INTRODUCTION:

Inflammatory bowel disease (IBD) is a chronic digestive inflammation that consists of ulcerative colitis (UC) and Crohn's disease (CD), which are different in pathophysiology and clinical characteristics. Risk factor for IBD include environmental pollutants, low fiber-high fat diet, low vitamin D level, non-steroidal anti-inflammatory drugs (NSAID), smoking, and genetics.¹ Millions of people in the world suffers from this disease, but the western and industrialized population are most commonly affected.²

The prevalence of IBD in Asia and Middle Eastern Asia is approximately 6.3 per 100.000 people per year for UC and 5.0 per 100.000 people per year for CD.³ IBD prevalence is estimated to be varied in Indonesia due to the difference in diagnostic tools used. According to the Endoscopy Unit from several hospital databases in Jakarta, Indonesia, the IBD-like case occurred in 12.2% of chronic diarrhea cases, 3.9% of hematochezia cases, and 25.9% of chronic diarrhea with blood and stomach pain.⁴Data also showed that the case of UC tends to be higher than CD.⁴

IBD is commonly linked to the deterioration of metabolism and concentration of short-chain fatty acid (SCFA). SCFA is a group of chemical substances resulting from bacterial fermentation that has important roles in maintaining intestinal homeostasis. In intestinal epithelial cells, SCFA acts as the energy source. The molecule is also linked to microorganisms and the immune system by activating G-coupled protein on receptor FFAR2, FFAR3, GPR109a, and Olfr78 modulate enzymatic activities and other factors, such as histone acetyltransferase, histone deacetylase, and hypoxia-inducible factor (HIF).⁵

Among SCFA derivatives, acetic acid, propionic acid, and butyric acid are the most discussed. Butyrate is known as an energy source for colonocytes.⁵ Butyrate is a crucial metabolic signal digestive tract due to its effect on epithelial barrier tightness. It makes this compound potential for the treatment of IBD.⁶To date, the exact pathogenesis of IBD is still being researched. A previous study that linked IBD with n-butyric acid concentration showed sensitivity disruption of the inhibition mechanism modulated by n-butyrate. Higher n-butyrate was needed for giving a similar inhibition effect like in normal people.⁷

Furthermore, IBD is also characterized by gastrointestinal dysbiosis. Research showed decreased amounts of butyrate-producing bacteria, especially Faecalibacterium prausnitzii, both in UC and CD. This phenomenon led to decreased SCFA concentration in feces, intake, and butyrate oxidation.⁸ The hypothesis related to the microorganism in SCFA concentration is that the microorganism species increases SCFA production, thus modulating cytokines production in intestinal mucosa.⁹ It leads to a clinical correlation between butyrate-producing bacteria, UC, and CD. Therefore, this systematic review aimed to evaluate the role of SCFA in any outcomes of IBD.

MATERIAL AND METHODS:

Search strategy:

This systematic review was carried out according to Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) and based on the Cochrane Handbook for Systematic Reviews of Interventions.¹⁰^,¹¹ The computerized searching process was done in several databases such as CENTRAL, Scopus, and PubMed in the past ten years for relevant terms related to IBD and SCFA. We retrieved relevant study to June 2020 using the keywords: "Short-chain fatty acid”, "SCFA", and "inflammatory bowel disease" by MeSH terms. Boolean operators (AND, OR, NOT) were applied to broaden and narrow the search result. The search was limited to human subjects, and the language was restricted to English and Bahasa Indonesia as the only readable language by the reviewers.

Eligibility criteria:

Furthermore, our study inclusion criteria were: i) observational study or clinical trial, ii) investigating SCFA, and iii) evaluating IBD cases, CD and/or PC. In addition, the exclusion criteria defined included: i) irrelevant topics, ii) no complete text, iii) non-human study subjects, iv) incompatible language, v) not having control or comparison variables, and vi) studies more than 10 years

Data extraction and risk of bias Assessment:

Two investigators (DN and NA) conducted a literature search and data extraction independently from eligible studies, including: author and year of publication, study design and setting, sample size, mean or age range of samples, statistical analysis method used, outcomes measured, and the p-value for each factor (p<0.05 is considered as significant). Then, the quality assessment of the eligible studies was carried out using the Newcastle-Ottawa Scale (NOS) to minimize the risk of bias.¹² Any disagreement between investigators was adjudicated by a third investigator (V).

