Microbial functional change is linked with clinical outcomes after capsular fecal transplant in cirrhosis

Jasmohan S. Bajaj; Nita Salzman; Chathur Acharya; Hajime Takei; Genta Kakiyama; Andrew Fagan; Melanie B. White; Edith A. Gavis; Mary L. Holtz; Michael Hayward; Hiroshi Nittono; Phillip B. Hylemon; I. Jane Cox; Roger Williams; Simon D. Taylor-Robinson; Richard K. Sterling; Scott C. Matherly; Michael Fuchs; Hannah Lee; Puneet Puri; R. Todd Stravitz; Arun J. Sanyal; Lola Ajayi; Adrien Le Guennec; R. Andrew Atkinson; Mohammad S. Siddiqui; Velimir Luketic; William M. Pandak; Masoumeh Sikaroodi; Patrick M. Gillevet

doi:10.1172/jci.insight.133410

Microbial functional change is linked with clinical outcomes after capsular fecal transplant in cirrhosis

Jasmohan S. Bajaj^*, Nita Salzman, Chathur Acharya, Hajime Takei, Genta Kakiyama, Andrew Fagan, Melanie B. White, Edith A. Gavis, Mary L. Holtz, Michael Hayward, Hiroshi Nittono, Phillip B. Hylemon, I. Jane Cox, Roger Williams, Simon D. Taylor-Robinson, Richard K. Sterling, Scott C. Matherly, Michael Fuchs, Hannah Lee, Puneet PuriR. Todd Stravitz, Arun J. Sanyal, Lola Ajayi, Adrien Le Guennec, R. Andrew Atkinson, Mohammad S. Siddiqui, Velimir Luketic, William M. Pandak, Masoumeh Sikaroodi, Patrick M. Gillevet

^*Corresponding author for this work

Randall Centre of Cell & Molecular Biophysics

Research output: Contribution to journal › Article › peer-review

51 Citations (Scopus)

Abstract

BACKGROUND. Hepatic encephalopathy (HE) is associated with poor outcomes. A prior randomized, pilot trial demonstrated safety after oral capsular fecal microbial transplant (FMT) in HE, with favorable changes in microbial composition and cognition. However, microbial functional changes are unclear. The aim of this study was to determine the effect of FMT on the gut-brain axis compared with placebo, using microbial function based on bile acids (BAs), inflammation (serum IL-6, LPS-binding protein [LBP]), and their association with EncephalApp. METHODS. Twenty cirrhotic patients were randomized 1:1 into groups that received 1-time FMT capsules from a donor enriched in Lachnospiraceae and Ruminococcaceae or placebo capsules, with 5-month follow-up for safety outcomes. Stool microbiota and BA; serum IL-6, BA, and LBP; and EncephalApp were analyzed at baseline and 4 weeks after FMT/placebo. Correlation networks among microbiota, BAs, EncephalApp, IL-6, and LBP were performed before/after FMT. RESULTS. FMT-assigned participants had 1 HE recurrence and 2 unrelated infections. Six placebo-assigned participants developed negative outcomes. FMT, but not placebo, was associated with reduced serum IL-6 and LBP and improved EncephalApp. FMT-assigned participants demonstrated higher deconjugation and secondary BA formation in feces and serum compared with baseline. No change was seen in placebo. Correlation networks showed greater complexity after FMT compared with baseline. Beneficial taxa, such as Ruminococcaceae, Verrucomicrobiaceae, and Lachnospiraceae, were correlated with cognitive improvement and decrease in inflammation after FMT. Fecal/serum secondary/primary ratios and PiCRUST secondary BA pathways did not increase in participants who developed poor outcomes. CONCLUSION. Gut microbial function in cirrhosis is beneficially affected by capsular FMT, with improved inflammation and cognition. Lower secondary BAs in FMT recipients could select for participants who develop negative outcomes.

Original language	English
Article number	e133410
Journal	JCI Insight
Volume	4
Issue number	24
DOIs	https://doi.org/10.1172/jci.insight.133410
Publication status	Published - 21 Nov 2019

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Bajaj, J. S., Salzman, N., Acharya, C., Takei, H., Kakiyama, G., Fagan, A., White, M. B., Gavis, E. A., Holtz, M. L., Hayward, M., Nittono, H., Hylemon, P. B., Cox, I. J., Williams, R., Taylor-Robinson, S. D., Sterling, R. K., Matherly, S. C., Fuchs, M., Lee, H., ... Gillevet, P. M. (2019). Microbial functional change is linked with clinical outcomes after capsular fecal transplant in cirrhosis. JCI Insight, 4(24), Article e133410. https://doi.org/10.1172/jci.insight.133410

