Distinct Effects of Non-absorbed Agents Rifaximin and Berberine on the Microbiota-Gut-Brain Axis in Dysbiosis-induced Visceral Hypersensitivity in Rats

다국어 초록 (Multilingual Abstract)

Background/AimsIrritable bowel syndrome (IBS) is accepted as a disorder of gut-brain interactions. Berberine and rifaximin are non-absorbed antibiotics and have been confirmed effective for IBS treatment, but there is still lack of direct comparison of their effects. This study aims to compare the effect of the 2 drugs on the alteration of gut-brain axis caused by gut microbiota from IBS patients.
MethodsGerm-free rats received fecal microbiota transplantation from screened IBS patients and healthy controls. After 14 days’ colonization, rats were administrated orally with berberine, rifaximin or vehicle respectively for the next 14 days. The visceral sensitivity was evaluated, fecal microbiota profiled and microbial short chain fatty acids were determined. Immunofluorescence staining and morphological analysis were performed to evaluate microglial activation.
ResultsVisceral hypersensitivity induced by IBS–fecal microbiota transplantation was relieved by berberine and rifaximin, and berberine increased sucrose preference rate. Microbial α-diversity were reduced by both drugs. Compared with rifaximin, berberine significantly changed microbial structure and enriched Lachnoclostridium. Furthermore, berberine but not rifaximin significantly increased fecal concentrations of acetate and propionate acids. Berberine restored the morphological alterations of microglia induced by dysbiosis, which may be associated with its effect on the expression of microbial gene pathways involved in peptidoglycan biosynthesis. Rifaximin affected neither the numbers of activated microglial cells nor the microglial morphological alterations.
ConclusionsBerberine enriched Lachnoclostridium, reduced the expression of peptidoglycan biosynthesis genes and increased acetate and propionate. The absence of these actions of rifaximin may explain the different effects of the drugs on microbiota-gut-brain axis.

참고문헌 (Reference)