RESULTS:

Study selection:

Figure 1 showed the selection process of this study and how the selection process was conducted. We initially obtained 320 relevant titles and abstracts encompassing 47 studies from CENTRAL, 120 studies from Scopus, and 153 studies from PubMed. Among them, 35 studies were duplicated, and 225 studies were excluded after title and abstract screening. Furthermore, 55 full-text studies were further assessed based on the exclusion criteria. Finally, 5 studies were included and analyzed for qualitative synthesis. The quality assessment of all studies using the NOS scale showed a low risk of bias.

Figure 1: Flowchart diagram of literature search strategy

Study characteristics:

As shown in table 1, the designs of all included study were case-control and conducted in various locations in the world, mostly in developed countries. A pooled of 484 patients with 287 cases and 197 controls were included in our systematic review. In detail, there were 160 UC patients and 127 CD patients extracted from five studies. Among them, three studies observed a decrease in the number of major SCFA producing bacteria, while two studies demonstrated a reduction in SCFA derivatives concentration, both in UC or CD. In addition, one study reported that the SCFA oxidation rate in IBD patients was diminished. All observed outcomes were statistically significant (p<0.05).

SCFA Derivatives Concentration on IBD:

The change of SCFA concentration was associated with disease progressivity. A study conducted by Kumari et al. with gas chromatography resulted in decreased butyric acid (p = 0.003), iso-butyric acid (p = 0.044), and acetic acid (p = 0.047) concentration significantly in severe UC compared to control, while the decrease was not significant in moderate UC.¹³

Fecal samples of CD counted using high-performance liquid chromatography showed no significant change in SCFA derivatives concentration between CD and control.¹⁴ Different results showed by Bjerrum et al. (2014) where butyric acid decreased significantly in UC and CD, especially in the active phase (p<0.05).¹⁵ This difference happened due to different collecting methods and measuring instruments used. Decrease of butyric acid production in inflammatory bowel disease disrupts mitochondrial function, resulting in increased reactive oxygen species, epithelial permeability, and commensal microbes translocation.¹⁶

Significant increase of n-butyric acid concentration was seen in remission phase (p = 0.05).¹³^,¹⁵ This increase was associated with the improvement of butyric acid-producing microorganism composition with the genetic product¹⁷and decreased inflammation effect to butyric acid metabolism.¹⁸

