1. Introduction

The gut ecosystem with myriads of microorganisms and the high concentration of immune system cells is considered as a separate organ on its own. Intricate host–microbe symbiotic relationships in the human gut have evolved during the long-term coevolution between the two. It resulted in fine-tuned inter kingdom molecular adaptations that benefit both sides. The microbiome is essential for food digestion, generation of anti-inflammatory substances, drug activation, immune induction, training and function and finally, zooming on the present topic, production of short-chain fatty acids (SCFAs). Being an integral part of our immune makeup, the microbiota mitigates against untoward effects, by establishing a biotic barrier against the hostile environment.

In dysbiotic conditions, however, this balance is compromised and results in abnormal interaction between the host and the microbiota ^[1]. Some members of the gut microbiota have been linked to various autoimmune diseases. Changing a single bacterial species and/or the entire commensal community can alter the outcome of a specific condition due to the imbalance of pathological/protective immune responses. In this regards, a summary of specific microbial species in relation to defined animal models of autoimmune diseases and their functions, in relation to disease progression, was recently published ^[1]. In celiac disease (CD), increased diversity of the following microbial species: Lachnoanaerobaculum, Prevotella, Actinomycetes, Lachnoanaerobaculum umeaense was detected. In human CD, however, genetic factors, antibiotic usage and breast feeding were related to microbiota changes, representing risk factors that might induce dysbiosis ^[2]. Decrease in Bifidobacterium ssp, Bacteroides, Parabacteroides and increases in Candida albicance, Escherichia and Helicobacter were observed. Due to the complexity of the 100 trillion gut microbiota and the additional alteration occurring in CD dysbiome, the eternal question of a hen or an egg is still ongoing ^[3]. If it is the cause, consequence or co-evolution, is still obscure.

Not less important is the transcriptome, proteinome and the metabolome associated with those changes. Those components are the direct messengers between the bugs and us. One of the most characterized metabolic products group is the SCFAs, recently explored in the stools of CD children ^[4]. The authors studied the correlations between selected stool microbiota/dysbiota and the faecal concentrations of SCFAs, in pediatric CD. They found clear changes in the faecal bugs and in SCFAs concentrations and concluded that those changes relate to CD pathogenesis. Furthermore, the pro-inflammatory SCFAs, namely acetic and propionic acids, can potentially represent disease related markers. Interestingly, their bacterial origin was not conclusive and rest debatable. Due to the importance of the above mentioned topics, the new observations on the luminal and systemic function of SCFAs and the continuing efforts for new therapeutic strategies, the present editorial will update and expand on them.

2. The Dysbiotic Origin of SCFA in CD is Debatable

Microbe-generated metabolites are intertwined with the enteral mucosa cell biology and functions, and SCFAs-mediated signaling pathways are essential for gut microbe’s communication with the host. Acetate, propionate, butyrate, and pentanoate, having respectively, 2, 3, 4, and 5 carbon atoms are SCFAs, largely produced by microbial fermentation of complex non-digestible polysaccharides like starches and fibers in the colon. They are absorbed by the colonic epithelium where the preferred fuel source of colonocytes is butyrate. Microbiota-produced SCFAs enter the bloodstream through the portal vein of the host and/or the distal colon. Then, they are distributed to remote organs where they are taken up, metabolized and used in a variety of cellular responses ^[5]. Similarly to the variability in the loss of diversity of the microbiome repertoire in CD, not a lot is known about the origin of the luminal metabolic compounds. It is well established that SCFAs production is heavily related to the diet, but the specific bacterial species rate of SCFAs production is yet, unknown. Several groups observed a metabolic signature in CD lumen and stools of specific and total SCFAs ^{[6, 7, 8]}. Interestingly, as shown by the parallel microbiology and metabolome approach, the long-term gluten-free diet did not completely restore the microbiota and, consequently, the metabolome of CD children ^[7]. This points to a genetic CD predisposition that influences those intestinal events. Despite the suggestion that probiotic bacteria (e.g., Lactobacillus and Bifidobacterium) may modify the metabolism in the large intestine by increasing the synthesis of SCFAs, we are far from “Rebiosis” or the answer to the question: how to restore the microbial diversity and functionality in CD ^[8]?

3. Luminal and Systemic Function of SCFAs

Food intake regulates energy balance, and its dysregulation leads to metabolic disorders such as obesity and/or diabetes. Free fatty acids are not only essential nutrients they can also act as signaling molecules in various cellular processes. Table 1 summarizes the luminal, as well as, the systemic effects attributed to SCFAs. Their functions span numerous biological domains and pathways, attesting to their essentiality, evolutionary conservation and biological importance.

Table 1. Luminal and systemic function of SCFAs

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4. Is SCFA a Potential Therapeutic Target for CD?

Accumulating evidence established the microbiotic and the metabolic signature in CD. Further elucidation of the role and functions of the metabolic products produced by the CD associated dysbiosis, might open a new line of therapeutical strategies. Until today efforts were concentrated on bacterial degradation of gluten in the bakery or in the intestinal lumen ^[16]. Even probiotics didn’t deliver the goods, since once pathogenic dysbiosis sets in, probiotics have not proven to be remedial. Based on the above, one can foresee several new alternatives, based on the synthetic biology ^[17]. “Living pills” are engineered bacteria having the potential to be an effective mean for delivering, enhancing, or themselves acting as therapeutic agents to treat certain diseases, including CD ^[18]. Such a pill, harboring the enzymatic activity with high through output of SCFAs synthesis and delivery, might be beneficial. Ongoing efforts are being made to adapt a variety of commensal microbial species for remodeling the gut ecobiotics in disease-treating indications ^[19]. One can consider it as a science fiction, but, engineered viruses can also selectively destroy pathogenic bacteria ^[20]. In CD we are not at this stage, but scientific visions can always fasten medical solutions.

5. Conclusions

Intestinal lumen microbiotic and metabolic signature is well established in CD. SCFAs are only part of these events, but accumulating data attribute multiple beneficial effects to them. Changes in microbiota and SCFAs production are clearly related to the pathogenesis of CD. However, the origin of the specific CD microbiota that secrete and influence CD initiation or progression is still unknown. Understanding the eco-events that drive CD genesis and the function of the luminal SCFAs might open new horizon for future remedies. The data outlined herein provide encouraging road-map toward new therapeutical strategies to help the gluten intolerant populations.

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