The Bile Salt Giveth and the Bile Salt Taketh Away

by Elio

We needn't be re­minded that path­o­genic mi­cro­bi­ol­ogy is a branch of mi­cro­bial ecol­ogy but a nice ex­am­ple helps makes the point. The story is about a nasty dis­ease, pseu­­domembranous col­i­tis, which af­fects mainly immu­nocompromised peo­ple who have been on an­tibi­otics and are ly­ing in a hos­pi­tal bed. The dis­ease, as the name sug­gests, is an in­flam­ma­tion of the large in­tes­tine ac­companied by the for­ma­tion of a mem­brane-like fib­rin de­posit that lines the sur­face of the gut. The usual cul­prit is an anaer­o­bic spore­former, Clostrid­ium dif­fi­cile. Most peo­ple do not nor­mally har­bor C. dif­fi­cile, al­though many in­fants and young adults do so with­out any prob­lem. When the nor­mal gut biota is re­duced by an­tibi­otics, C. dif­fi­cile grows and pro­duces tox­ins that are re­spon­si­ble for the pathol­ogy. Ac­tu­ally, the typ­i­cal out­come of this in­fec­tion is not pseudomem­bra­nous col­i­tis, but, more of­ten, di­ar­rhea.

Clostrid­ium dif­fi­cile. Color-en­hanced SEM mi­crograph by Dave Mc­Carthy and An­nie Ca­vanagh. Source: Well­come Im­age Awa­rds

Be­ing a spore­former, C. dif­fi­cile is in­sen­si­tive to com­mon dis­in­fec­tants and thus can sur­vive on hos­pi­tal sur­faces to be­come the cause of the next in­fec­tion. Strong agents are re­quired to kill the spores, e.g., bleach. But what causes the dis­ease to erupt?

Since peo­ple who have not re­ceived an­tibi­otics don't come down with it, the usual thought is that the abun­dant nor­mal bac­te­r­ial biota out­com­petes these or­gan­isms for the de­sir­able sites and ne­cessary nu­tri­ents. This is not an easy thing to sort out. There is, how­ever, at least one fac­tor that helps ex­plain the ecol­ogy of this un­usual en­tan­gle­ment be­tween some peo­ple, their drugs, and these bugs.

As first re­ported by Wil­son in 1983 (in the Jour­nal of Clin­i­cal Mi­cro­bi­ol­ogy) and ex­tended in more de­tail by Sorg and So­nen­shein in a re­cent is­sue of the Jour­nal of Bac­te­ri­ol­ogy, bile salts may be a key fac­tor in in­duc­ing C. dif­fi­cile spore ger­mi­na­tion in the gut. This ger­mi­na­tion step is crit­i­cal for in­fec­tion since the bugs are likely to be trans­mit­ted as spores. (Spores are a meta­bol­i­cally dorm­ant form of C. dif­fi­cile that does not pro­duce toxin; only when spores ger­mi­nate and grow out as veg­e­ta­tive cells do they ex­press the toxin genes.) The liver pro­duces bile salts for sol­u­bi­liz­ing fats; their in­duc­tion of C. dif­fi­cile spore ger­mi­na­tion is an un­in­tended and un­wanted re­sponse.

Bile salts are se­creted as con­ju­gates of tau­rine or glycine. The nor­mal gut bac­te­ria me­tab­o­lize them, con­vert­ing them into sim­pler com­pounds (known as sec­ondary bile salts) such as de­oxy­cholate. These com­pounds also sti­mulate spore ger­mi­na­tion, but de­oxy­cholate in­hibits the growth of the veg­e­ta­tive cells that arise from them. In other words, bile salts in­duce C. dif­fi­cile spore germina­tion, but what hap­pens next de­pends on the gut biota. When the nor­mal biota is present, de­oxy­cholate is pro­duced, growth of C. dif­fi­cile is in­hib­ited, and the host is un­harmed. Purge the gut of its nor­mal bac­te­ria by an­tibiotic treat­ment, and the un­mod­i­fied bile salts in­duce the spores to ger­mi­nate with­out then hin­der­ing the re­sult­ing veg­e­ta­tive cells. Presto, the per­son gets sick.

There are two fancy words that ap­ply to pseudomem­bra­nous col­i­tis: noso­co­mial, mean­ing hos­pi­tal-ac­quired, and ia­tro­genic, mean­ing doc­tor-in­duced. This dis­ease prob­a­bly ex­isted be­fore the an­tibi­otic era, but achieved promi­nence cour­tesy of their ex­ten­sive use. A dou­ble edged-sword, an­tibi­otics.

On a per­sonal note, the dis­cov­ery and elu­ci­da­tion of C. dif­fi­cile as the cause of pseudomembran­ous col­i­tis was car­ried out by in­ves­ti­ga­tors at Tufts Med­ical School, J. Bartlett, S. Gor­bach, T. Chang, and A. On­der­donk. The Sorg and So­nen­shein pa­per is also from Tufts, which is were I hung out for most of my ca­reer.