Table 1: Study Characteristics

Location	Sample Size and Age			Result	*P value*	Reference	NOS score
	Control (Age Mean and SD)	UC (Age Mean and SD)	CD (Age Mean and SD)
SCFA derivatives concentration
New Delhi, India	14 (35 + 14.14)	26 (38.35 + 11.49)	-	Butyrate concentration significantly decreases in severe UC stool than control	0.003	Kumari et al., 2013	8/9
				Iso-butyrate concentration significantly decreases in severe UC stool than control	0.044
				Acetate concentration significantly decreases in severe UC stool than control	0.047
Spain	62 (53.6)	45 (38.2)	30 (43.5)	No significant differences of SCFA in stool	0.05	Ferrer-Pićon et al., 2020	8/9
SCFA metabolism alteration
Cork, Ireland	75 (41.2 + 16.2)	58 (48.9 + 12)	71 (44.3 + 12.3)	BCoAT gene reduction in CD	<0.001	Laserna-Mendieta et al., 2018	9/9
Belgium	25 (47)	26 (36)	-	Decrease of butyrate oxidation velocity rate in UC compared with control	<0.0001	De Preter et al., 2011	6/9
				Butyrate oxidation rate is inversely proportional with disease activity	<0.0001
Spain	62 (53.6)	45 (38.2)	30 (43.5)	Decrease of BCoAT gene level in active CD stool compared with control	<0.05	Ferrer-Pićon et al., 2020	8/9
				Increase of GPR43 mRNA and intestinal epithelial cell protein expression in inflammation	<0.001
				Decrease of SLC16A1 and ABCG2 gene expression in the presence of TNF-α	<0.05
Microorganism composition alteration
Cork, Ireland	75 (41.2 + 16.2)	58 (48.9 + 12)	71 (44.3 + 12.3)	Intra-individual microbial diversity reduction in CD and UC	<0.001	Laserna-Mendieta et al., 2018	9/9
				Inter-individual microbial composition change in CD and UC	<0.001
				Reduction of 3 butyrogenic taxa in CD with BCoAT gene level <9.5	<0.001
New Delhi, India	14 (35 + 14.14)	26 (38.35 + 11.49)	-	Decrease of C. coccoides, C. leptum, and F. prausnitzii in severe UC	0.0001	Kumari et al., 2013	8/9
				C. coccoides reduction in moderate UC	0.0021
				C. leptum reduction on moderate UC compared with control	0.0032
Wuhan, China	21 (no data)	11 (no data)	20 (no data)	C. coccoides reduction in active CD stool	0.004	Wang et al., 2013	7/9
				C. coccoides reduction in active CD intestinal mucosa biopsy	<0.0001
				C. coccoides reduction in active UC stool	0.015
				F. prausnitzii reduction in active CD stool	<0.0001
				F. prausnitzii reduction in active UC stool	0.0001
				C. leptum reduction in active CD and UC intestinal mucosa biopsy	<0.0001

BCoAT, butyril-CoA:acetate CoA-transferase; CD, Crohn’s disease; NOS, Newcastle-Ottawa Scale; PCR, polymerase chain reaction; SD, standard deviation; UC, ulcerative colitis

SCFA Metabolism Change in IBD:

SCFA metabolism is influenced by various factors, including levels of the Butyryl-CoA: acetate CoA-transferase (BCoAT) gene, transport and receptor genes, inflammatory mediators, and the rate of butyrate oxidation. The level of butyrate in feces is still considered inaccurate in providing information about the capacity of butyrate production by the intestinal microbiota. An approach is suggested to perform this calculation using the BcoAT level by using acetate as the cosubstrate.¹⁹ BcoAT gene expression in fecal samples can be used as an indicator of the microbiota's capacity to produce butyrate.¹⁴^,¹⁶^,²⁰

Bacteria often carry different CoA-transferases in their genomes with Intestinimonas AF211 encoding at least 14 enzymes.²¹ So it is actually still difficult to pinpoint a single gene that plays a role in the formation of short-chain fatty acids.²² However, gene expression on Intestinimonas AF211 suggests that the enzyme AtoD-A, which is responsible for BcoAT activity, is the one that plays the key role in the conversion of lysine to butyrate, while the BcoAT gene product acts in the final pathway for butyrate formation from glucose.²¹

The use of fecal butyrate concentration also depends on several factors. The first factor is severely affected by the patient's consumption of butyrate. Second, physiological processes in the gut, such as binding, degradation, and absorption. This interferes with reliable estimates when analysis is carried out by fecal specimens. Other factors, such as the use of various techniques also influence the result.²⁰

The levels of BcoAT on CD were significantly lower than controls (p <0.001) and UC (p <0.05). It had no correlation with age, sex, and time after diagnosis.²⁰ A different study also found a significant decrease in BCoAT gene levels on active CD (p <0.05) compared to controls.¹⁴ In addition, fecal samples of patients with ileal inflammation sites had significantly lower levels of the BCoAT gene (p <0.01) than colonic inflammation. Univariate analysis showed an association with lower levels of BCoAT and CD genes, but not UC.²⁰ BCoAT gene levels also increased significantly in the CD remission phase (p <0.01) compared to the active phase.¹⁴ The more significant reduction in BcoAT on CD, most probably due to the dietary differences between patients with CD and controls. Patients with CD in recent times seem to consume foods that are low in fiber.²⁰ Associated with calprotectin as a marker of inflammation in that study, the levels of the BCoAT gene did not change in stool samples of control and UC with high calprotectin, but increased insignificantly on CD with BCoAT gene levels <9.5 log10 copies/gram.²⁰ This appears to be related to mucosal inflammation in patients with IBD to interfere with epithelial butyrate metabolism and transport. Some of the expression of the butyrate transporter such as SLC16A1 and ABCG2, together with the ACADS enzyme, is simultaneously decreased in both patients with active UC and CD.¹⁴^,²³