@article{195135a80de74ba38ecc21336e35d2ea,

title = "Microbial functional change is linked with clinical outcomes after capsular fecal transplant in cirrhosis",

abstract = "BACKGROUND. Hepatic encephalopathy (HE) is associated with poor outcomes. A prior randomized, pilot trial demonstrated safety after oral capsular fecal microbial transplant (FMT) in HE, with favorable changes in microbial composition and cognition. However, microbial functional changes are unclear. The aim of this study was to determine the effect of FMT on the gut-brain axis compared with placebo, using microbial function based on bile acids (BAs), inflammation (serum IL-6, LPS-binding protein [LBP]), and their association with EncephalApp. METHODS. Twenty cirrhotic patients were randomized 1:1 into groups that received 1-time FMT capsules from a donor enriched in Lachnospiraceae and Ruminococcaceae or placebo capsules, with 5-month follow-up for safety outcomes. Stool microbiota and BA; serum IL-6, BA, and LBP; and EncephalApp were analyzed at baseline and 4 weeks after FMT/placebo. Correlation networks among microbiota, BAs, EncephalApp, IL-6, and LBP were performed before/after FMT. RESULTS. FMT-assigned participants had 1 HE recurrence and 2 unrelated infections. Six placebo-assigned participants developed negative outcomes. FMT, but not placebo, was associated with reduced serum IL-6 and LBP and improved EncephalApp. FMT-assigned participants demonstrated higher deconjugation and secondary BA formation in feces and serum compared with baseline. No change was seen in placebo. Correlation networks showed greater complexity after FMT compared with baseline. Beneficial taxa, such as Ruminococcaceae, Verrucomicrobiaceae, and Lachnospiraceae, were correlated with cognitive improvement and decrease in inflammation after FMT. Fecal/serum secondary/primary ratios and PiCRUST secondary BA pathways did not increase in participants who developed poor outcomes. CONCLUSION. Gut microbial function in cirrhosis is beneficially affected by capsular FMT, with improved inflammation and cognition. Lower secondary BAs in FMT recipients could select for participants who develop negative outcomes.",

author = "Bajaj, {Jasmohan S.} and Nita Salzman and Chathur Acharya and Hajime Takei and Genta Kakiyama and Andrew Fagan and White, {Melanie B.} and Gavis, {Edith A.} and Holtz, {Mary L.} and Michael Hayward and Hiroshi Nittono and Hylemon, {Phillip B.} and Cox, {I. Jane} and Roger Williams and Taylor-Robinson, {Simon D.} and Sterling, {Richard K.} and Matherly, {Scott C.} and Michael Fuchs and Hannah Lee and Puneet Puri and Stravitz, {R. Todd} and Sanyal, {Arun J.} and Lola Ajayi and {Le Guennec}, Adrien and Atkinson, {R. Andrew} and Siddiqui, {Mohammad S.} and Velimir Luketic and Pandak, {William M.} and Masoumeh Sikaroodi and Gillevet, {Patrick M.}",

year = "2019",

month = nov,

day = "21",

doi = "10.1172/jci.insight.133410",

language = "English",

volume = "4",

journal = "JCI Insight",

issn = "2379-3708",

publisher = "The American Society for Clinical Investigation",

number = "24",

}

Bajaj, JS, Salzman, N, Acharya, C, Takei, H, Kakiyama, G, Fagan, A, White, MB, Gavis, EA, Holtz, ML, Hayward, M, Nittono, H, Hylemon, PB, Cox, IJ, Williams, R, Taylor-Robinson, SD, Sterling, RK, Matherly, SC, Fuchs, M, Lee, H, Puri, P, Stravitz, RT, Sanyal, AJ, Ajayi, L, Le Guennec, A, Atkinson, RA, Siddiqui, MS, Luketic, V, Pandak, WM, Sikaroodi, M & Gillevet, PM 2019, 'Microbial functional change is linked with clinical outcomes after capsular fecal transplant in cirrhosis', JCI Insight, vol. 4, no. 24, e133410. https://doi.org/10.1172/jci.insight.133410

TY - JOUR

T1 - Microbial functional change is linked with clinical outcomes after capsular fecal transplant in cirrhosis

AU - Bajaj, Jasmohan S.

AU - Salzman, Nita

AU - Acharya, Chathur

AU - Takei, Hajime

AU - Kakiyama, Genta

AU - Fagan, Andrew

AU - White, Melanie B.

AU - Gavis, Edith A.

AU - Holtz, Mary L.

AU - Hayward, Michael

AU - Nittono, Hiroshi

AU - Hylemon, Phillip B.

AU - Cox, I. Jane

AU - Williams, Roger

AU - Taylor-Robinson, Simon D.

AU - Sterling, Richard K.

AU - Matherly, Scott C.

AU - Fuchs, Michael

AU - Lee, Hannah

AU - Puri, Puneet

AU - Stravitz, R. Todd

AU - Sanyal, Arun J.

