the passage for metabolites to gain direct access to liver and lead to liver-related diseases (9)^[9]. Existing evidence links gut-derived indole and indole derivatives to liver health and integrity (10)^[10]. IPA and other tryptophan derivatives have also been found to be associated with cardiovascular events, a common co-morbidity in NAFLD, NASH, and T2D (11)^[11]. IPA is well known for its hydroxyl radical and lipid peroxide scavenging activity and has been found to regulate low-grade inflammation and affecting mechanisms linked to liver health and functioning (12)^[12]. In various studies involving obese adolescents and adults, IPA levels have been identified to be altered (13,14)^[13][14]. These results demand future research projects focusing on a deep understanding of the mechanisms of action of IPA specifically in metabolic disorders, yet not forgetting the important role of diet in the prevention of these diseases.

4. Conclusions

WResearchers conclude that the discovery of the connection between the microbiota and gut-derived metabolites, particularly IPA, has opened up new options for T2D prevention and treatment. In addition to providing new therapeutic options, the biological effects of IPA have increased ourthe understanding of the intricate relationship between diet, gut microbiota, and the risk of cardio-metabolic disorders. New information on IPA's beneficial effects on intestinal integrity, neuronal function, oxidative stress, lipid metabolism, glucose metabolism, including insulin secretion, inflammation, liver injury, and cellular damage has already been provided by its numerous interactions with various biological processes. To be more specific, the fact that there is a strong connection between IPA and T2D and NAFLD opens the door to developing strategies for using IPA as potential treatments. These findings call for subsequent research projects that place a strong emphasis on gaining a comprehensive understanding of the mechanisms of action of IPA, particularly in cardio-metabolic disorders, without neglecting the significant role that diet plays in the prevention of these conditions.

References

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