The inflammatory state in IBD is characterized by an increase of TNF-ɑ concentration in response of cytokines produced by immune system.² The presence of TNF-α was also found to decrease the ability to intake and metabolize butyrate by the intestinal epithelium. TNF-α is known to have a role against butyrate.¹⁴^,²⁴ Organoids from noninflammatory IBD patients respond to butyrate similarly to healthy people.¹⁴^,²⁵ Epithelial culture in patients with inflammation, particularly in the presence of TNF-ɑ, shows the impact of TNF-ɑ on butyrate uptake and oxidation. TNF-ɑ appears to be responsible for down-regulation of the butyrate transporter in the human intestinal epithelium leading to a decrease in butyrate consumption.¹⁴^,²⁵

The decreased rate of butyrate oxidation is associated with endoscopic and histologic disease activity on colon biopsy.²⁶^,²⁷ On endoscopic examination, the butyrate oxidation rate was decreased significantly in moderate (p = 0.042) and severe (p <0.001) UC compared to controls. Histologically, the butyrate oxidation rate decreased significantly at moderate (p = 0.032) and severe (p = 0.012) UC. There was also a negative correlation between the rate of butyrate oxidation and disease activity both endoscopically and histologically (p <0.001) and a positive correlation between endoscopic and histological disease activity (p <0.001).²⁶ Kinetic analysis using the Lineweaver-Burk chart showed a significant decrease in butyrate oxidation Vmax in severe UC (p = 0.042) compared to controls, whereas changes in Kmax were not significant.²⁶

Intestinal Microorganism Composition Change in IBD:

Bacterial counts in bowel biopsy samples tended to be consistent regardless of biopsy location but were reported to be lower on CD and UC than controls, but not significantly.²⁸ In line with these studies, the Laserna-Mendieta et al. study (2018) showed that CD and UC patients had significantly lower intra-individual microbiota diversity than controls (p <0.001).²⁰ The proportion of microbiota in the Clostridium coccoides group in fecal specimens was reported to be significantly reduced in active CD patients (p = 0.004) and active UC patients (p = 0.015).²⁸ Similar results were also found in fecal specimens of moderate (p = 0.0021) and severe (p = 0.0001) UC patients.¹³ This study is in line with Mottawea et al. that reported a decrease in firmicutes, including C. coccoides, the most common sign that is often found in IBD, especially CD.¹⁶

Furthermore, Clostridium leptum was reported to be decreased on both CD and UC. The study results showed that C. leptum decreased significantly at moderate (p = 0.0032) and severe (p = 0.0001) UC.¹³ The proportion of C. leptum was decreased in the stool sample of active UC, and lower in active CD.²⁸ Faecalibacterium prausnitzii, belonging to the C. leptum group, was also found to be significantly reduced in severe UC (p = 0.0001) and CD (p<0.001) with low BCoAT gene levels compared to controls.¹³^,²⁰ From these data, it can be seen that the decrease in the number of C. leptum, especially F. prausnitzii, is not specific for one disease. However, it can be interpreted that there is a decrease in butyrate production capacity as an anti-inflammatory and protective effect.²⁹