• 1 De Palma G, "Transplantation of fecal microbiota from patients with irritable bowel syndrome alters gut function and behavior in recipient mice" 9 : eaaf6397-, 2017
• 2 Frost G, "The short-chain fatty acid acetate reduces appetite via a central homeostatic mechanism" 5 : 3611-, 2014
• 3 Dalile B, "The role of shortchain fatty acids in microbiota-gut-brain communication" 16 : 461-478, 2019
• 4 Crouzet L, "The hypersensitivity to colonic distension of IBS patients can be transferred to rats through their fecal microbiota" 25 : e272-e282, 2013
• 5 Sperber AD, "The global prevalence of IBS in adults remains elusive due to the heterogeneity of studies : a rome foundation working team literature review" 66 : 1075-1082, 2017
• 6 Liu Y, "Similar fecal microbiota signatures in patients with diarrhea-predominant irritable bowel syndrome and patients with depression" 14 : 1602-1611, 2016
• 7 Drossman DA, "Rome IV-functional GI disorders : disorders of gut-brain interaction" 150 : 1257-1261, 2016
• 8 Bradesi S, "Role of spinal microglia in visceral hyperalgesia and NK1R up-regulation in a rat model of chronic stress" 136 : 1339-1348, 2009
• 9 Pimentel M, "Rifaximin therapy for patients with irritable bowel syndrome without constipation" 364 : 22-32, 2011
• 10 Maccaferri S, "Rifaximin modulates the colonic microbiota of patients with crohn’s disease : an in vitro approach using a continuous culture colonic model system" 65 : 2556-2565, 2010
• 11 Xu D, "Rifaximin alters intestinal bacteria and prevents stress-induced gut inflammation and visceral hyperalgesia in rats" 146 : 484-496, 2014
• 12 Pimentel M, "Review article : potential mechanisms of action of rifaximin in the management of irritable bowel syndrome with diarrhoea" 43 (43): 37-49, 2016
• 13 Seminowicz DA, "Regional gray matter density changes in brains of patients with irritable bowel syndrome" 139 : 48-57, 2010
• 14 Wang Y, "Oral berberine improves brain dopa/dopamine levels to ameliorate parkinson’s disease by regulating gut microbiota" 6 : 77-, 2021
• 15 Pimentel M, "Normalization of lactulose breath testing correlates with symptom improvement in irritable bowel syndrome. a double-blind, randomized, placebo-controlled study" 98 : 412-419, 2003
• 16 Xu C, "Multiomics study of gut bacteria and host metabolism in irritable bowel syndrome and depression patients" 10 : 580980-, 2020
• 17 Li S, "Modulation of gut microbiota mediates berberine-induced expansion of immuno-suppressive cells to against alcoholic liver disease" 10 : e112-, 2020
• 18 Pimentel M, "Mo1268 characterization of stool microbiota in subjects with IBS-D receiving repeat treatments with rifaximin in the TARGET 3 study" 148 : S-655. -, 2015
• 19 Wolf SA, "Microglia in physiology and disease" 79 : 619-643, 2017
• 20 Saab CY, "Microglia : a newly discovered role in visceral hypersensitivity?" 2 : 271-277, 2006
• 21 Ford AC, "Irritable bowel syndrome" 396 : 1675-1688, 2020
• 22 Ford AC, "Irritable bowel syndrome" 376 : 2566-2578, 2017
• 23 Ramaswamy V, "Inflammasome induction in rasmussen’s encephalitis : cortical and associated white matter pathogenesis" 10 : 152-, 2013
• 24 Erny D, "Host microbiota constantly control maturation and function of microglia in the CNS" 18 : 965-977, 2015
• 25 Pittayanon R, "Gut microbiota in patients with irritable bowel syndrome-a systematic review" 157 : 97-108, 2019
• 26 Zhang Y, "Gut microbiome-related effects of berberine and probiotics on type 2 diabetes(the PREMOTE study)" 11 : 5015-, 2020
• 27 Li Y, "Fecal bacteria can predict the efficacy of rifaximin in patients with diarrhea-predominant irritable bowel syndrome" 159 : 104936-, 2020
• 28 Acosta A, "Effects of rifaximin on transit, permeability, fecal microbiome, and organic acid excretion in irritable bowel syndrome" 7 : e173-, 2016
• 29 Ming J, "Effectiveness and safety of Bifidobacterium and berberine in human hyperglycemia and their regulatory effect on the gut microbiota : a multi-center, double-blind, randomized, parallelcontrolled study" 13 : 125-, 2021
• 30 Chen YX, "Berberine versus placebo for the prevention of recurrence of colorectal adenoma : a multicentre, doubleblinded, randomised controlled study" 5 : 267-275, 2020
• 31 Fang Y, "Berberine ameliorates ovariectomyinduced anxiety-like behaviors by enrichment in equol generating gut microbiota" 165 : 105439-, 2021
• 32 Zhang JD, "Berberine alleviates visceral hypersensitivity in rats by altering gut microbiome and suppressing spinal microglial activation" 42 : 1821-1833, 2021
• 33 Jin Y, "Beneficial effects of rifaximin in post-infectious irritable bowel syndrome mouse model beyond gut microbiota" 33 : 443-452, 2018
• 34 Laman JD, "Bacterial peptidoglycan as a driver of chronic brain inflammation" 26 : 670-682, 2020
• 35 Wouters MM, "Altered brain activation to colorectal distention in visceral hypersensitive maternal-separated rats" 24 : 678-685, 2012
• 36 Zhang G, "Activation of corticotropin-releasing factor neurons and microglia in paraventricular nucleus precipitates visceral hypersensitivity induced by colorectal distension in rats" 55 : 93-104, 2016
• 37 Chen C, "A randomized clinical trial of berberine hydrochloride in patients with diarrhea-predominant irritable bowel syndrome" 29 : 1822-1827, 2015
• 38 Al–Chaer ED, "A new model of chronic visceral hypersensitivity in adult rats induced by colon irritation during postnatal development" 119 : 1276-1285, 2000