AU - Ajayi, Lola

AU - Le Guennec, Adrien

AU - Atkinson, R. Andrew

AU - Siddiqui, Mohammad S.

AU - Luketic, Velimir

AU - Pandak, William M.

AU - Sikaroodi, Masoumeh

AU - Gillevet, Patrick M.

PY - 2019/11/21

Y1 - 2019/11/21

N2 - BACKGROUND. Hepatic encephalopathy (HE) is associated with poor outcomes. A prior randomized, pilot trial demonstrated safety after oral capsular fecal microbial transplant (FMT) in HE, with favorable changes in microbial composition and cognition. However, microbial functional changes are unclear. The aim of this study was to determine the effect of FMT on the gut-brain axis compared with placebo, using microbial function based on bile acids (BAs), inflammation (serum IL-6, LPS-binding protein [LBP]), and their association with EncephalApp. METHODS. Twenty cirrhotic patients were randomized 1:1 into groups that received 1-time FMT capsules from a donor enriched in Lachnospiraceae and Ruminococcaceae or placebo capsules, with 5-month follow-up for safety outcomes. Stool microbiota and BA; serum IL-6, BA, and LBP; and EncephalApp were analyzed at baseline and 4 weeks after FMT/placebo. Correlation networks among microbiota, BAs, EncephalApp, IL-6, and LBP were performed before/after FMT. RESULTS. FMT-assigned participants had 1 HE recurrence and 2 unrelated infections. Six placebo-assigned participants developed negative outcomes. FMT, but not placebo, was associated with reduced serum IL-6 and LBP and improved EncephalApp. FMT-assigned participants demonstrated higher deconjugation and secondary BA formation in feces and serum compared with baseline. No change was seen in placebo. Correlation networks showed greater complexity after FMT compared with baseline. Beneficial taxa, such as Ruminococcaceae, Verrucomicrobiaceae, and Lachnospiraceae, were correlated with cognitive improvement and decrease in inflammation after FMT. Fecal/serum secondary/primary ratios and PiCRUST secondary BA pathways did not increase in participants who developed poor outcomes. CONCLUSION. Gut microbial function in cirrhosis is beneficially affected by capsular FMT, with improved inflammation and cognition. Lower secondary BAs in FMT recipients could select for participants who develop negative outcomes.

AB - BACKGROUND. Hepatic encephalopathy (HE) is associated with poor outcomes. A prior randomized, pilot trial demonstrated safety after oral capsular fecal microbial transplant (FMT) in HE, with favorable changes in microbial composition and cognition. However, microbial functional changes are unclear. The aim of this study was to determine the effect of FMT on the gut-brain axis compared with placebo, using microbial function based on bile acids (BAs), inflammation (serum IL-6, LPS-binding protein [LBP]), and their association with EncephalApp. METHODS. Twenty cirrhotic patients were randomized 1:1 into groups that received 1-time FMT capsules from a donor enriched in Lachnospiraceae and Ruminococcaceae or placebo capsules, with 5-month follow-up for safety outcomes. Stool microbiota and BA; serum IL-6, BA, and LBP; and EncephalApp were analyzed at baseline and 4 weeks after FMT/placebo. Correlation networks among microbiota, BAs, EncephalApp, IL-6, and LBP were performed before/after FMT. RESULTS. FMT-assigned participants had 1 HE recurrence and 2 unrelated infections. Six placebo-assigned participants developed negative outcomes. FMT, but not placebo, was associated with reduced serum IL-6 and LBP and improved EncephalApp. FMT-assigned participants demonstrated higher deconjugation and secondary BA formation in feces and serum compared with baseline. No change was seen in placebo. Correlation networks showed greater complexity after FMT compared with baseline. Beneficial taxa, such as Ruminococcaceae, Verrucomicrobiaceae, and Lachnospiraceae, were correlated with cognitive improvement and decrease in inflammation after FMT. Fecal/serum secondary/primary ratios and PiCRUST secondary BA pathways did not increase in participants who developed poor outcomes. CONCLUSION. Gut microbial function in cirrhosis is beneficially affected by capsular FMT, with improved inflammation and cognition. Lower secondary BAs in FMT recipients could select for participants who develop negative outcomes.

UR - http://www.scopus.com/inward/record.url?scp=85077874836&partnerID=8YFLogxK

U2 - 10.1172/jci.insight.133410

DO - 10.1172/jci.insight.133410

M3 - Article

C2 - 31751317

AN - SCOPUS:85077874836

SN - 2379-3708

VL - 4

JO - JCI Insight

JF - JCI Insight

IS - 24

M1 - e133410

ER -

Microbial functional change is linked with clinical outcomes after capsular fecal transplant in cirrhosis

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