Roseburia genus were decreased in CD (p<0.001) and UC (p<0.05) with low BCoAT gene levels compared to controls.²⁰ This is supported by the study of Kumari et al. (2013) that showed a decrease in R. intestinalis in severe UC (p = 0.02) compared to controls.¹³ Previous studies found that a decrease in Roseburia sp. is associated with lower levels of short-chain fatty acids, particularly butyrate, and this is also associated with lower levels of the patient's fiber diet.³⁰ Eubacterium hallii was also decreased on CD with low levels of the BCoAT gene (p <0.001)²⁰, while there was no significant decline in these species at UC.¹³

Wang et al. (2013) also studied Bifidobacterium, Lactobacillus, and Escherichia coli. Bifidobacterium was significantly higher in active UC biopsy samples compared to active CD where it was found to be higher in biopsy samples than in feces (p = 0.032). Lactobacillus was increased significantly in active CD biopsy samples (p = 0.036) while E. coli was increased significantly in active CD stool samples (p = 0.005) and were higher in active UC (p = 0.026).²⁸ A preclinical animal study reported that Bifidobacterium could prevent intestinal inflammation by inducing Tr1 cells that secrete interleukin-10 resolving inflammation.³¹ Lactobacillus can secrete lactocepin, an anti-inflammatory substance, which selectively degrades pro-inflammatory cytokines.³² In addition, Lactobacillus strains also produce SCFA derivatives mainly acetic acid and 13 strains had been identified prospective for oral intestinal probiotic.³³

This systematic review shows that IBD causes a decrease in SCFA producing bacteria, especially butyrate-producing bacteria. The main groups of butyrate producing bacteria include C. leptum, C. coccoiddes, Roseburia sp., and F. prausnitzii were found to be decreased on both CD and UC.²⁰ This decrease has an inverse relationship with disease severity.

DISCUSSION AND FUTURE PERSPECTIVE:

The development of information about SCFAs suggests potential treatment for IBD. Decreased in SCFAs concentration in patient with IBD suggest the use of SCFAs for IBD improvement. A study shows that SCFAs can inhibit inflammation and maintain epithelium barrier integrity in the TNBS-induced colitis model.³⁴Moreover, anti-inflammatory properties of butyrate acts by inhibit the activation of NF-kB transcription factor.³⁵ Butyrate enemas have been proven to improve the recovery of tissue integrity in a randomized trial.³⁶

The reduction in BcoAT due to the low fiber diet also promotes diet modification as a complementary therapy for individuals suffering gastrointestinal disruption associated with IBD. Fiber-rich diet may provide beneficial physiologic effects to improve health-related quality of life in patients with IBD.³⁷ There has also been an increasing focus on the interaction between fecal microbiota use for the treatment of patients with IBD. Many studies suggest that supplementation of butyrate-producing bacteria can restore gut homeostasis and maintain the health of IBD patients.³⁸ This also supports a study reported by Geirnaert et al. that the supplementation can increase the butyrate concentration in CD patients.³⁹ Beside of intestinal health, oral probiotic Lactobacillus also reduces oral Streptococcus mutans, thus decrease dental caries risk.⁴⁰ Another promising probiotic microbiota is yeast, mainly Saccharomycopsis fibuligera that ferment various types of carbohydrate and has high catalase activity for reducing oxidative stress.⁴¹ The use of probiotics in combination with anti-inflammatory agents was found to be a potential novel treatment for left-side colitis.⁴² Probiotic supplementation plays a key role in in the prevention and treatment of gastrointestinal disorders, especially IBD since it has capacity to produce anti-inflammatory properties and help modulate the host’s immune response.⁴³ In addition, a previous study mentioned that the use of prebiotics, a fermentable ingredient from food intake, could also help to reduce the need of steroid and surgical intervention.³⁵ Nevertheless, in the IBD treatment, it is necessary to consider suitable delivery of the drug to the colon region.⁴⁴ The ideal drug delivery should be capable of releasing drugs localized in the colon at appropriate doses.⁴⁵

As in other studies, this review also has several limitations. Most of the studies included were still case-control studies. In addition, the total sample size included in this review is relatively small. Nevertheless, this is the first systematic review to directly evaluate the change in bacterial composition, concentration, and metabolism of SCFA in IBD. The results of this study are expected to provide useful clinical implications and as a basis for encouraging further studies in this field of research.

CONCLUSION:

In conclusion, there was a decrease in SCFA concentrations due to the low composition of the main butyrate-producing bacteria group in IBD patients. The reduced concentration of SCFA has implications for decreased protective and anti-inflammatory effects in IBD and disruption of SCFA metabolism.

ACKNOWLEDGEMENT:

Not applicable

CONFLICT OF INTEREST:

The authors declare no conflict of interest.

REFERENCES:

1. Dubey P, Sumithra M, Chitra V. Assessment of inflammatory bowel disease and its herbal cure: A review. Research J Pharm Tech. 2019; 12(3): 1432–40.

2. Deshmukh R, Kumari S, Harwansh RK. Inflammatory bowel disease: A snapshot of current knowledge. .Research Journal of Pharmacy and Technology. Research J Pharm Tech. 2020; (13): p.956–62.

3. Ye Y, Pang Z, Chen W, Ju S, Zhou C. Epidemiology and risk factors of inflammatory bowel diseases. Int J Clin Exp Med. 2015; 8(12): 22529–42.

4. Kelompok Studi Inflammatory Bowel Disease (IBD) Indonesia, Djojoningrat D, Simadibrata M, Makmun D, Abdullah M, Syam A, et al. Konsensus Nasional Penatalaksanaan IBD di Indonesia. Clin Transl Immunol. 2011;

5. Corrêa-Oliveira R, Fachi JL, Vieira A, Sato FT, Vinolo MAR. Regulation of immune cell function by short-chain fatty acids. Clin Transl Immunol. 2016; 5(4): 1–8.

6. Plöger S, Stumpff F, Penner GB, Schulzke JD, Gäbel G, Martens H, et al. Microbial butyrate and its role for barrier function in the gastrointestinal tract. Ann N Y Acad Sci. 2012; 1258(1): 52–9.

7. Kovarik JJ, Tillinger W, Hofer J, Hölzl MA, Heinzl H, Saemann MD, et al. Impaired anti-inflammatory efficacy of n-butyrate in patients with IBD. Eur J Clin Invest. 2011; 41(3): 291–8.

8. Venegas DP, De La Fuente MK, Landskron G, González MJ, Quera R, Dijkstra G, et al. Short chain fatty acids (SCFAs)mediated gut epithelial and immune regulation and its relevance for inflammatory bowel diseases. Front Immunol. 2019; 10.

9. Scaldaferri F, Gerardi V, Lopetuso LR, Zompo F Del, Mangiola F, Boškoski I, et al. Gut Microbial Flora, Prebiotics, and Probiotics in IBD: Their Current Usage and Utility. 2013; 2013: 1–9.

10. Higgins J, Green S. Cochrane handbook for systematic reviews of interventions version 5.1.0. The Cochrane Collaboration; 2011.

11. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JPA, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ. 2009; 339.

12. Wells G, Shea B, O’Connell D, Peterson J, Welch V, Losos M, et al. The Newcastle-Ottawa scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses.

13. Kumari R, Ahuja V, Paul J. Fluctuations in butyrate-producing bacteria in ulcerative colitis patients of North India. World J Gastroenterol. 2013; 19(22): 3404–14.

14. Ferrer-Picón E, Dotti I, Corraliza AM, Mayorgas A, Esteller M, Perales JC, et al. Intestinal Inflammation Modulates the Epithelial Response to Butyrate in Patients with Inflammatory Bowel Disease. Inflamm Bowel Dis. 2020; 26(1): 43–55.

15. Bjerrum JT, Wang Y, Hao F, Coskun M, Ludwig C, Günther U, et al. Metabonomics of human fecal extracts characterize ulcerative colitis, Crohn’s disease and healthy individuals. Metabolomics. 2014; 11(1): 122–33.

16. Mottawea W, Chiang CK, Mühlbauer M, Starr AE, Butcher J, Abujamel T, et al. Altered intestinal microbiota-host mitochondria crosstalk in new onset Crohn’s disease. Nat Commun. 2016; 7: 1–14.

17. Wright EK, Kamm MA, Teo SM, Inouye M, Wagner J, Kirkwood CD. Recent advances in characterizing the gastrointestinal microbiome in Crohn’s disease: A systematic review. Inflamm Bowel Dis [Internet]. 2015; 21(6): 1219–28.

18. Canani RB, Costanzo M Di, Leone L, Pedata M, Meli R, Calignano A. Potential beneficial effects of butyrate in intestinal and extraintestinal diseases. World J Gastroenterol. 2011; 17(12): 1519–28.

19. Mu C, Zhang L, He X, Smidt H, Zhu W. Dietary fibres modulate the composition and activity of butyrate-producing bacteria in the large intestine of suckling piglets. Antonie van Leeuwenhoek, Int J Gen Mol Microbiol. 2017; 110(5): 687–96.

20. Laserna-Mendieta EJ, Clooney AG, Carretero-Gomez JF, Moran C, Sheehan D, Nolan JA, et al. Determinants of reduced genetic capacity for butyrate synthesis by the gut microbiome in Crohn’s disease and ulcerative colitis. J Crohn’s Colitis. 2018; 12(2): 204–16.

21. Bui TPN, Ritari J, Boeren S, De Waard P, Plugge CM, De Vos WM. Production of butyrate from lysine and the Amadori product fructoselysine by a human gut commensal. Nat Commun. 2015; 6.

22. Louis P, Flint H. Formation of propionate and butyrate by the human colonic microbiota. Environ Microbiol. 2016; 19(1): 29-41.

23. Deuring J, de Haar C, Koelewijn C, Kuipers E, Peppelenbosch M, van der Woude C. Absence of ABCG2-mediated mucosal detoxification in patients with active inflammatory bowel disease is due to impeded protein folding. Biochem J. 2012; 441: 87–93.

24. Ohira H, Fujioka Y, Katagiri C, Mamoto R, Aoyama-Ishikawa M, Amako K, et al. Butyrate Attenuates Inflammation and Lipolysis Generated by the Interaction of Adipocytes and Macrophages. Journal of Atherosclerosis and Thrombosis. J Atheroscler Thromb. 2013; 20(5): 425–42.

25. Vancamelbeke M, Laeremans T, Vanhove W, Arnauts K, Ramalho A, Farré R, et al. Butyrate does not protect against inflammation-induced loss of epithelial barrier function and cytokine production in primary cell monolayers from patients with ulcerative colitis. J Crohns Colitis. 2019.

26. De Preter V, Geboes K, Bulteel V, Vandermeulen G, Suenaert P, Rutgeerts P, et al. Kinetics of butyrate metabolism in the normal colon and in ulcerative colitis: the effects of substrate concentration and carnitine on the β-oxidation pathway. Aliment Pharmacol Ther. 2011; 34(5): 526–32.

27. De Preter V, Arijs I, Windey K, Vanhove W, Vermeire S, Schuit F, et al. Impaired butyrate oxidation in ulcerative colitis is due to decreased butyrate uptake and a defect in the oxidation pathway. Inflamm Bowel Dis. 2012; 18(6): 1127–36.

28. Wang W, Chen L, Zhou R, Wang X, Song L, Huang S, et al. . Increased Proportions of Bifidobacterium and the Lactobacillus Group and Loss of Butyrate-Producing Bacteria in Inflammatory Bowel Disease. J Clin Microbiol. 2013; 52(2): 398–406.

29. Kabeerdoss J, Sankaran V, Pugazhendhi S, Ramakrishna B. Clostridium leptum group bacteria abundance and diversity in the fecal microbiota of patients with inflammatory bowel disease: a case– control study in India. BMC Gastroenterol. 2013; 13(1).

30. Van den Abbeele P, Belzer C, Goossens M, Kleerebezem M, De Vos W, Thas O, et al. Butyrate- producing Clostridium cluster XIVa species specifically colonize mucins in an in vitro gut model. ISME J. 2012; 7(5): 949–61.

31. Jeon S, Kayama H, Ueda Y, Takahashi T, Asahara T, Tsuji H, et al. Probiotic Bifidobacterium breve induces IL-10-producing Tr1 cells in the colon. PLoS Pathog. 2012; 8(5): e1002714.

32. Von Schillde MA, Hörmannsperger G, Weiher M, Alpert CA, Hahne H, Bäuerl C, et al. Lactocepin secreted by Lactobacillus exerts anti-inflammatory effects by selectively degrading proinflammatory chemokines. Cell Host Microbe. 2012; 11(4): 387–96.

33. Hossain MK, Nahar K, Shokryazdan P, Abdullah N, Hamid K, Jahromi MF. Probiotic potential of lactic acid bacteria isolated from cheese, yogurt and poultry faeces. Research J Pharm Tech. 2017; 10(9): 2991–8.

34. Chen G, Ran X, Li B, Li Y, He D, Huang B, et al. Sodium Butyrate Inhibits Inflammation and Maintains Epithelium Barrier Integrity in a TNBS-induced Inflammatory Bowel Disease Mice Model. EbioMedicine. 2018; 30: 317–25.

35. Mahore JG, Deshpande N V., Trivedi R V., Shelar AS. Ulcerative colitis: Treatment updates. Research J Pharm Tech, 2020; (13): p. 3466–71.

36. Luceri C, Femia A Pietro, Fazi M, Di Martino C, Zolfanelli F, Dolara P, et al. Effect of butyrate enemas on gene expression profiles and endoscopic/histopathological scores of diverted colorectal mucosa: A randomized trial. Dig Liver Dis. 2016; 48(1): 27–33.

37. Brotherton C, Taylor A, Bourguignon C, Anderson J. A High Fiber Diet May Improve Bowel Function and HealthRelated Quality of Life in Patients with Crohn’s Disease. Gastroenterol Nurs. 2014; 37(3): 206–16.

38. Tamanai-Shacoori Z, Smida I, Bousarghin L, Loreal O, Meuric V, Fong SB, et al. Roseburia spp.: A marker of health?. Future Microbiol. 2017; 12(2): 157–70.

39. Geirnaert A, Calatayud M, Grootaert C, Laukens D, Devriese S, Smagghe G. Butyrate-producing bacteria supplemented in vitro to Crohn’s disease patient microbiota increased butyrate production and enhanced intestinal epithelial barrier integrity. Sci Rep. 2017; 7(1).

40. Park HR. Effect of salivary Streptococci mutans and Lactobacilli levels after uptake of the probiotic for clinical trial. Research J Pharm Technol. 2017; 10(9): 2984–8.

41. Ragavan ML, Patnaik N, Muniyasamy R, Roy A, Deo L, Das N. Biochemical characterization and enzymatic profiling of potential probiotic yeast strains. Research J Pharm Tech. 2019; 12(8): 3941–4.

42. Bhagat B, Jagtap A, Hapse S, Pagar H, Wagh A, Kale N. Formulation and Evaluation of Probiotic Gel Containing Anti-inflammatory agent for Treatment of IBDS. Research J Pharm Tech. 2012; 5(3): 387–9.

43. Swathi K V. Probiotics –A human friendly bacteria. Research J Pharm Tech; 2016; (9): p. 1260–2.

44. Sudarshan S, Sangeeta S, Sheth N, Roshan P, Ushir Y, Gendle R. Colon Specific Drug Delivery System of Mesalamine for Eradication of Ulcerative Colitis. Research J Pharm Tech. 2009; 2(4): 819–23.

45. Jain P, Parkhe G. Alternative Colon Targeted Drug Delivery Approaches for the Treatment of Inflammatory Bowel Disease. Research J Pharm Tech. 2020; 13(11): 5562–8.

Received on 14.11.2020 Modified on 03.02.2021

Research J. Pharm. and Tech 2021; 14(11):5978-5984.

DOI: 10.52711/0974-360X.2021.01038